@article{ author = {Baysoy, A. and Tian, X. and Zhang, F. and Renauer, P. and Bai, Z. and Shi, H. and Li, H. and Tao, B. and Yang, M. and Enninful, A. and Gao, F. and Wang, G. and Zhang, W. and Tran, T. and Patterson, N. H. and Bao, S. and Dong, C. and Xin, S. and Zhong, M. and Rankin, S. and Guy, C. and Wang, Y. and Connelly, J. P. and Pruett-Miller, S. M. and Chi, H. and Chen, S. and Fan, R.}, title = {Spatially Resolved in vivo CRISPR Screen Sequencing via Perturb-DBiT}, journal = {bioRxiv}, note = {2692-8205 Baysoy, Alev Tian, Xiaolong Zhang, Feifei Renauer, Paul Bai, Zhiliang Shi, Hao Li, Haikuo Tao, Bo Yang, Mingyu Enninful, Archibald Gao, Fu Wang, Guangchuan Zhang, Wanqiu Tran, Thao Patterson, Nathan Heath Bao, Shuozhen Dong, Chuanpeng Xin, Shan Zhong, Mei Rankin, Sherri Guy, Cliff Wang, Yan Connelly, Jon P Pruett-Miller, Shondra M Chi, Hongbo Chen, Sidi}, abstract = {Perturb-seq enabled the profiling of transcriptional effects of genetic perturbations in single cells but lacks the ability to examine the impact on tissue environments. We present Perturb-DBiT for simultaneous co-sequencing of spatial transcriptome and guide RNAs (gRNAs) on the same tissue section for in vivo CRISPR screen with genome-scale gRNA libraries, offering a comprehensive understanding of how genetic modifications affect cellular behavior and tissue architecture. This platform supports a variety of delivery vectors, gRNA library sizes, and tissue preparations, along with two distinct gRNA capture methods, making it adaptable to a wide range of experimental setups. In applying Perturb-DBiT, we conducted un-biased knockouts of tens of genes or at genome-wide scale across three cancer models. We mapped all gRNAs in individual colonies and corresponding transcriptomes in a human cancer metastatic colonization model, revealing clonal dynamics and cooperation. We also examined the effect of genetic perturbation on the tumor immune microenvironment in an immune-competent syngeneic model, uncovering differential and synergistic perturbations in promoting immune infiltration or suppression in tumors. Perturb-DBiT allows for simultaneously evaluating the impact of each knockout on tumor initiation, development, metastasis, histopathology, and immune landscape. Ultimately, it not only broadens the scope of genetic inquiry, but also lays the groundwork for developing targeted therapeutic strategies.}, ISSN = {2692-8205}, DOI = {10.1101/2024.11.18.624106}, year = {2024}, type = {Journal Article} } @article{ author = {Chen, J. and Kwong, D. L. and Zhu, C. L. and Chen, L. L. and Dong, S. S. and Zhang, L. Y. and Tian, J. and Qi, C. B. and Cao, T. T. and Wong, A. M. and Kong, K. L. and Li, Y. and Liu, M. and Fu, L. and Guan, X. Y.}, title = {RBMS3 at 3p24 inhibits nasopharyngeal carcinoma development via inhibiting cell proliferation, angiogenesis, and inducing apoptosis}, journal = {PLoS One}, volume = {7}, number = {9}, pages = {e44636}, note = {1932-6203 Chen, Juan Kwong, Dora Lai-Wan Zhu, Cai-Lei Chen, Lei-Lei Dong, Sui-Sui Zhang, Li-Yi Tian, Jun Qi, Chu-Bo Cao, Ting-Ting Wong, Alissa Michelle Go Kong, Kar-Lok Li, Yan Liu, Ming Fu, Li Guan, Xin-Yuan Journal Article Research Support, Non-U.S. Gov't United States PLoS One. 2012;7(9):e44636. doi: 10.1371/journal.pone.0044636. Epub 2012 Sep 5.}, abstract = {Deletion of the short arm of chromosome 3 is one of the most frequent genetic alterations in many solid tumors including nasopharyngeal carcinoma (NPC), suggesting the existence of one or more tumor suppressor genes (TSGs) within the frequently deleted region. A putative TSG RBMS3 (RNA binding motif, single stranded interacting protein 3), located at 3p24-p23, has been identified in our previous study. Here, we reported that downregulation of RBMS3 was detected in 3/3 NPC cell lines and 13/15 (86.7%) primary NPC tissues. Functional studies using both overexpression and suppression systems demonstrated that RBMS3 has a strong tumor suppressive role in NPC. The tumor suppressive mechanism of RBMS3 was associated with its role in cell cycle arrest at the G1/S checkpoint by upregulating p53 and p21, downregulating cyclin E and CDK2, and the subsequent inhibition of Rb-ser780. Further analysis demonstrated that RBMS3 had a pro-apoptotic role in a mitochondrial-dependent manner via activation of caspase-9 and PARP. Finally, RBMS3 inhibited microvessel formation, which may be mediated by down-regulation of MMP2 and β-catenin and inactivation of its downstream targets, including cyclin-D1, c-Myc, MMP7, and MMP9. Taken together, our findings define a function for RBMS3 as an important tumor suppressor gene in NPC.}, keywords = {Adult Aged Apoptosis Carcinoma Cell Cycle Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic *Chromosomes, Human, Pair 3 Down-Regulation Female Gene Deletion Gene Expression Profiling Gene Silencing Genes, Tumor Suppressor Humans Male Microcirculation Middle Aged Nasopharyngeal Carcinoma Nasopharyngeal Neoplasms/*metabolism/pathology Neovascularization, Pathologic RNA-Binding Proteins/metabolism/*physiology Trans-Activators/metabolism/*physiology}, ISSN = {1932-6203}, DOI = {10.1371/journal.pone.0044636}, year = {2012}, type = {Journal Article} } @article{ author = {Fan, R. and Zhang, D. and Rodríguez-Kirby, L. and Lin, Y. and Song, M. and Wang, L. and Wang, L. and Kanatani, S. and Jimenez-Beristain, T. and Dang, Y. and Zhong, M. and Kukanja, P. and Wang, S. and Chen, X. and Gao, F. and Wang, D. and Xu, H. and Lou, X. and Liu, Y. and Chen, J. and Sestan, N. and Uhlen, P. and Kriegstein, A. R. and Zhao, H. and Castelo-Branco, G.}, title = {Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping}, journal = {Res Sq}, note = {2693-5015 Fan, Rong}, abstract = {The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.}, ISSN = {2693-5015}, DOI = {10.21203/rs.3.rs-4814866/v1}, year = {2024}, type = {Journal Article} } @article{ author = {Gao, Y. and Zens, P. and Su, M. and Gemperli, C. A. and Yang, H. and Deng, H. and Yang, Z. and Xu, D. and Hall, S. R. R. and Berezowska, S. and Dorn, P. and Peng, R. W. and Schmid, R. A. and Wang, W. and Marti, T. M.}, title = {Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5'-deoxy-5-fluorocytidine (5'-DFCR)}, journal = {J Exp Clin Cancer Res}, volume = {40}, number = {1}, pages = {138}, note = {1756-9966 Gao, Yanyun Zens, Philipp Su, Min Gemperli, Camila Anna Yang, Haitang Deng, Haibin Yang, Zhang Xu, Duo Hall, Sean R R Berezowska, Sabina Dorn, Patrick Peng, Ren-Wang Schmid, Ralph Alexander Wang, Wenxiang Marti, Thomas Michael KFS-4694-02-2019/Krebsforschung Schweiz/ KFS-4265-08-2017/Krebsforschung Schweiz/ 20171008/Bernische Krebsliga/ kq1801110/Changsha University of Science and Technology/ Journal Article England J Exp Clin Cancer Res. 2021 Apr 19;40(1):138. doi: 10.1186/s13046-021-01938-2.}, abstract = {BACKGROUND: Pemetrexed (MTA) plus cisplatin combination therapy is considered the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, in advanced NSCLC, the 5-year survival rate is below 10%, mainly due to resistance to therapy. We have previously shown that the fraction of mesenchymal-like, chemotherapy-resistant paraclone cells increased after MTA and cisplatin combination therapy in the NSCLC cell line A549. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) are key enzymes of the pyrimidine salvage pathway. 5'-deoxy-5-fluorocytidine (5'-DFCR) is a cytidine analogue (metabolite of capecitabine), which is converted by CDA and subsequently by TYMP into 5-fluorouracil, a chemotherapeutic agent frequently used to treat solid tumors. The aim of this study was to identify and exploit chemotherapy-induced metabolic adaptations to target resistant cancer cells. METHODS: Cell viability and colony formation assays were used to quantify the efficacy of MTA and cisplatin treatment in combination with schedule-dependent addition of 5'-DFCR on growth and survival of A549 paraclone cells and NSCLC cell lines. CDA and TYMP protein expression were monitored by Western blot. Finally, flow cytometry was used to analyze the EMT phenotype, DNA damage response activation and cell cycle distribution over time after treatment. CDA expression was measured by immunohistochemistry in tumor tissues of patients before and after neoadjuvant chemotherapy. RESULTS: We performed a small-scale screen of mitochondrial metabolism inhibitors, which revealed that 5'-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. In the cell line A549, CDA and TYMP expression was further increased by chemotherapy in a time-dependent manner, which was also observed in the KRAS-addicted NSCLC cell lines H358 and H411. The addition of 5'-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy. CONCLUSIONS: Chemotherapy increases CDA and TYMP expression thereby rendering resistant lung cancer cells susceptible to subsequent 5'-DFCR treatment.}, keywords = {Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics Cytidine Deaminase/*metabolism Deoxycytidine/*analogs & derivatives/metabolism Humans Lung Neoplasms/drug therapy/*genetics}, ISSN = {0392-9078 (Print) 0392-9078}, DOI = {10.1186/s13046-021-01938-2}, year = {2021}, type = {Journal Article} } @article{ author = {Gigon, L. and Fettrelet, T. and Yousefi, S. and Simon, D. and Simon, H. U.}, title = {Eosinophils from A to Z}, journal = {Allergy}, volume = {78}, number = {7}, pages = {1810-1846}, note = {1398-9995 Gigon, Lea Fettrelet, Timothée}, abstract = {Eosinophils are bone marrow-derived granulocytes and are found in low numbers in the peripheral blood of healthy subjects. In type 2 inflammatory diseases, eosinopoiesis in the bone marrow is increased, resulting in a rise in the number of mature eosinophils released in the circulation. From the blood, eosinophils can migrate in multiple tissues and organs under both physiological and pathological conditions. Eosinophils exert their various functions through the synthesis and release of a variety of granule proteins and pro-inflammatory mediators. Despite being present in all species of vertebrates, the functional role of eosinophils is still a matter of debate. Eosinophils may play a role in host defense against various pathogens. In addition, eosinophils have been reported to be involved in tissue homeostasis and exhibit immunomodulatory activities. In this review, we aim to provide a broad overview of eosinophil biology and eosinophilic diseases in a lexicon-style format using keywords starting from A until Z with cross-references to other chapters indicated in italics in the text or specified in parentheses.}, keywords = {Animals Humans *Eosinophils/physiology Italy}, ISSN = {0105-4538}, DOI = {10.1111/all.15751}, year = {2023}, type = {Journal Article} } @article{ author = {Górnicki, T. and Lambrinow, J. and Mrozowska, M. and Romanowicz, H. and Smolarz, B. and Piotrowska, A. and Gomułkiewicz, A. and Podhorska-Okołów, M. and Dzięgiel, P. and Grzegrzółka, J.}, title = {Expression of RBMS3 in Breast Cancer Progression}, journal = {Int J Mol Sci}, volume = {24}, number = {3}, note = {1422-0067 Górnicki, Tomasz Orcid: 0000-0002-7277-8036 Lambrinow, Jakub Mrozowska, Monika Orcid: 0000-0003-0554-4325 Romanowicz, Hanna Smolarz, Beata Orcid: 0000-0003-3168-062x Piotrowska, Aleksandra Orcid: 0000-0003-4093-7386 Gomułkiewicz, Agnieszka Orcid: 0000-0003-2256-1055 Podhorska-Okołów, Marzena Dzięgiel, Piotr Grzegrzółka, Jędrzej Journal Article Switzerland Int J Mol Sci. 2023 Feb 2;24(3):2866. doi: 10.3390/ijms24032866.}, abstract = {The aim of the study was to evaluate the localization and intensity of RNA-binding motif single-stranded-interacting protein 3 (RBMS3) expression in clinical material using immunohistochemical (IHC) reactions in cases of ductal breast cancer (in vivo), and to determine the level of RBMS3 expression at both the protein and mRNA levels in breast cancer cell lines (in vitro). Moreover, the data obtained in the in vivo and in vitro studies were correlated with the clinicopathological profiles of the patients. Material for the IHC studies comprised 490 invasive ductal carcinoma (IDC) cases and 26 mastopathy tissues. Western blot and RT-qPCR were performed on four breast cancer cell lines (MCF-7, BT-474, SK-BR-3 and MDA-MB-231) and the HME1-hTERT (Me16C) normal immortalized breast epithelial cell line (control). The Kaplan-Meier plotter tool was employed to analyze the predictive value of overall survival of RBMS3 expression at the mRNA level. Cytoplasmatic RBMS3 IHC expression was observed in breast cancer cells and stromal cells. The statistical analysis revealed a significantly decreased RBMS3 expression in the cancer specimens when compared with the mastopathy tissues (p < 0.001). An increased expression of RBMS3 was corelated with HER2(+) cancer specimens (p < 0.05) and ER(-) cancer specimens (p < 0.05). In addition, a statistically significant higher expression of RBMS3 was observed in cancer stromal cells in comparison to the control and cancer cells (p < 0.0001). The statistical analysis demonstrated a significantly higher expression of RBMS3 mRNA in the SK-BR-3 cell line compared with all other cell lines (p < 0.05). A positive correlation was revealed between the expression of RBMS3, at both the mRNA and protein levels, and longer overall survival. The differences in the expression of RBMS3 in cancer cells (both in vivo and in vitro) and the stroma of breast cancer with regard to the molecular status of the tumor may indicate that RBMS3 could be a potential novel target for the development of personalized methods of treatment. RBMS3 can be an indicator of longer overall survival for potential use in breast cancer diagnostic process.}, keywords = {Humans Female *Breast Neoplasms/metabolism Breast/metabolism *Carcinoma, Ductal, Breast/pathology MCF-7 Cells RNA, Messenger/genetics Cell Line, Tumor Trans-Activators/metabolism RNA-Binding Proteins/metabolism RNA-binding protein 3 (RBMS3) cancer prevention carcinogenesis epithelial–mesenchymal transition (EMT) target discovery target therapy}, ISSN = {1422-0067}, DOI = {10.3390/ijms24032866}, year = {2023}, type = {Journal Article} } @article{ author = {Gross, N. D. and Miller, D. M. and Khushalani, N. I. and Divi, V. and Ruiz, E. S. and Lipson, E. J. and Meier, F. and Su, Y. B. and Swiecicki, P. L. and Atlas, J. and Geiger, J. L. and Hauschild, A. and Choe, J. H. and Hughes, B. G. M. and Schadendorf, D. and Patel, V. A. and Homsi, J. and Taube, J. M. and Lim, A. M. and Ferrarotto, R. and Yoo, S. Y. and Mathias, M. and Han, H. and Seebach, F. and Lowy, I. and Fury, M. G. and Rischin, D.}, title = {Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study}, journal = {Lancet Oncol}, volume = {24}, number = {11}, pages = {1196-1205}, note = {1474-5488 Gross, Neil D Miller, David M Khushalani, Nikhil I Divi, Vasu Ruiz, Emily S Lipson, Evan J Meier, Friedegund Su, Yungpo Bernard Swiecicki, Paul L Atlas, Jennifer Geiger, Jessica L Hauschild, Axel Choe, Jennifer H Hughes, Brett G M Schadendorf, Dirk Patel, Vishal A Homsi, Jade Taube, Janis M Lim, Annette M Ferrarotto, Renata Yoo, Suk-Young Mathias, Melissa Han, Hyunsil Seebach, Frank Lowy, Israel Fury, Matthew G Rischin, Danny Clinical Trial, Phase II Journal Article Multicenter Study Research Support, Non-U.S. Gov't England Lancet Oncol. 2023 Nov;24(11):1196-1205. doi: 10.1016/S1470-2045(23)00459-X. Epub 2023 Oct 21.}, abstract = {BACKGROUND: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. METHODS: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. FINDINGS: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. FUNDING: Regeneron Pharmaceuticals and Sanofi.}, keywords = {Humans Male Female Aged *Carcinoma, Squamous Cell/drug therapy/surgery/etiology Neoadjuvant Therapy/adverse effects Follow-Up Studies *Skin Neoplasms/drug therapy/surgery Neoplasm Staging Antineoplastic Combined Chemotherapy Protocols/therapeutic use Regeneron Pharmaceuticals speaker honoraria from AiCME and advisory board and consulting fees from PDS Biotechnology, Replimmune, Regeneron Pharmaceuticals, and Merck. DMM reports honoraria for advisory or consultant roles from Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron Pharmaceuticals, Incyte, Sanofi Genzyme, and Bristol Myers Squibb equity options from Checkpoint Therapeutics and Avstera Therapeutics Corp and research funding from Kartos Therapeutics, NeoImmune Tech, and Regeneron Pharmaceuticals. NIK reports grants and advisory board fees from Regeneron Pharmaceuticals, Bristol Myers Squibb, Merck, Replimmune, and Novartis advisory board fees from Iovance, Instil Bio, Castle Biosciences, Nektar, Incyte (data safety monitoring committee), AstraZeneca (data safety monitoring committee), and Jounce Therapeutics grants from GlaxoSmithKline, HUYA, and Celgene honoraria from Genzyme, National Comprehensive Cancer Network (paid by Pfizer), Nektar (study steering committee), Regeneron Pharmaceuticals (study steering committee), Bristol Myers Squibb (study steering committee). and Replimmune (study steering committee) grant from Modulation Therapeutics travel support from Regeneron Pharmaceuticals and common stock ownership of Bellicum Pharmaceuticals, Amarin, and Asensus Surgical (formerly Transenetrix). VD reports institutional research funding from Genentech, and advisory board fees from Regeneron Pharmaceuticals. ESR reports advisory board and consulting fees from Genentech, Feldan Therapeutics, Regeneron Pharmaceuticals, and Sanofi, and serves on the board of directors for Checkpoint Therapeutics. EJL reports institutional research funding from Regeneron Pharmaceuticals and Sanofi institutional grants from Bristol Myers Squibb and Merck advisory board fees from Bristol Myers Squibb, Eisai, Genentech, Instil Bio, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, Pfizer, Rain Therapeutics, Regeneron Pharmaceuticals, Replimmune, and Sanofi payment for speaker's fee from Bristol Myers Squibb and consulting fees from Bristol Myers Squibb, Macrogenics, OncoSec, Merck, Novartis, CareDX, and Pfizer. FM reports travel support, speaker's fees or advisor's honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi and research funding from Novartis and Roche. PLS reports institutional research grants from Ascentage Pharma and Pfizer, and advisory board roles for Elevar Therapeutics, Prelude Therapeutics, and Regeneron Pharmaceuticals. JA reports payment or honoraria for speakers bureaus and presentations from Bristol Myers Squibb and Regeneron Pharmaceuticals advisory board and consulting fees from Bristol Myers Squibb, Castle Biosciences, Pfizer, Regeneron Pharmaceuticals, and Sanofi. JLG reports institutional research funding from Alkermes, EMD Serono, Merck, Regeneron Pharmaceuticals, and Roche/Genentech and advisory board or consultant fees from Astellas, Exelixis, EMD Serono, Merck, and Regeneron Pharmaceuticals. AH reports grants and personal fees from Amgen, Bristol Myers Squibb, Merck-Pfizer, MSD/Merck, Philogen, Pierre Fabre, Regeneron Pharmaceuticals, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Replimmune, NeraCare consulting fees from Seagen, IO Biotech, Dermagnostix, Incyte, Highlight Therapeutics, and Iovance speaker's honoraria from Kyowa Kirin advisory board fees from Immunocore and institutional grants from Huya Biosciences outside the submitted work. JHC reports consulting or advisory roles for Exelixis, Coherus Biosciences, Merck Sharp & Dohme, Eisai, and Regeneron Pharmaceuticals, and institutional research funding from Arcus Biosciences and Genmab. BGMH reports consulting or advisory roles at AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer, and Roche, and institutional research funding from Amgen. DS reports honoraria from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron Pharmaceuticals, 4SC, Sanofi, Regeneron Pharmaceuticals, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, and Sandoz consulting fees from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar speaker fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Merck advisory board fees from AstraZeneca, Daiichi-Sankyo, Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar institutional research funding from Bristol Myers Squibb, Novartis, Roche, MSD Oncology, and Array BioPharma/Pfizer unpaid leadership or fiduciary roles with Dermatologic Cooperative Oncology Group, European Organisation for Research and Treatment of Cancer-Melanoma Group, Hiege-Stiftung, and Nationale Versorgungskonferenz Hautkrebs and travel and accommodation expenses from Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals. VAP reports honoraria for advisory or consulting roles from Sun Pharma, Almirall, Biofrontera, PhD Biosciences, Regeneron Pharmaceuticals, and Sanofi Genzyme speakers bureau fees from Regeneron Pharmaceuticals, and Sanofi Genzyme, equity in Avstera Therapeutics and Science 37 and research funding from Regeneron Pharmaceuticals. JMT reports honoraria for advisory or consultant roles for Bristol Myers Squibb, Merck & Co, AstraZeneca, Genentech/Roche, Regeneron Pharmaceuticals, Compugen, Lunaphore, and Akoya Biosciences stock options in Akoya Biosciences equipment loan and reagent provision from Akoya Biosciences and research funding from Bristol Myers Squibb and Akoya Biosciences. AML reports uncompensated consultancy for Eisai, research funding support from Sanofi/Regeneron Pharmaceuticals, and support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship. RF reports grants or investigator-initiated trial support from Merck, Pfizer, Gilead, and Ayala royalties from UpToDate for a chapter on olfactory neuroblastoma payment for expert testimony from Guidepoint and advisory board participation with Regeneron Pharmaceuticals, Prelude Therapeutics, Elevar Therapeutics, Eisai, Remix Therapeutics, and Coherus BioSciences. S-YY, HH, FS, and IL are employees and shareholders of Regeneron Pharmaceuticals. MM and MGF report receipt of support for attending meetings or travel, and are also employees, patent holders, and shareholders of Regeneron Pharmaceuticals. DR reports institutional research grant and funding from Regeneron Pharmaceuticals, Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Decibel Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, and ALX Oncology and uncompensated scientific committee and advisory board roles for Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, and Eisai. YBS and JH declare no competing interests.}, ISSN = {1470-2045}, DOI = {10.1016/s1470-2045(23)00459-x}, year = {2023}, type = {Journal Article} } @article{ author = {Guo, Y. J. and Pan, W. W. and Liu, S. B. and Shen, Z. F. and Xu, Y. and Hu, L. L.}, title = {ERK/MAPK signalling pathway and tumorigenesis}, journal = {Exp Ther Med}, volume = {19}, number = {3}, pages = {1997-2007}, note = {1792-1015 Guo, Yan-Jun Pan, Wei-Wei Liu, Sheng-Bing Shen, Zhong-Fei Xu, Ying Hu, Ling-Ling Journal Article Review Greece Exp Ther Med. 2020 Mar;19(3):1997-2007. doi: 10.3892/etm.2020.8454. Epub 2020 Jan 15.}, abstract = {Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.}, ISSN = {1792-0981 (Print) 1792-0981}, DOI = {10.3892/etm.2020.8454}, year = {2020}, type = {Journal Article} } @article{ author = {Herbst, R. S. and Morgensztern, D. and Boshoff, C.}, title = {The biology and management of non-small cell lung cancer}, journal = {Nature}, volume = {553}, number = {7689}, pages = {446-454}, note = {1476-4687 Herbst, Roy S Morgensztern, Daniel Boshoff, Chris Journal Article Research Support, Non-U.S. Gov't Review England Nature. 2018 Jan 24;553(7689):446-454. doi: 10.1038/nature25183.}, abstract = {Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.}, keywords = {Carcinoma, Non-Small-Cell Lung/genetics/*metabolism/pathology/*therapy Clinical Trials as Topic Humans Immunotherapy Lung Neoplasms/genetics/*metabolism/pathology/*therapy Molecular Targeted Therapy Precision Medicine Survival Rate Tumor Microenvironment/genetics}, ISSN = {0028-0836}, DOI = {10.1038/nature25183}, year = {2018}, type = {Journal Article} } @article{ author = {Hirsch, F. R. and Scagliotti, G. V. and Mulshine, J. L. and Kwon, R. and Curran, W. J., Jr. and Wu, Y. L. and Paz-Ares, L.}, title = {Lung cancer: current therapies and new targeted treatments}, journal = {Lancet}, volume = {389}, number = {10066}, pages = {299-311}, note = {1474-547x Hirsch, Fred R Scagliotti, Giorgio V Mulshine, James L Kwon, Regina Curran, Walter J Jr Wu, Yi-Long Paz-Ares, Luis Journal Article Review England Lancet. 2017 Jan 21;389(10066):299-311. doi: 10.1016/S0140-6736(16)30958-8. Epub 2016 Aug 27.}, abstract = {Lung cancer is the most frequent cause of cancer-related deaths worldwide. Every year, 1·8 million people are diagnosed with lung cancer, and 1·6 million people die as a result of the disease. 5-year survival rates vary from 4-17% depending on stage and regional differences. In this Seminar, we discuss existing treatment for patients with lung cancer and the promise of precision medicine, with special emphasis on new targeted therapies. Some subgroups, eg-patients with poor performance status and elderly patients-are not specifically addressed, because these groups require special treatment considerations and no frameworks have been established in terms of new targeted therapies. We discuss prevention and early detection of lung cancer with an emphasis on lung cancer screening. Although we acknowledge the importance of smoking prevention and cessation, this is a large topic beyond the scope of this Seminar.}, keywords = {Antineoplastic Agents/therapeutic use Carcinoma, Non-Small-Cell Lung/diagnosis/genetics/mortality/therapy Combined Modality Therapy Early Detection of Cancer Humans Immunotherapy Lung Neoplasms/diagnosis/genetics/mortality/*therapy Mutation Survival Rate}, ISSN = {0140-6736}, DOI = {10.1016/s0140-6736(16)30958-8}, year = {2017}, type = {Journal Article} } @article{ author = {Howlader, N. and Forjaz, G. and Mooradian, M. J. and Meza, R. and Kong, C. Y. and Cronin, K. A. and Mariotto, A. B. and Lowy, D. R. and Feuer, E. J.}, title = {The Effect of Advances in Lung-Cancer Treatment on Population Mortality}, journal = {N Engl J Med}, volume = {383}, number = {7}, pages = {640-649}, note = {1533-4406 Howlader, Nadia Forjaz, Gonçalo Mooradian, Meghan J Meza, Rafael Kong, Chung Yin Cronin, Kathleen A Mariotto, Angela B Lowy, Douglas R Feuer, Eric J Z99 CA999999/ImNIH/Intramural NIH HHS/United States Journal Article United States N Engl J Med. 2020 Aug 13;383(7):640-649. doi: 10.1056/NEJMoa1916623.}, abstract = {BACKGROUND: Lung cancer is made up of distinct subtypes, including non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although overall mortality from lung cancer has been declining in the United States, little is known about mortality trends according to cancer subtype at the population level because death certificates do not record subtype information. METHODS: Using data from Surveillance, Epidemiology, and End Results (SEER) areas, we assessed lung-cancer mortality and linked deaths from lung cancer to incident cases in SEER cancer registries. This allowed us to evaluate population-level mortality trends attributed to specific subtypes (incidence-based mortality). We also evaluated lung-cancer incidence and survival according to cancer subtype, sex, and calendar year. Joinpoint software was used to assess changes in incidence and trends in incidence-based mortality. RESULTS: Mortality from NSCLC decreased even faster than the incidence of this subtype, and this decrease was associated with a substantial improvement in survival over time that corresponded to the timing of approval of targeted therapy. Among men, incidence-based mortality from NSCLC decreased 6.3% annually from 2013 through 2016, whereas the incidence decreased 3.1% annually from 2008 through 2016. Corresponding lung cancer-specific survival improved from 26% among men with NSCLC that was diagnosed in 2001 to 35% among those in whom it was diagnosed in 2014. This improvement in survival was found across all races and ethnic groups. Similar patterns were found among women with NSCLC. In contrast, mortality from SCLC declined almost entirely as a result of declining incidence, with no improvement in survival. This result correlates with limited treatment advances for SCLC in the time frame we examined. CONCLUSIONS: Population-level mortality from NSCLC in the United States fell sharply from 2013 to 2016, and survival after diagnosis improved substantially. Our analysis suggests that a reduction in incidence along with treatment advances - particularly approvals for and use of targeted therapies - is likely to explain the reduction in mortality observed during this period.}, keywords = {Carcinoma, Non-Small-Cell Lung/epidemiology/*mortality Female Humans Incidence Lung Neoplasms/epidemiology/*mortality Male Mortality/trends SEER Program Sex Factors United States/epidemiology}, ISSN = {0028-4793 (Print) 0028-4793}, DOI = {10.1056/NEJMoa1916623}, year = {2020}, type = {Journal Article} } @article{ author = {Hu, X. L. and Zhu, Y. J. and Hu, C. H. and You, L. and Wu, J. and He, X. Y. and Huang, W. J. and Wu, Z. H.}, title = {Ghrelin Affects Gastric Cancer Progression by Activating AMPK Signaling Pathway}, journal = {Biochem Genet}, volume = {59}, number = {3}, pages = {652-667}, note = {1573-4927 Hu, Xiao-Lin Zhu, Yong-Jun Hu, Chang-Hua You, Li Wu, Juan He, Xiao-Yan Huang, Wen-Jie Wu, Zong-Hui}, abstract = {As the endogenous ligand for the GH secretagogue receptor (GHSR), Ghrelin is aberrant expressed in multiple malignant carcinoma, and involved in regulating a number of progression of cancer, especially in metastasis and proliferation. However, the precise role of Ghrelin in tumorigenesis of gastric cancer (GC) is still poorly understood. In this study, we extensively investigated the roles and mechanisms of Ghrelin in human gastric cancer. Ghrelin levels in cancer tissues and cell lines were analyzed by immunohistochemistry, qRT-PCR, and Western blot. Functional studies were performed after Ghrelin overexpressed or knockdown in AGS cell line. Cell proliferation was evaluated in by MTT and clone formation assays. The wound healing and Transwell system were used to assess the cell migration and invasive ability of GC cells. Cell apoptosis was detected by flow cytometry, and metabolic assays were performed to reveal the function of Warburg effect in the process. Ghrelin was lowly expressed in gastric cancer tissues and cell lines. Overexpression of Ghrelin inhibited gastric cancer cell proliferation, migration, invasion, and promoted apoptosis by activating the AMPK pathway, while D-[lys3]-GHRP-6 (a GHSR agonist) treatment relieved the effect, promoting tumorigenesis. Ghrelin knockdown increased the glucose uptake and lactic acid release, suggesting that Ghrelin elicited an anti-Warburg effect via AMPK pathway to inhibit gastric tumorigenesis. Ghrelin inhibits cell proliferation, migration, and invasion by eliciting an anti-Warburg effect via AMPK signaling pathway in gastric cancer cells.}, ISSN = {0006-2928}, DOI = {10.1007/s10528-020-10022-x}, year = {2021}, type = {Journal Article} } @article{ author = {Jr, Frank E Harrell}, title = {rms: Regression Modeling Strategies}, year = {2015}, type = {Journal Article} } @article{ author = {Kaderbhaï, C. and Tharin, Z. and Ghiringhelli, F.}, title = {The Role of Molecular Profiling to Predict the Response to Immune Checkpoint Inhibitors in Lung Cancer}, journal = {Cancers (Basel)}, volume = {11}, number = {2}, note = {2072-6694 Kaderbhaï, Courèche Tharin, Zoé Ghiringhelli, François Journal Article Review Switzerland Cancers (Basel). 2019 Feb 10;11(2):201. doi: 10.3390/cancers11020201.}, abstract = {Immune checkpoint inhibitors radically changed the treatment of patients with non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies when used as monotherapy. The assessment of Program Death Ligand-1 (PD-L1) tumor expression by immunohistochemistry is used to select potential responder patients, but this not an optimal marker since it does not predict the absence of anti PD-1 efficacy. Despite this shortcoming, PD-L1 remains the gold standard biomarker in many studies and the only biomarker available for clinicians. In addition to histological markers, transcriptomic and exome analyses have revealed potential biomarkers requiring further confirmation. Recently, tumor mutational burden has emerged as a good surrogate marker of outcome. In this review we will detail current knowledge on DNA and RNA related biomarkers.}, ISSN = {2072-6694 (Print) 2072-6694}, DOI = {10.3390/cancers11020201}, year = {2019}, type = {Journal Article} } @article{ author = {Kalbasi, A. and Ribas, A.}, title = {Tumour-intrinsic resistance to immune checkpoint blockade}, journal = {Nat Rev Immunol}, volume = {20}, number = {1}, pages = {25-39}, note = {1474-1741 Kalbasi, Anusha Ribas, Antoni}, abstract = {'Immune checkpoint blockade' for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT-β-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade.}, ISSN = {1474-1733 (Print) 1474-1733}, DOI = {10.1038/s41577-019-0218-4}, year = {2020}, type = {Journal Article} } @article{ author = {Kanehisa, M.}, title = {Toward understanding the origin and evolution of cellular organisms}, journal = {Protein Sci}, volume = {28}, number = {11}, pages = {1947-1951}, note = {1469-896x Kanehisa, Minoru Journal Article Research Support, Non-U.S. Gov't Review United States Protein Sci. 2019 Nov;28(11):1947-1951. doi: 10.1002/pro.3715. Epub 2019 Sep 9.}, abstract = {In this era of high-throughput biology, bioinformatics has become a major discipline for making sense out of large-scale datasets. Bioinformatics is usually considered as a practical field developing databases and software tools for supporting other fields, rather than a fundamental scientific discipline for uncovering principles of biology. The KEGG resource that we have been developing is a reference knowledge base for biological interpretation of genome sequences and other high-throughput data. It is now one of the most utilized biological databases because of its practical values. For me personally, KEGG is a step toward understanding the origin and evolution of cellular organisms.}, keywords = {*Computational Biology *Databases, Genetic *High-Throughput Screening Assays Humans Software}, ISSN = {0961-8368 (Print) 0961-8368}, DOI = {10.1002/pro.3715}, year = {2019}, type = {Journal Article} } @article{ author = {Kanehisa, M. and Furumichi, M. and Sato, Y. and Matsuura, Y. and Ishiguro-Watanabe, M.}, title = {KEGG: biological systems database as a model of the real world}, journal = {Nucleic Acids Res}, volume = {53}, number = {D1}, pages = {D672-d677}, note = {1362-4962 Kanehisa, Minoru Furumichi, Miho Sato, Yoko Matsuura, Yuriko Ishiguro-Watanabe, Mari JPMJND2203/NBDC Database Integration Coordination Program/ Japan Science and Technology Agency/ Journal Article England Nucleic Acids Res. 2025 Jan 6;53(D1):D672-D677. doi: 10.1093/nar/gkae909.}, abstract = {KEGG (https://www.kegg.jp/) is a database resource for representation and analysis of biological systems. Pathway maps are the primary dataset in KEGG representing systemic functions of the cell and the organism in terms of molecular interaction and reaction networks. The KEGG Orthology (KO) system is a mechanism for linking genes and proteins to pathway maps and other molecular networks. Each KO is a generic gene identifier and each pathway map is created as a network of KO nodes. This architecture enables KEGG pathway mapping to uncover systemic features from KO assigned genomes and metagenomes. Additional roles of KOs include characterization of conserved genes and conserved units of genes in organism groups, which can be done by taxonomy mapping. A new tool has been developed for identifying conserved gene orders in chromosomes, in which gene orders are treated as sequences of KOs. Furthermore, a new dataset called VOG (virus ortholog group) is computationally generated from virus proteins and expanded to proteins of cellular organisms, allowing gene orders to be compared as VOG sequences as well. Together with these datasets and analysis tools, new types of pathway maps are being developed to present a global view of biological processes involving multiple organism groups.}, keywords = {*Databases, Genetic Software Humans}, ISSN = {0305-1048 (Print) 0305-1048}, DOI = {10.1093/nar/gkae909}, year = {2025}, type = {Journal Article} } @article{ author = {Kanehisa, M. and Goto, S.}, title = {KEGG: kyoto encyclopedia of genes and genomes}, journal = {Nucleic Acids Res}, volume = {28}, number = {1}, pages = {27-30}, note = {1362-4962 Kanehisa, M Goto, S Journal Article Research Support, Non-U.S. Gov't England Nucleic Acids Res. 2000 Jan 1;28(1):27-30. doi: 10.1093/nar/28.1.27.}, abstract = {KEGG (Kyoto Encyclopedia of Genes and Genomes) is a knowledge base for systematic analysis of gene functions, linking genomic information with higher order functional information. The genomic information is stored in the GENES database, which is a collection of gene catalogs for all the completely sequenced genomes and some partial genomes with up-to-date annotation of gene functions. The higher order functional information is stored in the PATHWAY database, which contains graphical representations of cellular processes, such as metabolism, membrane transport, signal transduction and cell cycle. The PATHWAY database is supplemented by a set of ortholog group tables for the information about conserved subpathways (pathway motifs), which are often encoded by positionally coupled genes on the chromosome and which are especially useful in predicting gene functions. A third database in KEGG is LIGAND for the information about chemical compounds, enzyme molecules and enzymatic reactions. KEGG provides Java graphics tools for browsing genome maps, comparing two genome maps and manipulating expression maps, as well as computational tools for sequence comparison, graph comparison and path computation. The KEGG databases are daily updated and made freely available (http://www. genome.ad.jp/kegg/).}, keywords = {Animals *Databases, Factual Gene Expression *Genome Humans Information Storage and Retrieval Japan Proteins/genetics/metabolism}, ISSN = {0305-1048 (Print) 0305-1048}, DOI = {10.1093/nar/28.1.27}, year = {2000}, type = {Journal Article} } @article{ author = {Klion, A. D. and Ackerman, S. J. and Bochner, B. S.}, title = {Contributions of Eosinophils to Human Health and Disease}, journal = {Annu Rev Pathol}, volume = {15}, pages = {179-209}, note = {1553-4014 Klion, Amy D Ackerman, Steven J Bochner, Bruce S R56 AI072265/AI/NIAID NIH HHS/United States U19 AI136443/AI/NIAID NIH HHS/United States R01 AI105839/AI/NIAID NIH HHS/United States R01 FD004086/FD/FDA HHS/United States R01 AI072265/AI/NIAID NIH HHS/United States R56 AI105839/AI/NIAID NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Review United States Annu Rev Pathol. 2020 Jan 24;15:179-209. doi: 10.1146/annurev-pathmechdis-012419-032756.}, abstract = {The human eosinophil has long been thought to favorably influence innate mucosal immunity but at times has also been incriminated in disease pathophysiology. Research into eosinophil biology has uncovered a number of interesting contributions by eosinophils to health and disease. However, it appears that not all eosinophils from all species are created equal. It remains unclear, for example, exactly how having eosinophils benefits the human host when helminth infections in the developed world have become scarce. This review focuses on our current state of knowledge as it relates to human eosinophils. When information is lacking, we discuss lessons learned from mouse studies that may or may not directly apply to human biology and disease. It is an exciting time to be an "eosinophilosopher" because the use of biologic agents that selectively target eosinophils provides an unprecedented opportunity to define the contribution of this cell to eosinophil-associated human diseases.}, keywords = {Animals Disease/*etiology Eosinophils/*physiology Helminthiasis/immunology Humans Immunity, Innate/*physiology Leukocyte Count Mice}, ISSN = {1553-4006 (Print) 1553-4006}, DOI = {10.1146/annurev-pathmechdis-012419-032756}, year = {2020}, type = {Journal Article} } @article{ author = {Kumar, V. and Yadavilli, S. and Kannan, R.}, title = {A review on RNAi therapy for NSCLC: Opportunities and challenges}, journal = {Wiley Interdiscip Rev Nanomed Nanobiotechnol}, volume = {13}, number = {2}, pages = {e1677}, note = {1939-0041 Kumar, Vignesh Yadavilli, Sairam Kannan, Raghuraman}, abstract = {Non-small cell lung cancer (NSCLC) is the primary cause of cancer death worldwide. Despite developments in chemotherapy and targeted therapies, the 5-year survival rate has remained at approximately 16% for the last four decades. NSCLC is a heterogeneous group of tumors that, through mutations and drivers, also demonstrate intra-tumor heterogeneity. Thus, current treatment approaches revolve around targeting these oncogenes, often using small molecule inhibitors and chemotherapeutics. However, the efficacy of these therapies has been crippled by acquired and inherent drug-resistance in the tumor, accompanied by increased therapeutic dosages and subsequent devastating off-target effects for patients. Evidently, there is a critical need for developing treatment methodologies more effective than the current standard of care. Fortunately, RNA interference, particularly small interfering RNA (siRNA), presents an alternative of silencing specific oncogenes to control tumor growth. Although siRNA therapy is subject to rapid degradation and poor internalization in vivo, nanoparticles can serve as nontoxic and efficient delivery vehicles, even introducing combinational delivery of multiple therapeutic agents. Indeed, siRNA-nanoconstructs possess extraordinary potential as an innovative modality to address clinical needs. This state-of-the-art review summarizes the recent advancements in the development of novel nanosystems for delivering siRNA to NSCLC tumors and analyzes the efficacy of representative examples. By illuminating the most promising biomarkers for silencing, we hope to streamline current therapeutic efforts and highlight powerful translational opportunities to combat NSCLC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.}, ISSN = {1939-0041}, DOI = {10.1002/wnan.1677}, year = {2021}, type = {Journal Article} } @article{ author = {Lee, H. and Jung, J. H. and Ko, H. M. and Park, H. and Segall, A. M. and Sheffmaker, R. L. and Wang, J. and Frey, W. D. and Pham, N. and Wang, Y. and Zhang, Y. and Jackson, J. G. and Zeng, S. X. and Lu, H.}, title = {RNA-binding motif protein 10 inactivates c-Myc by partnering with ribosomal proteins uL18 and uL5}, journal = {Proc Natl Acad Sci U S A}, volume = {120}, number = {49}, pages = {e2308292120}, note = {1091-6490 Lee, Hyemin Jung, Ji Hoon Ko, Hyun Min Park, Heewon Segall, Allyson M Sheffmaker, Roger L Wang, Jieqiong}, abstract = {RNA-binding motif protein 10 (RBM10) is a frequently mutated tumor suppressor in lung adenocarcinoma (LUAD). Yet, it remains unknown whether cancer-derived mutant RBM10 compromises its tumor suppression function and, if so, the molecular insight of the underlying mechanisms. Here, we show that wild-type RBM10 suppresses lung cancer cell growth and proliferation by inactivating c-Myc that is essential for cancer cell survival. RBM10 directly binds to c-Myc and promotes c-Myc's ubiquitin-dependent degradation, while RBM10 knockdown leads to the induction of c-Myc level and activity. This negative action on c-Myc is further boosted by ribosomal proteins (RPs) uL18 (RPL5) and uL5 (RPL11) via their direct binding to RBM10. Cancer-derived mutant RBM10-I316F fails to bind to uL18 and uL5 and to inactivate c-Myc, thus incapable of suppressing tumorigenesis. Our findings uncover RBM10 as a pivotal c-Myc repressor by cooperating with uL18 and uL5 in lung cancer cells, as its failure to do so upon mutation favors tumorigenesis.}, ISSN = {0027-8424 (Print) 0027-8424}, DOI = {10.1073/pnas.2308292120}, year = {2023}, type = {Journal Article} } @article{ author = {Li, H. and Li, Y. and Zheng, X. and Chen, F. and Zhang, S. and Xu, S. and Mu, Y. and Shen, W. and Tong, J. and Chen, H. and Hu, Z. and Zhang, J. and Qiu, K. and Chen, W. and Cheng, X. and Xu, G.}, title = {RBM15 facilitates osimertinib resistance of lung adenocarcinoma through m6A-dependent epigenetic silencing of SPOCK1}, journal = {Oncogene}, volume = {44}, number = {5}, pages = {307-321}, note = {1476-5594 Li, Hongxiang Li, Yin}, abstract = {Lung cancer is the leading cause of cancer-related mortality globally. N6-methyladenosine (m6A) is the most abundant modification in mammalian mRNA and is involved in the biological regulation of tumors, including lung cancer. However, the role of m6A-related proteins, such as RNA-binding motif protein 15 (RBM15), in lung cancer progression remains largely unknown. Our study indicated that RBM15 is significantly overexpressed in lung adenocarcinoma, serving as an independent prognostic factor for poor outcomes and facilitating tumor cell proliferation and migration. RBM15 was markedly elevated in patients with EGFR mutations, correlating with a poorer prognosis, while it had negligible prognostic value in EGFR wild-type patients. As EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with EGFR mutations, we subsequently determined that RBM15 drives osimertinib resistance via a novel mechanism: enhancing m6A modification of cwcv- and kazal-like domains proteoglycan 1 (SPOCK1) mRNA, promoting epithelial-mesenchymal transition-mediated osimertinib resistance through a bypass activation pathway. These findings were validated in osimertinib-resistant H1975 cells and organoids from patients with osimertinib-resistant lung adenocarcinoma. Furthermore, the RBM15-SPOCK1 axis was activated in drug-tolerant persister cells, indicating that early targeting of RBM15 during EGFR-TKI treatment could dramatically extend the patient response and benefit from TKI therapy. Our results emphasize the critical role of RBM15 in reversing EGFR-TKI resistance and propose it as a promising therapeutic target for prolonging TKI treatment benefits in patients with lung adenocarcinoma.}, ISSN = {0950-9232 (Print) 0950-9232}, DOI = {10.1038/s41388-024-03220-z}, year = {2025}, type = {Journal Article} } @article{ author = {Li, X. and Ma, C. and Luo, H. and Zhang, J. and Wang, J. and Guo, H.}, title = {Identification of the differential expression of genes and upstream microRNAs in small cell lung cancer compared with normal lung based on bioinformatics analysis}, journal = {Medicine (Baltimore)}, volume = {99}, number = {11}, pages = {e19086}, note = {1536-5964 Li, Xiuwei Ma, Chao Luo, Huan Zhang, Jian Wang, Jinan Guo, Hongtao Journal Article United States Medicine (Baltimore). 2020 Mar;99(11):e19086. doi: 10.1097/MD.0000000000019086.}, abstract = {Small cell lung cancer (SCLC) is one of the most lethal cancer, mainly attributing to its high tendency to metastasis. Mounting evidence has demonstrated that genes and microRNAs (miRNAs) are related to human cancer onset and progression including invasion and metastasis.An eligible gene dataset and an eligible miRNA dataset were downloaded from the Gene Expression Omnibus (GEO) database based our screening criteria. Differentially expressed genes (DE-genes) or DE-miRNAs for each dataset obtained by the R software package. The potential target genes of the top 10 DE-miRNAs were predicted by multiple databases. For annotation, visualization and integrated discovery, Metascape 3.0 was introduced to perform enrichment analysis for the DE-genes and the predicted target genes of the selected top 10 DE-miRNAs, including Pathway and Process Enrichment Analysis or protein-protein interaction enrichment analysis. The intersection of predicted target genes and DE-genes was taken as the final DE-genes. Then apply the predicted miRNAs-targets relationship of top 10 DE-miRNAs to the final DE-genes to gain more convinced DE-miRNAs, DE-genes and their one to one relationship.GSE19945 (miRNA microarray) and GSE40275 (gene microarray) datasets were selected and downloaded. 56 DE-miRNAs and 861 DE-genes were discovered. 297 miRNAs-targets relationships (284 unique genes) were predicted as the target of top 10 upregulating DE-miRNAs. 245 miRNAs-targets relationships (238 unique genes) were identified as the target of top 10 downregulating DE-miRNAs. The key results of enrichment analysis include protein kinase B signaling, transmembrane receptor protein tyrosine kinase signaling pathway, negative regulation of cell differentiation, response to growth factor, cellular response to lipid, muscle structure development, response to growth factor, signaling by Receptor Tyrosine Kinases, epithelial cell migration, cellular response to organic cyclic compound, Cell Cycle (Mitotic), DNA conformation change, cell division, DNA replication, cell cycle phase transition, blood vessel development, inflammatory response, Staphylococcus aureus infection, leukocyte migration, and myeloid leukocyte activation. Differential expression of genes-upstream miRNAs (RBMS3-hsa-miR-7-5p, NEDD9-hsa-miR-18a-5p, CRIM1-hsa-miR-18a-5p, TGFBR2-hsa-miR-9-5p, MYO1C-hsa-miR-9-5p, KLF4-hsa-miR-7-5p, EMP2-hsa-miR-1290, TMEM2-hsa-miR-18a-5p, CTGF-hsa-miR-18a-5p, TNFAIP3-hsa-miR-18a-5p, THBS1-hsa-miR-182-5p, KPNA2-hsa-miR-144-3p, GPR137C-hsa-miR-1-3p, GRIK3-hsa-miR-144-3p, and MTHFD2-hsa-miR-30a-3p) were identified in SCLC.RBMS3, NEDD9, CRIM1, KPNA2, GPR137C, GRIK3, hsa-miR-7-5p, hsa-miR-18a-5p, hsa-miR-144-3p, hsa-miR-1-3p along with the pathways included protein kinase B signaling, muscle structure development, Cell Cycle (Mitotic) and blood vessel development may gain a high chance to play a key role in the prognosis of SCLC, but more studies should be conducted to reveal it more clearly.}, keywords = {Case-Control Studies Gene Expression Humans Kruppel-Like Factor 4 Lung/*metabolism Lung Neoplasms/*metabolism MicroRNAs/*metabolism Oligonucleotide Array Sequence Analysis Small Cell Lung Carcinoma/*metabolism Transcriptome}, ISSN = {0025-7974 (Print) 0025-7974}, DOI = {10.1097/md.0000000000019086}, year = {2020}, type = {Journal Article} } @article{ author = {Li, Y. and Chen, L. and Nie, C. J. and Zeng, T. T. and Liu, H. and Mao, X. and Qin, Y. and Zhu, Y. H. and Fu, L. and Guan, X. Y.}, title = {Downregulation of RBMS3 is associated with poor prognosis in esophageal squamous cell carcinoma}, journal = {Cancer Res}, volume = {71}, number = {19}, pages = {6106-15}, note = {1538-7445 Li, Yan Chen, Leilei Nie, Chang-jun Zeng, Ting-ting Liu, Haibo Mao, Xueying Qin, Yanru Zhu, Ying-Hui Fu, Li Guan, Xin-Yuan Journal Article Research Support, Non-U.S. Gov't United States Cancer Res. 2011 Oct 1;71(19):6106-15. doi: 10.1158/0008-5472.CAN-10-4291. Epub 2011 Aug 15.}, abstract = {Deletions on chromosome 3p occur often in many solid tumors, including esophageal squamous cell carcinoma (ESCC), suggesting the existence at this location of one or more tumor suppressor genes (TSG). In this study, we characterized RBMS3 gene encoding an RNA-binding protein as a candidate TSG located at 3p24. Downregulation of RBMS3 mRNA and protein levels was documented in approximately 50% of the primary ESCCs examined. Clinical association studies determined that RBMS3 downregulation was associated with poor clinical outcomes. RBMS3 expression effectively suppressed the tumorigenicity of ESCC cells in vitro and in vivo, including by inhibition of cell growth rate, foci formation, soft agar colony formation, and tumor formation in nude mice. Molecular analyses revealed that RBMS3 downregulated c-Myc and CDK4, leading to subsequent inhibition of Rb phosphorylation. Together, our findings suggest a tumor suppression function for the human RBMS3 gene in ESCC, acting through c-Myc downregulation, with genetic loss of this gene in ESCC contributing to poor outcomes in this deadly disease.}, keywords = {Animals Carcinoma, Squamous Cell/*genetics/pathology/physiopathology Cell Movement Cell Proliferation Cyclin-Dependent Kinase 4/genetics Down-Regulation Esophageal Neoplasms/*genetics/pathology/physiopathology Female Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Humans Male Mice Mice, Nude Middle Aged Prognosis Proto-Oncogene Proteins c-myc/genetics RNA-Binding Proteins/*genetics Trans-Activators/*genetics}, ISSN = {0008-5472}, DOI = {10.1158/0008-5472.Can-10-4291}, year = {2011}, type = {Journal Article} } @article{ author = {Li, Z. and Guo, Q. and Zhang, J. and Fu, Z. and Wang, Y. and Wang, T. and Tang, J.}, title = {The RNA-Binding Motif Protein Family in Cancer: Friend or Foe?}, journal = {Front Oncol}, volume = {11}, pages = {757135}, note = {2234-943x Li, Zhigang Guo, Qingyu Zhang, Jiaxin Fu, Zitong Wang, Yifei Wang, Tianzhen Tang, Jing Journal Article Review Switzerland Front Oncol. 2021 Nov 4;11:757135. doi: 10.3389/fonc.2021.757135. eCollection 2021.}, abstract = {The RNA-binding motif (RBM) proteins are a class of RNA-binding proteins named, containing RNA-recognition motifs (RRMs), RNA-binding domains, and ribonucleoprotein motifs. RBM proteins are involved in RNA metabolism, including splicing, transport, translation, and stability. Many studies have found that aberrant expression and dysregulated function of RBM proteins family members are closely related to the occurrence and development of cancers. This review summarizes the role of RBM proteins family genes in cancers, including their roles in cancer occurrence and cell proliferation, migration, and apoptosis. It is essential to understand the mechanisms of these proteins in tumorigenesis and development, and to identify new therapeutic targets and prognostic markers.}, ISSN = {2234-943X (Print) 2234-943x}, DOI = {10.3389/fonc.2021.757135}, year = {2021}, type = {Journal Article} } @article{ author = {Liang, Y. N. and Liu, Y. and Meng, Q. and Li, X. and Wang, F. and Yao, G. and Wang, L. and Fu, S. and Tong, D.}, title = {RBMS3 is a tumor suppressor gene that acts as a favorable prognostic marker in lung squamous cell carcinoma}, journal = {Med Oncol}, volume = {32}, number = {2}, pages = {459}, note = {1559-131x Liang, Ya-Nan Liu, Yu Meng, Qingwei Li, Xiaobo Wang, Fan Yao, Guodong Wang, Letian Fu, Songbin Tong, Dandan Journal Article Research Support, Non-U.S. Gov't United States Med Oncol. 2015 Feb;32(2):459. doi: 10.1007/s12032-014-0459-9. Epub 2015 Jan 15.}, abstract = {Recent research indicates that RBMS3 may act as a tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). It has been reported that RBMS3 directly binds to the promoter region of c-Myc in ESCC and that β-catenin from both whole cell extracts and nuclear fractionation was significantly downregulated in RBMS3-transfected NPC cells compared to control cells. The aim of this study was to evaluate the clinical significance of the RBMS3 gene expression in relation to the expression of Wnt pathway components in patients with lung squamous cell carcinoma (LSCC). RBMS3, c-Myc and cytoplasmic β-catenin were detected in 39.76, 56.63 and 89.16 % of 83 LSCC samples by immunohistochemistry, respectively, in 83 primary LSCC samples. Semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting demonstrated decreased RBMS3 mRNA and expression in 33.33 % (10/30) and 36.67 % (11/30) tumor tissues, respectively. Statistical correlation analysis showed RBMS3 to be negatively correlated with c-Myc (r = -0.384, p < 0.001) and not correlated with cytoplasmic β-catenin in the LSCC samples. Multivariate Cox proportional hazards model analysis showed that the combined marker RBMS3/c-Myc was an independent prognostic indicator of overall survival (p = 0.001; HR 3.470; IC 95 %, 1.652-7.290), and c-Myc was a prognostic indicator of disease-free survival (p < 0.001; HR 3.182; IC 95 %, 1.961-8.920). RBMS3 is a novel TSG in LSCC, and its downregulation facilitates development and progression of LSCC. Therefore, it is suggested that Rbms3 as a tumor marker may play an important role in diagnosis of LSCC.}, keywords = {Adult Aged Biomarkers, Tumor/*genetics Blotting, Western Carcinoma, Squamous Cell/*genetics/mortality/pathology Female Genes, Tumor Suppressor Humans Immunohistochemistry Kaplan-Meier Estimate Lung Neoplasms/*genetics/mortality/pathology Male Middle Aged Prognosis Proportional Hazards Models Proto-Oncogene Proteins c-myc/biosynthesis/genetics RNA-Binding Proteins/biosynthesis/*genetics Reverse Transcriptase Polymerase Chain Reaction Trans-Activators/biosynthesis/*genetics beta Catenin/biosynthesis/genetics}, ISSN = {1357-0560}, DOI = {10.1007/s12032-014-0459-9}, year = {2015}, type = {Journal Article} } @article{ author = {Liu, Y. and DiStasio, M. and Su, Graham and Asashima, Hiromitsu and Enninful, Archibald and Qin, Xiaoyu and Deng, Yanxiang and Nam, J. and Gao, F. and Bordignon, P. and Cassano, M. and Tomayko, M. and Xu, M. and Halene, S. and Craft, J. E. and Hafler, D. and Fan, R.}, title = {High-plex protein and whole transcriptome co-mapping at cellular resolution with spatial CITE-seq}, journal = {Nat Biotechnol}, volume = {41}, number = {10}, pages = {1405-1409}, note = {1546-1696 Liu, Yang DiStasio, Marcello}, abstract = {In this study, we extended co-indexing of transcriptomes and epitopes (CITE) to the spatial dimension and demonstrated high-plex protein and whole transcriptome co-mapping. We profiled 189 proteins and whole transcriptome in multiple mouse tissue types with spatial CITE sequencing and then further applied the method to measure 273 proteins and transcriptome in human tissues, revealing spatially distinct germinal center reactions in tonsil and early immune activation in skin at the Coronavirus Disease 2019 mRNA vaccine injection site.}, keywords = {Animals Mice Humans *Transcriptome/genetics Epitopes RNA, Messenger *Single-Cell Analysis Gene Expression Profiling/methods}, ISSN = {1087-0156 (Print) 1087-0156}, DOI = {10.1038/s41587-023-01676-0}, year = {2023}, type = {Journal Article} } @article{ author = {Lv, S. L. and Zhou, X. and Li, Y. J. and Luo, L. Y. and Huang, D. Q.}, title = {RBMS3, a downstream target of AMPK, Exerts Inhibitory Effects on Invasion and Metastasis of Lung Cancer}, journal = {J Cancer}, volume = {14}, number = {15}, pages = {2784-2797}, note = {1837-9664 Lv, Shi-Lin Zhou, Xu Li, Yuan-Jun Luo, Ling-Yu Huang, De-Qiang Journal Article Australia J Cancer. 2023 Sep 4;14(15):2784-2797. doi: 10.7150/jca.86572. eCollection 2023.}, abstract = {Background: Lung cancer is a highly malignant disease, primarily due to its propensity for metastasis. AMP-activated protein kinase (AMPK), the principal downstream effector of Liver Kinase B1 (LKB1), orchestrates a broad spectrum of molecular targets, thereby constraining tumor invasion and metastasis. In parallel, the RNA-binding protein RBMS3 (RNA-binding motif, single-stranded-interacting protein 3) plays a pivotal role in the epithelial-mesenchymal transition (EMT), a pivotal process in tumorigenesis. Therefore, our research aims to clarify the important role of RBMS3 as a mediator in the LKB1/AMPK inhibition of tumor invasion and metastasis. Methods: We investigated the expression and correlation between RBMS3 and LKB1 in lung cancer tissues utilizing immunohistochemistry and TCGA-LUAD data, respectively. The relationship between RBMS3 and clinical pathological features and prognosis of lung cancer was also analyzed. The functions of RBMS3 in lung cancer cell proliferation, invasion, and migration were investigated in real-time in vitro. Additionally, we investigated the effects of AMPK agonists and inhibitors to explore the mediating role of RBMS3 in AMPK-induced inhibition of lung cancer invasion and migration. Results: The IHC and TCGA data both revealed low expression of RBMS3 in lung cancer. Moreover, we found that low expression of RBMS3 was positively associated with lung cancer's histological grade, clinical stage, and N stage. Additionally, low RBMS3 expression was associated with poor overall survival. Cox regression analysis revealed that RBMS3 was an independent prognostic factor for lung cancer patients. In vitro experiments verified that RBMS3 inhibited lung cancer cell proliferation, invasion, and migration. Furthermore, our findings suggested that RBMS3 played an essential role in mediating AMPK's inhibitory effect on lung cancer invasion and migration. Conclusion: Our study highlights a novel mechanism by which LKB1/AMPK pathway activation inhibits lung cancer invasion and metastasis by promoting RBMS3 expression, offering insights in developing innovative lung cancer therapies.}, keywords = {Ampk Rbms3 invasion and metastasis lung cancer}, ISSN = {1837-9664 (Print) 1837-9664}, DOI = {10.7150/jca.86572}, year = {2023}, type = {Journal Article} } @article{ author = {Mattei, F. and Andreone, S. and Marone, G. and Gambardella, A. R. and Loffredo, S. and Varricchi, G. and Schiavoni, G.}, title = {Eosinophils in the Tumor Microenvironment}, journal = {Adv Exp Med Biol}, volume = {1273}, pages = {1-28}, note = {Mattei, Fabrizio Andreone, Sara Marone, Giancarlo Gambardella, Adriana Rosa Loffredo, Stefania Varricchi, Gilda Schiavoni, Giovanna Journal Article Review United States Adv Exp Med Biol. 2020;1273:1-28. doi: 10.1007/978-3-030-49270-0_1.}, abstract = {Eosinophils are rare blood-circulating and tissue-infiltrating immune cells studied for decades in the context of allergic diseases and parasitic infections. Eosinophils can secrete a wide array of soluble mediators and effector molecules, with potential immunoregulatory activities in the tumor microenvironment (TME). These findings imply that these cells may play a role in cancer immunity. Despite these cells were known to infiltrate tumors since many years ago, their role in TME is gaining attention only recently. In this chapter, we will review the main biological functions of eosinophils that can be relevant within the TME. We will discuss how these cells may undergo phenotypic changes acquiring pro- or antitumoricidal properties according to the surrounding stimuli. Moreover, we will analyze canonical (i.e., degranulation) and unconventional mechanisms (i.e., DNA traps, exosome secretion) employed by eosinophils in inflammatory contexts, which can be relevant for tumor immune responses. Finally, we will review the available preclinical models that could be employed for the study of the role in vivo of eosinophils in cancer.}, keywords = {Eosinophils/*cytology/immunology Humans Inflammation/immunology Neoplasms/*immunology Tumor Microenvironment/*immunology}, ISSN = {0065-2598 (Print) 0065-2598}, DOI = {10.1007/978-3-030-49270-0_1}, year = {2020}, type = {Journal Article} } @article{ author = {Polacino, P. S. and Pinchuk, L. M. and Sidorenko, S. P. and Clark, E. A.}, title = {Immunodeficiency virus cDNA synthesis in resting T lymphocytes is regulated by T cell activation signals and dendritic cells}, journal = {J Med Primatol}, volume = {25}, number = {3}, pages = {201-9}, note = {Polacino, P S Pinchuk, L M Sidorenko, S P Clark, E A GM37905/GM/NIGMS NIH HHS/United States RR00166/RR/NCRR NIH HHS/United States Journal Article Research Support, U.S. Gov't, P.H.S. Denmark J Med Primatol. 1996 Jun;25(3):201-9. doi: 10.1111/j.1600-0684.1996.tb00017.x.}, abstract = {We explored the relationship between T cell activation signals and dendritic cells (DC) in the replication cycle of immunodeficiency viruses. First we analyzed the effect of two cell cycle inhibitors (mimosine and aphidicolin) on SIV reverse transcription, circularization, and integration in macaque resting T cells stimulated with anti-CD3 mAb at the time of infection. The formation of SIV LTR circles was blocked by the G1 inhibitor mimosine. The G1/S inhibitor aphidicolin neither affected circularization nor integration of SIV DNA. Therefore, the induction of SIV LTR circle production is likely to be mediated by signaling events normally regulating the G1 to S transition. We further characterized DC-dependent HIV-expression in human T cells. We examined the effect of ligating two novel receptors, IPO-3 and Bgp95, on DC-dependent HIV-1 expression. Activation of DCs through IPO-3 receptors, and to a lesser extent Bgp95 ligation, upregulated HIV spread in these cells. The mechanisms by which IPO-3 vs. Bgp95 increase HIV-1 levels appear to be different. In particular, IPO-3 ligation alone on T cells also increased HIV-1 levels. Activation of T cells via defined surface receptors or with DCs is required for establishing HIV/SIV cDNA synthesis in T cells.}, keywords = {Animals Aphidicolin/pharmacology Cell Cycle/drug effects DNA Replication DNA, Complementary/biosynthesis DNA, Viral/*biosynthesis Dendritic Cells/*immunology Flow Cytometry HIV/isolation & purification/pathogenicity/*physiology Humans *Lymphocyte Activation Macaca mulatta Mimosine/pharmacology Polymerase Chain Reaction RNA-Directed DNA Polymerase/metabolism Repetitive Sequences, Nucleic Acid Signal Transduction Simian Immunodeficiency Virus/genetics/*physiology T-Lymphocytes/cytology/*immunology/*virology Virus Integration *Virus Replication}, ISSN = {0047-2565 (Print) 0047-2565}, DOI = {10.1111/j.1600-0684.1996.tb00017.x}, year = {1996}, type = {Journal Article} } @article{ author = {Qin, H. and Ni, H. and Liu, Y. and Yuan, Y. and Xi, T.}, title = {RNA-binding proteins in tumor progression}, journal = {J Hematol Oncol}, volume = {13}, number = {1}, pages = {90}, note = {1756-8722 Qin, Hai Ni, Haiwei Liu, Yichen Yuan, Yaqin Xi, Tao}, abstract = {RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.}, ISSN = {1756-8722}, DOI = {10.1186/s13045-020-00927-w}, year = {2020}, type = {Journal Article} } @article{ author = {Quek, C. and Pratapa, A. and Bai, X. and Al-Eryani, G. and Pires da Silva, I. and Mayer, A. and Bartonicek, N. and Harvey, K. and Maher, N. G. and Conway, J. W. and Kasalo, R. J. and Ben Cheikh, B. and Braubach, O. and Palendira, U. and Saw, R. P. M. and Stretch, J. R. and Shannon, K. F. and Menzies, A. M. and Scolyer, R. A. and Long, G. V. and Swarbrick, A. and Wilmott, J. S.}, title = {Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy}, journal = {Cell Rep}, volume = {43}, number = {7}, pages = {114392}, note = {2211-1247 Quek, Camelia Pratapa, Aditya Bai, Xinyu Al-Eryani, Ghamdan Pires da Silva, Inês Mayer, Aaron Bartonicek, Nenad Harvey, Kate Maher, Nigel G Conway, Jordan W Kasalo, Rebecca J Ben Cheikh, Bassem Braubach, Oliver Palendira, Umaimainthan Saw, Robyn P M Stretch, Jonathan R Shannon, Kerwin F Menzies, Alexander M Scolyer, Richard A Long, Georgina V Swarbrick, Alexander Wilmott, James S Journal Article Research Support, Non-U.S. Gov't United States Cell Rep. 2024 Jul 23;43(7):114392. doi: 10.1016/j.celrep.2024.114392. Epub 2024 Jun 29.}, abstract = {Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an "immune-striving" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF(+)SPARCL1(+) and CENPF(+) melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention.}, keywords = {*Tumor Microenvironment/immunology Humans *Single-Cell Analysis *Immunotherapy/methods *Drug Resistance, Neoplasm *Melanoma/therapy/immunology/pathology Multiomics}, DOI = {10.1016/j.celrep.2024.114392}, year = {2024}, type = {Journal Article} } @article{ author = {Reck, M. and Remon, J. and Hellmann, M. D.}, title = {First-Line Immunotherapy for Non-Small-Cell Lung Cancer}, journal = {J Clin Oncol}, volume = {40}, number = {6}, pages = {586-597}, note = {1527-7755 Reck, Martin Remon, Jordi}, abstract = {For patients with metastatic non-small-cell lung cancer (mNSCLC), the last decade has been characterized by critical progress that has contributed to substantially improved survival. In particular, the development of specific antibodies against the programmed death (PD-1) receptor, programmed death-ligand 1 (PD-L1), and the cytotoxic T-lymphocyte-associated protein 4 receptor in the therapeutic strategy of mNSCLC either in first- or in second-line settings have led to unprecedented prolonged survival for a proportion of these patients. Although clinical development of immune checkpoint inhibitors with anti-PD-1 and PD-L1 therapies largely began as monotherapy in the second-line setting, the more recent progress has shifted toward combination approaches in first-line settings as well as the integration of immunotherapy into the clinical paradigm in earlier stages. Today, with the exception of mNSCLC harboring targetable oncogenes, nearly all patients with mNSCLC receive PD-1 or PD-L1 therapy in first-line settings. Here we report the current status of first-line immunotherapy in mNSCLC together with current challenges in selecting the best immunotherapeutic approach for the individual patient.}, ISSN = {0732-183x}, DOI = {10.1200/jco.21.01497}, year = {2022}, type = {Journal Article} } @article{ author = {Ruan, X. and Liu, Y. and Wang, P. and Liu, L. and Ma, T. and Xue, Y. and Dong, W. and Zhao, Y. and E, T. and Lin, H. and Wang, D. and Yang, C. and Song, J. and Liu, J. and Deng, M. and An, P. and Lin, Y. and Yang, J. and Cui, Z. and Cao, Y. and Liu, X.}, title = {RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme}, journal = {Cell Death Dis}, volume = {14}, number = {11}, pages = {745}, note = {2041-4889 Ruan, Xuelei Liu, Yunhui Wang, Ping Liu, Libo Ma, Teng Xue, Yixue}, abstract = {Glioblastoma multiforme (GBM) is a highly vascularized malignant cancer of the central nervous system, and the presence of vasculogenic mimicry (VM) severely limits the effectiveness of anti-vascular therapy. In this study, we identified downregulated circHECTD1, which acted as a key VM-suppressed factor in GBM. circHECTD1 elevation significantly inhibited cell proliferation, migration, invasion and tube-like structure formation in GBM. RIP assay was used to demonstrate that the flanking intron sequence of circHECTD1 can be specifically bound by RBMS3, thereby inducing circHECTD1 formation to regulate VM formation in GBM. circHECTD1 was confirmed to possess a strong protein-encoding capacity and the encoded functional peptide 463aa was identified by LC-MS/MS. Both circHECTD1 and 463aa significantly inhibited GBM VM formation in vivo and in vitro. Analysis of the 463aa protein sequence revealed that it contained a ubiquitination-related domain and promoted NR2F1 degradation by regulating the ubiquitination of the NR2F1 at K396. ChIP assay verified that NR2F1 could directly bind to the promoter region of MMP2, MMP9 and VE-cadherin, transcriptionally promoting the expression of VM-related proteins, which in turn enhanced VM formation in GBM. In summary, we clarified a novel pathway for RBMS3-induced circHECTD1 encoding functional peptide 463aa to mediate the ubiquitination of NR2F1, which inhibited VM formation in GBM. This study aimed to reveal new mechanisms of GBM progression in order to provide novel approaches and strategies for the anti-vascular therapy of GBM. The schematic illustration showed the inhibitory effect of circHECTD1-463aa in the VM formation in GBM.}, DOI = {10.1038/s41419-023-06269-y}, year = {2023}, type = {Journal Article} } @article{ author = {Ruiz de Galarreta, M. and Bresnahan, E. and Molina-Sánchez, P. and Lindblad, K. E. and Maier, B. and Sia, D. and Puigvehi, M. and Miguela, V. and Casanova-Acebes, M. and Dhainaut, M. and Villacorta-Martin, C. and Singhi, A. D. and Moghe, A. and von Felden, J. and Tal Grinspan, L. and Wang, S. and Kamphorst, A. O. and Monga, S. P. and Brown, B. D. and Villanueva, A. and Llovet, J. M. and Merad, M. and Lujambio, A.}, title = {β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma}, journal = {Cancer Discov}, volume = {9}, number = {8}, pages = {1124-1141}, note = {2159-8290 Ruiz de Galarreta, Marina Bresnahan, Erin Molina-Sánchez, Pedro Lindblad, Katherine E Maier, Barbara Sia, Daniela Puigvehi, Marc}, abstract = {PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti-PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53 (-/-) HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53 (-/-) HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin-driven tumors were resistant to anti-PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti-PD-1 and could represent a novel biomarker for HCC patient exclusion. SIGNIFICANCE: Determinants of response to anti-PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti-PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion.See related commentary by Berraondo et al., p. 1003.This article is highlighted in the In This Issue feature, p. 983.}, ISSN = {2159-8274 (Print) 2159-8274}, DOI = {10.1158/2159-8290.cd-19-0074}, year = {2019}, type = {Journal Article} } @article{ author = {Shao, C. and Yang, B. and Zhao, L. and Wang, S. and Zhang, J. and Wang, K.}, title = {Tumor suppressor gene RBM5 delivered by attenuated Salmonella inhibits lung adenocarcinoma through diverse apoptotic signaling pathways}, journal = {World J Surg Oncol}, volume = {11}, pages = {123}, note = {1477-7819 Shao, Chen Yang, Baoxue Zhao, Lijing Wang, Song Zhang, Jie Wang, Ke Journal Article Research Support, Non-U.S. Gov't England World J Surg Oncol. 2013 May 31;11:123. doi: 10.1186/1477-7819-11-123.}, abstract = {BACKGROUND: RBM5 (RNA-binding motif protein 5, also named H37/LUCA-15) gene from chromosome 3p21.3 has been demonstrated to be a tumor suppressor. Current researches in vitro confirm that RBM5 can suppress the growth of lung adenocarcinoma cells by inducing apoptosis. There is still no effective model in vivo, however, that thoroughly investigates the effect and molecular mechanism of RBM5 on lung adenocarcinoma. METHOD: We established the transplanted tumor model on BALB/c nude mice using the A549 cell line. The mice were treated with the recombinant plasmids carried by attenuated Salmonella to induce the overexpression of RBM5 in tumor tissues. RBM5 overexpression was confirmed by immunohistochemistry staining. H&E staining was performed to observe the histological performance on plasmids-treated A549 xenografts. Apoptosis was assessed by TUNEL staining with a TUNEL detection kit. Apoptosis-regulated genes were detected by Western blot. RESULTS: We successful established the lung adenocarcinoma animal model in vivo. The growth of tumor xenografts was significantly retarded on the mice treated with pcDNA3.1-RBM5 carried by attenuated Salmonella compared to that on mice treated with pcDNA3.1. Overexpression of RBM5 enhanced the apoptosis in tumor xenografts. Furthermore, the expression of Bcl-2 protein was decreased significantly, while the expression of BAX, TNF-α, cleaved caspase-3, cleaved caspase-8, cleaved caspase-9 and cleaved PARP proteins was significantly increased in the pcDNA3.1-RBM5-treated mice as compared to that in the control mice. CONCLUSIONS: In this study, we established a novel animal model to determine RBM5 function in vivo, and concluded that RBM5 inhibited tumor growth in mice by inducing apoptosis. The study suggests that although RBM5's involvement in the death receptor-mediated apoptotic pathway is still to be investigated, RBM5-mediated growth suppression, at least in part, employs regulation of the mitochondrial apoptotic pathways.}, keywords = {Adenocarcinoma/metabolism/pathology/*prevention & control Animals *Apoptosis Blotting, Western Caspases/metabolism Cell Cycle Proteins/genetics/*metabolism Cell Proliferation DNA-Binding Proteins/genetics/*metabolism *Genetic Vectors Humans Immunoenzyme Techniques Lung Neoplasms/metabolism/pathology/*prevention & control Male Mice Mice, Inbred BALB C Mice, Nude Mitochondria/metabolism/pathology RNA-Binding Proteins/genetics/*metabolism Salmonella typhi/*genetics *Signal Transduction Tumor Necrosis Factor-alpha/metabolism Tumor Suppressor Proteins/genetics/*metabolism bcl-2-Associated X Protein/metabolism}, ISSN = {1477-7819}, DOI = {10.1186/1477-7819-11-123}, year = {2013}, type = {Journal Article} } @article{ author = {Siegel, R. L. and Miller, K. D. and Jemal, A.}, title = {Cancer statistics, 2020}, journal = {CA Cancer J Clin}, volume = {70}, number = {1}, pages = {7-30}, note = {1542-4863 Siegel, Rebecca L Miller, Kimberly D}, abstract = {Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.}, ISSN = {0007-9235}, DOI = {10.3322/caac.21590}, year = {2020}, type = {Journal Article} } @article{ author = {Siegel, R. L. and Miller, K. D. and Wagle, N. S. and Jemal, A.}, title = {Cancer statistics, 2023}, journal = {CA Cancer J Clin}, volume = {73}, number = {1}, pages = {17-48}, note = {1542-4863 Siegel, Rebecca L Orcid: 0000-0001-5247-8522 Miller, Kimberly D Orcid: 0000-0002-2609-2260 Wagle, Nikita Sandeep Orcid: 0000-0003-1337-483x Jemal, Ahmedin Journal Article United States CA Cancer J Clin. 2023 Jan;73(1):17-48. doi: 10.3322/caac.21763.}, abstract = {Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.}, keywords = {Male Humans Female United States/epidemiology Middle Aged Aged *Neoplasms/epidemiology Registries Incidence Racial Groups *Lung Neoplasms/epidemiology *Melanoma *Multiple Endocrine Neoplasia Type 1 cancer cases cancer statistics death rates mortality}, ISSN = {0007-9235}, DOI = {10.3322/caac.21763}, year = {2023}, type = {Journal Article} } @article{ author = {Stewart, D. J.}, title = {Wnt signaling pathway in non-small cell lung cancer}, journal = {J Natl Cancer Inst}, volume = {106}, number = {1}, pages = {djt356}, note = {1460-2105 Stewart, David J Journal Article Review United States J Natl Cancer Inst. 2014 Jan;106(1):djt356. doi: 10.1093/jnci/djt356. Epub 2013 Dec 5.}, abstract = {Wnt/β-catenin alterations are prominent in human malignancies. In non-small cell lung cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1, -2, -3, and -5a and of Wnt-pathway components Frizzled-8, Dishevelled, Porcupine, and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely, noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved prognosis in some series, possibly because of E-cadherin interactions. Downregulation of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and resected samples; may be associated with high stage, dedifferentiation, and poor prognosis; and has been reported for AXIN, sFRPs 1-5, WIF-1, Dkk-1, Dkk-3, HDPR1, RUNX3, APC, CDX2, DACT2, TMEM88, Chibby, NKD1, EMX2, ING4, and miR-487b. AXIN is also destabilized by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically, restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity. Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis, prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific β-catenin interactions and approaches to increase expression of downregulated Wnt inhibitors may be of particular interest.}, keywords = {Apoptosis Cadherins/metabolism Carcinoma, Non-Small-Cell Lung/*metabolism/*pathology Cell Line, Tumor Cell Proliferation DNA Methylation Down-Regulation *Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic Humans Lung Neoplasms/*metabolism/*pathology Neoplasm Staging Prognosis Wnt Proteins/metabolism *Wnt Signaling Pathway/drug effects beta Catenin/metabolism}, ISSN = {0027-8874}, DOI = {10.1093/jnci/djt356}, year = {2014}, type = {Journal Article} } @article{ author = {Tsunetsugu-Yokota, Y. and Akagawa, K. and Kimoto, H. and Suzuki, K. and Iwasaki, M. and Yasuda, S. and Häusser, G. and Hultgren, C. and Meyerhans, A. and Takemori, T.}, title = {Monocyte-derived cultured dendritic cells are susceptible to human immunodeficiency virus infection and transmit virus to resting T cells in the process of nominal antigen presentation}, journal = {J Virol}, volume = {69}, number = {7}, pages = {4544-7}, note = {1098-5514 Tsunetsugu-Yokota, Y Akagawa, K Kimoto, H Suzuki, K Iwasaki, M Yasuda, S Häusser, G Hultgren, C Meyerhans, A Takemori, T Journal Article Research Support, Non-U.S. Gov't United States J Virol. 1995 Jul;69(7):4544-7. doi: 10.1128/JVI.69.7.4544-4547.1995.}, abstract = {The susceptibility of monocyte-derived cultured dendritic cells (DCs) to human immunodeficiency virus (HIV) infection and their role in viral transmission in the immune response were studied in detail. We observed that highly purified cultured DCs were infected with the T-tropic Lai strain of HIV type 1 (HIV-1Lai) via the CD4 receptor, and this was followed by formation of the complete provirus as detected by PCR. HIV mRNAs were transcribed at only low levels, and virus production was undectable; however, the addition of the purified protein derivative antigen of tuberculin and of autologous resting T cells to HIV-1Lai-infected DCs but not to HIV-1Lai-infected macrophages led to massive HIV transmission and production. These data suggest that the interaction of infected DCs with T cells during the normal immune response could play an important role in the activation and expansion of HIV.}, keywords = {*Antigen Presentation Base Sequence Cell Communication Cells, Cultured Dendritic Cells/*virology HIV Core Protein p24/biosynthesis HIV-1/*physiology Humans Molecular Sequence Data Monocytes/*virology RNA, Messenger/analysis T-Lymphocytes/*virology}, ISSN = {0022-538X (Print) 0022-538x}, DOI = {10.1128/jvi.69.7.4544-4547.1995}, year = {1995}, type = {Journal Article} } @article{ author = {Vaishnavi, A. and Juan, J. and Jacob, M. and Stehn, C. and Gardner, E. E. and Scherzer, M. T. and Schuman, S. and Van Veen, J. E. and Murphy, B. and Hackett, C. S. and Dupuy, A. J. and Chmura, S. A. and van der Weyden, L. and Newberg, J. Y. and Liu, A. and Mann, K. and Rust, A. G. and Weiss, W. A. and Kinsey, C. G. and Adams, D. J. and Grossmann, A. and Mann, M. B. and McMahon, M.}, title = {Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis}, journal = {Cancer Res}, volume = {82}, number = {22}, pages = {4261-4273}, note = {1538-7445 Vaishnavi, Aria Orcid: 0000-0002-7814-3234 Juan, Joseph Orcid: 0000-0002-2949-8338 Jacob, Maebh Orcid: 0000-0002-3687-2033 Stehn, Christopher Orcid: 0000-0003-2911-1954 Gardner, Eric E Orcid: 0000-0002-1552-2675 Scherzer, Michael T Orcid: 0000-0001-9092-0529 Schuman, Sophia Orcid: 0000-0003-0385-9016 Van Veen, J Edward Orcid: 0000-0003-1798-3210 Murphy, Brandon Orcid: 0000-0002-5692-3643 Hackett, Christopher S Orcid: 0000-0003-4692-2433 Dupuy, Adam J Orcid: 0000-0002-8561-4911 Chmura, Steven A Orcid: 0000-0001-9857-2506 van der Weyden, Louise Orcid: 0000-0002-0645-1879 Newberg, Justin Y Orcid: 0000-0002-3764-4956 Liu, Annie Orcid: 0000-0001-5135-6144 Mann, Karen Orcid: 0000-0002-7161-4523 Rust, Alistair G Orcid: 0000-0001-7287-192x Weiss, William A Orcid: 0000-0003-2230-9132 Kinsey, Conan G Orcid: 0000-0001-5614-8627 Adams, David J Orcid: 0000-0001-9490-0306 Grossmann, Allie Orcid: 0000-0002-7665-1403 Mann, Michael B Orcid: 0000-0002-7515-6515 McMahon, Martin Orcid: 0000-0003-2812-1042 R01 CA131261/CA/NCI NIH HHS/United States K99 CA246084/CA/NCI NIH HHS/United States P30 CA042014/CA/NCI NIH HHS/United States F32 CA228267/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Cancer Res. 2022 Nov 15;82(22):4261-4273. doi: 10.1158/0008-5472.CAN-21-3214.}, abstract = {Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression of Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/β-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of The Cancer Genome Atlas patient samples revealed that chromosome 3p24, which encompasses RBMS3, is frequently lost in non-small cell lung cancer and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest that RBMS3 silencing may contribute to malignant NSCLC progression. SIGNIFICANCE: Loss of RBMS3 cooperates with BRAFV600E to induce lung tumorigenesis, providing a deeper understanding of the molecular mechanisms underlying mutant BRAF-driven lung cancer and potential strategies to more effectively target this disease.}, keywords = {Animals Humans Mice *Adenocarcinoma of Lung/genetics *Carcinoma, Non-Small-Cell Lung/genetics Cell Proliferation Lung/pathology *Lung Neoplasms/genetics Mutagenesis *Proto-Oncogene Proteins B-raf/metabolism *RNA-Binding Proteins/genetics *Trans-Activators/metabolism Wnt Signaling Pathway *Carcinogenesis/genetics}, ISSN = {0008-5472 (Print) 0008-5472}, DOI = {10.1158/0008-5472.Can-21-3214}, year = {2022}, type = {Journal Article} } @article{ author = {Wang, H. and Cao, Y. and Zhang, L. and Zhao, Q. and Li, S. and Li, D.}, title = {RBM15 Drives Breast Cancer Cell Progression and Immune Escape via m6A-Dependent Stabilization of KPNA2 mRNA}, journal = {Clin Breast Cancer}, volume = {25}, number = {2}, pages = {96-107}, note = {1938-0666 Wang, Hu Cao, Yu Zhang, Li Zhao, Qian Li, Shuangjian Li, Dan Journal Article United States Clin Breast Cancer. 2025 Feb;25(2):96-107. doi: 10.1016/j.clbc.2024.09.006. Epub 2024 Sep 26.}, abstract = {BACKGROUND: Breast cancer is the most frequently diagnosed cancer among women worldwide with high morbidity and mortality. Previous studies have indicated that RNA-binding motif protein-15 (RBM15), an N6-methyladenosine (m6A) writer, is implicated in the growth of breast cancer cells. Herein, we aimed to explore the function and detailed mechanism of RBM15 in breast cancer. METHODS: In this research, UALCAN databases were applied to analyze the expression of RBM15 or Karyopherin-2 alpha (KPNA2) in BRCA. RBM15 and KPNA2 mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR) assay. RBM15, KPNA2, and Programmed cell death ligand 1 (PD-L1) protein levels were measured using western blot. Cell proliferation, migration, and invasion were assessed using 5-ethynyl-2'-deoxyuridine (EdU) and Transwell assays. The biological role of RBM15 on breast cancer tumor growth was verified using the xenograft tumor model in vivo. Effects of breast cancer cells on the proliferation and apoptosis of CD8(+) T cells were analyzed using flow cytometry. Interaction between RBM15 and KPNA2 was validated using methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assays. RESULTS: RBM15 and KPNA2 were highly expressed in breast cancer tissues and cell lines. Furthermore, RBM15 silencing might suppress breast cancer cell proliferation, migration, invasion, and lymphocyte immunity in vitro, as well as block tumor growth in vivo. At the molecular level, RBM15 might improve the stability and expression of KPNA2 mRNA via m6A methylation. CONCLUSION: RBM15 might contribute to the malignant progression and immune escape of breast cancer cells partly by modulating the stability of KPNA2 mRNA, providing a promising therapeutic target for breast cancer.}, keywords = {Humans Female *Breast Neoplasms/pathology/genetics/immunology *RNA-Binding Proteins/metabolism/genetics *alpha Karyopherins/genetics/metabolism Animals Mice *Cell Proliferation *RNA, Messenger/genetics/metabolism *Gene Expression Regulation, Neoplastic Tumor Escape/genetics Cell Line, Tumor Cell Movement Adenosine/analogs & derivatives/metabolism RNA Stability Disease Progression Apoptosis Mice, Nude}, ISSN = {1526-8209}, DOI = {10.1016/j.clbc.2024.09.006}, year = {2025}, type = {Journal Article} } @article{ author = {Wang, J. J. and Liu, X. Y. and Du, W. and Liu, J. Q. and Sun, B. and Zheng, Y. P.}, title = {RBMS3 delays disc degeneration by inhibiting Wnt/β-catenin signaling pathway}, journal = {Eur Rev Med Pharmacol Sci}, volume = {24}, number = {2}, pages = {499-507}, note = {2284-0729 Wang, J-J Liu, X-Y Du, W Liu, J-Q Sun, B Zheng, Y-P Journal Article Italy Eur Rev Med Pharmacol Sci. 2020 Jan;24(2):499-507. doi: 10.26355/eurrev_202001_20023.}, abstract = {OBJECTIVE: To study the effect of RBMS3 on nucleus pulposus cells and its effect on the Wnt/β-catenin signaling pathway. PATIENTS AND METHODS: We measured the expression of RBMS3 in human nucleus pulposus tissues with different degrees of degeneration. Recombinant human IL-1β is used to stimulate the degeneration of human nucleus pulposus cells. We used Wnt/β-catenin signaling pathway inhibitors and cell transfection to study the effect of RBMS3 on nucleus pulposus cells and its mechanism. RESULTS: RBMS3 was less expressed in the nucleus pulposus tissue of people with higher degeneration degree. IL-1β reduced the expression of RBMS3 in nucleus pulposus cells. Overexpression of RBMS3 can promote the proliferation of nucleus pulposus cells and reduce the apoptosis and inflammation of cells. In addition, RBMS3 can reduce the expression of β-catenin and c-myc in nucleus pulposus cells, and inhibit the activity of the Wnt/β-catenin signaling pathway. CONCLUSIONS: RBMS3 inhibits the Wnt/β-catenin signaling pathway, improves the proliferation ability of nucleus pulposus cells, inhibits their apoptosis and inflammation, and thus delays the degeneration of the intervertebral disc.}, keywords = {Cells, Cultured Humans Intervertebral Disc/metabolism/pathology Intervertebral Disc Degeneration/*metabolism/pathology/*prevention & control Lumbar Vertebrae Nucleus Pulposus/metabolism/pathology RNA-Binding Proteins/*biosynthesis Trans-Activators/*biosynthesis Wnt Signaling Pathway/*physiology beta Catenin/*antagonists & inhibitors/metabolism}, ISSN = {1128-3602}, DOI = {10.26355/eurrev_202001_20023}, year = {2020}, type = {Journal Article} } @article{ author = {Wang, M. and Fu, X. and Wang, W. and Zhang, Y. and Jiang, Z. and Gu, Y. and Chu, M. and Shao, Y. and Li, S.}, title = {Comprehensive bioinformatics analysis confirms RBMS3 as the central candidate biological target for ovarian cancer}, journal = {Med Eng Phys}, volume = {110}, pages = {103883}, note = {1873-4030 Wang, Mei Fu, Xiangjun Wang, Wei Zhang, Yuan Jiang, Zhenyi Gu, Yan Chu, Menglong Shao, Yanting Li, Shuqin Journal Article Research Support, Non-U.S. Gov't England Med Eng Phys. 2022 Dec;110:103883. doi: 10.1016/j.medengphy.2022.103883. Epub 2022 Aug 31.}, abstract = {Ovarian cancer (OC) is one of the most lethal malignancies in the female reproductive system. To find genes related to cancer progression targeting specific biological factors for targeted therapy, bioinformatics technology has been widely used. To screen the prognostic gene markers of OC by bioinformatics and explore their potential molecular biological mechanisms. Two data sets related to OC, GSE54388, and GSE119056, were rooted in the open comprehensive gene expression database (GEO). To correct the background of the data, standardize and screen differentially expressed genes (DEGs) using the R software limma package. The selected DEGs were enriched by Gene Ontology (GO) and through DAVID online database. Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis and protein-protein interaction network (PPI-network) map were constructed by STRING online database and Cytoscape software. Combined with the TCGA database, univariate and multivariate COX regression were used to screen prognostic genes. QRT-PCR was used to verify DEGs in clinical tissue samples. Eventually, the function of RBMS3 on the viability, migration, invasion, and apoptosis of OC cells was tested through functional experiments in vitro. 352 common DEGs were screened from GSE54388 and GSE119056 data sets. Survival analysis showed that MEIS2, TSTA3, CNTN1, RBMS3, and TRA2A were considered to be connected with the prognosis of OC. We discover that the expression level of RBMS3 was positively connected with the overall survival (OS) rate of sufferers with OC. The level of RBMS3 in OC tissues was markedly lower than that in neighboring structures and the outcomes of the GEPIA database were consistent with those of the qRT-PCR experiment. Through gene transfection technology it was found that overexpression of RBMS3 in OC cells substantially suppressed the vitality, migration, and invasion of OC cells and raised the rates of apoptosis in the OC cells. In this experiment, we distinguish 5 genes that may participate in the prognosis of OC and showed the key genes and pathways related to OC. It is speculated that RBMS3, a tumor suppressor gene, can be applied as a potential biological marker for the treatment of OC, gene expression summary, and prognosis.}, keywords = {Humans Female Gene Expression Profiling *Ovarian Neoplasms/genetics/metabolism/pathology Computational Biology Signal Transduction Databases, Factual Trans-Activators/genetics/metabolism RNA-Binding Proteins/genetics/metabolism Carbohydrate Epimerases/metabolism *Ketone Oxidoreductases/metabolism Bioinformatics analysis Molecular biology technology Ovarian cancer RBMS3 conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.}, ISSN = {1350-4533}, DOI = {10.1016/j.medengphy.2022.103883}, year = {2022}, type = {Journal Article} } @article{ author = {Wang, S. W. and Gao, C. and Zheng, Y. M. and Yi, L. and Lu, J. C. and Huang, X. Y. and Cai, J. B. and Zhang, P. F. and Cui, Y. H. and Ke, A. W.}, title = {Current applications and future perspective of CRISPR/Cas9 gene editing in cancer}, journal = {Mol Cancer}, volume = {21}, number = {1}, pages = {57}, note = {1476-4598 Wang, Si-Wei Gao, Chao Zheng, Yi-Min Yi, Li Lu, Jia-Cheng Huang, Xiao-Yong Cai, Jia-Bin Zhang, Peng-Fei Cui, Yue-Hong Ke, Ai-Wu Journal Article Research Support, Non-U.S. Gov't Review England Mol Cancer. 2022 Feb 21;21(1):57. doi: 10.1186/s12943-022-01518-8.}, abstract = {Clustered regularly interspaced short palindromic repeats (CRISPR) system provides adaptive immunity against plasmids and phages in prokaryotes. This system inspires the development of a powerful genome engineering tool, the CRISPR/CRISPR-associated nuclease 9 (CRISPR/Cas9) genome editing system. Due to its high efficiency and precision, the CRISPR/Cas9 technique has been employed to explore the functions of cancer-related genes, establish tumor-bearing animal models and probe drug targets, vastly increasing our understanding of cancer genomics. Here, we review current status of CRISPR/Cas9 gene editing technology in oncological research. We first explain the basic principles of CRISPR/Cas9 gene editing and introduce several new CRISPR-based gene editing modes. We next detail the rapid progress of CRISPR screening in revealing tumorigenesis, metastasis, and drug resistance mechanisms. In addition, we introduce CRISPR/Cas9 system delivery vectors and finally demonstrate the potential of CRISPR/Cas9 engineering to enhance the effect of adoptive T cell therapy (ACT) and reduce adverse reactions.}, keywords = {Animals CRISPR-Cas Systems *Gene Editing/methods Genomics Humans *Neoplasms/genetics/therapy Oncogenes}, ISSN = {1476-4598}, DOI = {10.1186/s12943-022-01518-8}, year = {2022}, type = {Journal Article} } @article{ author = {Wang, Z. and Wang, N. and Liu, P. and Xie, X.}, title = {AMPK and Cancer}, journal = {Exp Suppl}, volume = {107}, pages = {203-226}, note = {Wang, Zhiyu Wang, Neng Liu, Pengxi Xie, Xiaoming Journal Article Research Support, Non-U.S. Gov't Review Switzerland Exp Suppl. 2016;107:203-226. doi: 10.1007/978-3-319-43589-3_9.}, abstract = {This chapter focuses on the role of AMPK as a stress-response molecule with an emphasis on its duplex implication in carcinogenesis and cancer drug resistance. AMPK is closely correlated to the tumor-suppressive functions of LKB1 and P53, consequently modulating the activity of cellular survival signaling such as mTOR and Akt, leading to cell growth inhibition and cell cycle arrest. On the contrary, AMPK is tightly involved in cancer drug resistance via interacting with multiple known mechanisms of chemoresistance such as ABCG2 expression, autophagy induction, and cancer stem cells enrichment. Targeting AMPK has become a novel strategy for cancer prevention and treatment.}, keywords = {AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases/*genetics/metabolism Antineoplastic Agents/therapeutic use Autophagy/drug effects/genetics Carcinogenesis/*genetics/metabolism/pathology Drug Resistance, Neoplasm/genetics *Gene Expression Regulation, Neoplastic Humans Molecular Targeted Therapy Neoplasms/drug therapy/enzymology/*genetics/pathology Neoplastic Stem Cells/*enzymology/pathology Phosphorylation/drug effects Protein Serine-Threonine Kinases/genetics/metabolism Protein Subunits/genetics/metabolism Proto-Oncogene Proteins c-akt/genetics/metabolism Signal Transduction TOR Serine-Threonine Kinases/genetics/metabolism Tumor Suppressor Protein p53/genetics/metabolism}, ISSN = {1664-431X (Print) 1664-431x}, DOI = {10.1007/978-3-319-43589-3_9}, year = {2016}, type = {Journal Article} } @article{ author = {Wu, G. and Cao, L. and Zhu, J. and Tan, Z. and Tang, M. and Li, Z. and Hu, Y. and Yu, R. and Zhang, S. and Song, L. and Li, J.}, title = {Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling}, journal = {Clin Cancer Res}, volume = {25}, number = {3}, pages = {1022-1035}, note = {1557-3265 Wu, Geyan Cao, Lixue Zhu, Jinrong Tan, Zhanyao Tang, Miaoling Li, Ziwen Hu, Yameng Yu, Ruyuan Zhang, Shuxia Song, Libing Li, Jun Journal Article Research Support, Non-U.S. Gov't United States Clin Cancer Res. 2019 Feb 1;25(3):1022-1035. doi: 10.1158/1078-0432.CCR-18-2554. Epub 2018 Oct 2.}, abstract = {PURPOSE: The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/β-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/β-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. RESULTS: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited β-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/β-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. CONCLUSIONS: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.}, keywords = {Animals Antineoplastic Combined Chemotherapy Protocols/pharmacology Bridged Bicyclo Compounds, Heterocyclic/administration & dosage Carcinoma, Ovarian Epithelial/drug therapy/*genetics/pathology Cisplatin/administration & dosage Drug Resistance, Neoplasm/*genetics Female *Gene Deletion Gene Expression Regulation, Neoplastic/drug effects Humans Kaplan-Meier Estimate Mice, Inbred NOD Mice, Knockout Mice, SCID MicroRNAs/*genetics Peptide Fragments/*genetics Pyrimidinones/administration & dosage RNA-Binding Proteins/*genetics/metabolism Sialoglycoproteins/*genetics Signal Transduction/drug effects/genetics Trans-Activators/*genetics/metabolism Xenograft Model Antitumor Assays beta Catenin/*genetics}, ISSN = {1078-0432}, DOI = {10.1158/1078-0432.ccr-18-2554}, year = {2019}, type = {Journal Article} } @article{ author = {Yan, Y. and Ren, L. and Liu, Y. and Liu, L.}, title = {Long non-coding RNA CRNDE as potential biomarkers facilitate inflammation and apoptosis in alcoholic liver disease}, journal = {Aging (Albany NY)}, volume = {13}, number = {19}, pages = {23233-23244}, note = {1945-4589 Yan, Yifeng Ren, Liang Liu, Yan Liu, Liang Journal Article Research Support, Non-U.S. Gov't United States Aging (Albany NY). 2021 Oct 11;13(19):23233-23244. doi: 10.18632/aging.203614. Epub 2021 Oct 11.}, abstract = {Due to persistent inconsistencies in the expression data of alcoholic liver disease (ALD), it is necessary to turn to "pre-laboratory" comprehensive analysis in order to accelerate effective precision medicine and transformation research. We screened pseudogene-derived lncRNA associated with ALD by comparative analysis of 2 independent data sets from GEO. Three lncRNAs (CRNDE, RBMS3-AS3, and LINC01088) were demonstrated to be potentially useful diagnostic markers in ALD. Among them, the expression of CRNDE is up-regulated. Therefore, we focus on CRNDE. Kyoto Encyclopedia of Genes and Genomes pathways analysis revealed higher CRNDE can activate MAPK signaling pathway, apoptosis, wnt signaling pathway, and hematopoietic cell lineage. Next, we established ALD animal model and verified the success of the modeling. The result showed ALD tissues in mice had significantly higher CRNDE levels than normal tissues. Moreover, the increase of IL-6 in the serum of mice in the low-dose group is related to the activation of inflammatory factors after alcohol-induced liver injury. In addition, alcohol can induce apoptosis, and knockdown of CRNDE can reduce apoptosis. Our integrated expression profiling identified CRNDE independently associated with ALD. CRNDE can facilitate inflammation and apoptosis in ALD.}, keywords = {Animals Apoptosis/*genetics Biomarkers/blood/metabolism Humans Inflammation/*genetics Interleukin-6/blood *Liver Diseases, Alcoholic/genetics/metabolism/pathology Male Mice Mice, Inbred BALB C RNA, Long Noncoding/*genetics/metabolism}, ISSN = {1945-4589}, DOI = {10.18632/aging.203614}, year = {2021}, type = {Journal Article} } @article{ author = {Yang, Y. and Quan, L. and Ling, Y.}, title = {RBMS3 Inhibits the Proliferation and Metastasis of Breast Cancer Cells}, journal = {Oncol Res}, volume = {26}, number = {1}, pages = {9-15}, note = {1555-3906 Yang, Yuan Quan, Lingli Ling, Ye Journal Article United States Oncol Res. 2018 Jan 19;26(1):9-15. doi: 10.3727/096504017X14871200709504. Epub 2017 Apr 12.}, abstract = {RBMS3, a gene encoding a glycine-rich RNA-binding protein, belongs to the family of c-Myc gene single-strand binding proteins (MSSP). Recently, several reports have provided evidence that RBMS3 was deregulated in a diverse range of solid tumors and played a critical role in tumor progression. However, it remains unclear whether RBMS3 inhibits the progression of human breast cancer. Thus, the aim of this study was to investigate the role of RBMS3 in breast cancer and explore the underlying mechanism in breast cancer progression. Our results showed, for the first time, that the expression of RBMS3 at both the mRNA and protein levels was significantly downregulated in human breast cancer tissues and cell lines. In addition, RBMS3 overexpression dramatically suppressed the proliferation, migration, and invasion of breast cancer cells in vitro and attenuated tumor growth in vivo. Furthermore, we observed that RBMS3 greatly inhibited the protein expression of β-catenin, cyclin D1, and c-Myc in breast cancer cells. In summary, we have shown that RBMS3 inhibited the proliferation and tumorigenesis of breast cancer cells, at least in part, through inactivation of the Wnt/β-catenin signaling pathway. Thus, RBMS3 may be a potential treatment target for breast cancer.}, keywords = {Animals Breast Neoplasms/metabolism/*pathology Cell Line, Tumor Cell Movement/physiology Cell Proliferation/*physiology Female Gene Expression Regulation, Neoplastic/physiology Heterografts Humans Mice Mice, Inbred BALB C Mice, Nude Neoplasm Invasiveness/*pathology RNA-Binding Proteins/*metabolism Trans-Activators/*metabolism Wnt Signaling Pathway/physiology}, ISSN = {0965-0407 (Print) 0965-0407}, DOI = {10.3727/096504017x14871200709504}, year = {2018}, type = {Journal Article} } @article{ author = {Yin, T. and Zhang, Y. and Zhao, Y. and Zhang, X. and Han, S. and Wang, Y. and Yang, B.}, title = {Tumor suppressor function of RBMS3 overexpression in EOC associated with immune cell infiltration}, journal = {Heliyon}, volume = {10}, number = {9}, pages = {e30603}, note = {2405-8440 Yin, Tian Zhang, Ying Zhao, Yue Zhang, Xinyi Han, Shuqi Wang, Yixiao Yang, Bo Journal Article England Heliyon. 2024 May 1;10(9):e30603. doi: 10.1016/j.heliyon.2024.e30603. eCollection 2024 May 15.}, abstract = {OBJECTIVES: Epithelial ovarian cancer (EOC) is considered to be a prevalent female malignancy with both high incidence and mortality. It is reported that RNA-binding protein 3 (RBMS3) executives a tumor suppressor function in different cancers. This investigation was designed to examine the expression of RBMS3 in epithelial ovarian cancer, the effects on EOC cells, and its connection to immune cells that infiltrate tumors in the EOC microenvironment. METHODS: The expression levels of RBMS3 in EOC tissues as well as their correlations with immune cell infiltration and clinical outcome were examined using bioinformatics approaches. Western blotting as well as immunohistochemistry were carried out to determine the protein levels in EOC tissues. In addition, qRT-PCR was employed to look at the expression of the mRNA. The role of RBMS3 in EOC cells was investigated, and an RBMS3 lentiviral vector was developed. The effects of RBMS3 on subcutaneous tumor development, the proliferation protein Ki-67, the tumor angiogenesis indicator CD31, and its function in controlling the tumor immune microenvironment were evaluated by in vivo tests. RESULTS: There was a considerable decrease in RBMS3 expression in EOC tissues, which was linked to a poor prognosis for patients and the infiltration of multiple immune cell. Given immunohistochemical studies, tissues with increased RBMS3 expression had decreased markers of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages, whereas M1 macrophage markers were elevated. RBMS3 appears to suppress the capabilities of proliferating, invading, and migrating in EOC cells according to in vitro tests, whereas tumors overexpressing RBMS3 developed more slowly in syngeneic mouse models. The overexpression of RBMS3 led to a decline in the levels of Ki-67 protein and CD31. Additionally, it showed a negatively correlation with markers of regulatory T cell, myeloid-derived suppressor cell, and M2 macrophage but a positive correlation with markers of M1 macrophage. CONCLUSIONS: The findings revealed that elevated RBMS3 expression plays a tumor suppressor role in EOC and was connected to patient survival in EOC. The studies conducted in vitro and in vivo demonstrated a link between RBMS3 expression and the infiltration of certain immune cells, indicating a function for RBMS3 in the immunosuppressive tumor microenvironment and its promising efficiency as a novel target for immunotherapy against EOC.}, ISSN = {2405-8440 (Print) 2405-8440}, DOI = {10.1016/j.heliyon.2024.e30603}, year = {2024}, type = {Journal Article} } @article{ author = {Yuan, Y. and Adam, A.}, title = {Recent Advancements in the Mechanisms Underlying Resistance to PD-1/PD-L1 Blockade Immunotherapy}, journal = {Cancers (Basel)}, volume = {13}, number = {4}, pages = {663}, note = {2072-6694 Yuan, Yu Adam, Abdalla}, abstract = {Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.}, ISSN = {2072-6694 (Print) 2072-6694}, DOI = {10.3390/cancers13040663}, year = {2021}, type = {Journal Article} } @article{ author = {Zhang, D. and Rubio Rodríguez-Kirby, L. A. and Lin, Y. and Song, M. and Wang, L. and Wang, L. and Kanatani, S. and Jimenez-Beristain, T. and Dang, Y. and Zhong, M. and Kukanja, P. and Wang, S. and Chen, X. L. and Gao, F. and Wang, D. and Xu, H. and Lou, X. and Liu, Y. and Chen, J. and Sestan, N. and Uhlén, P. and Kriegstein, A. and Zhao, H. and Castelo-Branco, G. and Fan, R.}, title = {Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping}, journal = {bioRxiv}, note = {2692-8205 Zhang, Di Rubio Rodríguez-Kirby, Leslie A Lin, Yingxin Song, Mengyi Wang, Li}, abstract = {The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.}, ISSN = {2692-8205}, DOI = {10.1101/2024.07.28.605493}, year = {2024}, type = {Journal Article} } @article{ author = {Zhang, J. and Zhang, W. and Yang, L. and Zhao, W. and Liu, Z. and Wang, E. and Wang, J.}, title = {Phytochemical gallic acid alleviates nonalcoholic fatty liver disease via AMPK-ACC-PPARa axis through dual regulation of lipid metabolism and mitochondrial function}, journal = {Phytomedicine}, volume = {109}, pages = {154589}, note = {1618-095x Zhang, Jiaxin Zhang, Wenxin Yang, Li Zhao, Wenjing Liu, Zuojia Wang, Erkang Wang, Jin Journal Article Germany Phytomedicine. 2023 Jan;109:154589. doi: 10.1016/j.phymed.2022.154589. Epub 2022 Dec 10.}, abstract = {BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) usually includes NAFL called simple hepatosteatosis and nonalcoholic steatohepatitis (NASH) called more steatohepatitis. The latter is a leading pathogenic promotor of hepatocellular carcinoma (HCC). Phytochemical gallic acid (GA) has been proved to exert positive efficacy in HCC in our work, but it remains unclear whether its hepatoprotective effect attributes to the controlled transition from simple steatosis to steatohepatitis. PURPOSE: This work aims to provide mechanistic evidence that the therapeutic application of GA in NAFLD is indispensable for GA-meliorated NASH progression. METHODS: The high-fat diet (HFD)-fed mice and palmitic acid (PA) and oleic acid (OA)-treated hepatocytes were used collectively in this study. Bioinformatic analysis, clinical subjects, RNA-Seq, molecular docking, and confirmatory experiments were performed comprehensively to uncover the pathological link between the AMPK-ACC-PPARα axis and the treatment of NAFLD. RESULTS: By analyzing the clinical subjects and GEO database, we find a close link between the activation of AMPK-ACC-PPARα axis and the progression of NAFLD in human fatty liver. Subsequent assays show that GA exhibits pharmacological activation of AMPK, reprogramming lipid metabolism, and reversing mitochondrial function in cellular and murine fatty liver models. AMPK activation conferred substantial protection against murine NASH and fibrosis in the context of HFD-induced NAFLD. In contrast, silencing AMPK badly aggravates lipid deposition in hepatocytes, boosting NASH and NAFLD-associated HCC progression. The in silico docking, in vitro surface plasmon resonance and in vivo cellular thermal shift assay collectively reveal that GA directly interacts with AMPKα, which inactivates the ACC-PPARα axis signaling. Notably, GA repairs the liver damage, lipotoxicity, and mitochondrial respiratory capacity caused by excessive mtROS, while showing minimal effects in other major organs in mice. CONCLUSION: Our work identifies GA as an important suppressor of NAFLD-HCC progression, and underscores the AMPK-ACC-PPARα signal axis as a potential therapeutic target for NAFLD treatment.}, keywords = {Humans Mice Animals *Non-alcoholic Fatty Liver Disease/metabolism *Carcinoma, Hepatocellular/pathology AMP-Activated Protein Kinases/metabolism Gallic Acid/pharmacology Lipid Metabolism PPAR alpha/metabolism Molecular Docking Simulation *Liver Neoplasms/pathology Mitochondria/metabolism Liver/metabolism Mice, Inbred C57BL}, ISSN = {0944-7113}, DOI = {10.1016/j.phymed.2022.154589}, year = {2023}, type = {Journal Article} } @article{ author = {Zhang, S. and Bao, Y. and Shen, X. and Pan, Y. and Sun, Y. and Xiao, M. and Chen, K. and Wei, H. and Zuo, J. and Saffen, D. and Zong, W. X. and Sun, Y. and Wang, Z. and Wang, Y.}, title = {RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H}, journal = {EBioMedicine}, volume = {61}, pages = {103067}, note = {2352-3964 Zhang, Sirui Bao, Yufang Shen, Xianfeng Pan, Yunjian Sun, Yue Xiao, Man Chen, Kexuan Wei, Huanhuan Zuo, Ji Saffen, David Zong, Wei-Xing Sun, Yihua Wang, Zefeng Wang, Yongbo R01 CA129536/CA/NCI NIH HHS/United States R01 CA224550/CA/NCI NIH HHS/United States R01 CA232246/CA/NCI NIH HHS/United States Journal Article Netherlands EBioMedicine. 2020 Nov;61:103067. doi: 10.1016/j.ebiom.2020.103067. Epub 2020 Oct 23.}, abstract = {BACKGROUND: RNA splicing defects are emerging molecular hallmarks of cancer. The gene encoding splicing factor RNA binding motif protein 10 (RBM10) has been found frequently mutated in various types of cancer, particularly lung adenocarcinoma (LUAD), but how RBM10 affects cancer pathogenesis remains to be determined. Moreover, the functional roles and clinical significance of RBM10 mutation-associated splicing events in LUAD are largely unknown. METHODS: RBM10 mutations and their functional impacts were examined in LUAD patients from a Chinese patient cohort and The Cancer Genome Atlas (TCGA). Alternative splicing (AS) changes induced by RBM10 mutations in LUAD were identified by RNA sequencing and correlated with patient survival. Functions of RBM10 and the splice variants of eukaryotic translation initiation factor 4H containing or lacking exon 5 (EIF4H-L and EIF4H-S respectively) in LUAD development and progression were examined by cellular phenotypic assays and xenograft tumour formation. FINDINGS: RBM10 mutations in LUAD generally lead to loss-of-function and cause extensive alterations in splicing events that can serve as prognostic predictors. RBM10 suppresses LUADprogression largely by regulating alternative splicing of EIF4H exon 5. Loss of RBM10 in LUAD enhances the expression of EIF4H-L in LUAD. EIF4H-L, but not EIF4H-S, is critical for LUAD cell proliferation, survival and tumourigenesis. INTERPRETATION: Our study demonstrates a new molecular mechanism underlying RBM10 suppressive functions in lung cancer and the therapeutic value of RBM10-regulated AS events, providing important mechanistic and translational insights into splicing defects in cancer.}, keywords = {*Alternative Splicing Animals Cell Line, Tumor Cell Proliferation/genetics Disease Progression Eukaryotic Initiation Factors/*genetics *Gene Expression Regulation, Neoplastic Humans Immunohistochemistry Loss of Function Mutation Lung Neoplasms/*genetics/*metabolism/pathology Mice Mutation Phenotype RNA-Binding Proteins/*metabolism Xenograft Model Antitumor Assays}, ISSN = {2352-3964}, DOI = {10.1016/j.ebiom.2020.103067}, year = {2020}, type = {Journal Article} } @article{ author = {Zhang, T. and Wu, Y. and Fang, Z. and Yan, Q. and Zhang, S. and Sun, R. and Khaliq, J. and Li, Y.}, title = {Low expression of RBMS3 and SFRP1 are associated with poor prognosis in patients with gastric cancer}, journal = {Am J Cancer Res}, volume = {6}, number = {11}, pages = {2679-2689}, note = {2156-6976 Zhang, Tao Wu, Youliang Fang, Zheng Yan, Qiang Zhang, Shangxin Sun, Ruochuan Khaliq, Junaid Li, Yongxiang Journal Article United States Am J Cancer Res. 2016 Nov 1;6(11):2679-2689. eCollection 2016.}, abstract = {RNA binding motif, single stranded interacting protein 3 (RBMS3) has been reported as a tumor suppressor gene (TSG) in some squamous carcinoma. However, its expression levels and clinical significance in gastric cancer (GC) remains unclear. Secreted frizzled-related protein 1 (SFRP1) plays a role of tumor suppressor in many cancers by inhibiting Wnt/β-catenin pathway. Nevertheless, its expression levels and clinical significance in GC are in dispute. In this study, quantitative real-time PCR and Western Blot were used to measure the mRNA and protein level of RBMS3 and SFRP1 in 23 fresh GC and corresponding normal tissues. Immunohistochemistry assay was performed to further measure the protein level of RBMS3 and SFRP1 on population-based tissue microarrays consisting of 172 GC cases. We found that 69.57% (16/23) and 73.91% (17/23) GC tissues expressed remarkably lower RBMS3 than the matched normal tissues respectively in mRNA and protein levels. Similarly, 78.26% (18/23) and 65.22% (15/23) GC tissues expressed lower SFRP1 than the matched normal tissues respectively in mRNA and protein levels. Additionally, the low expression of RBMS3 and SFRP1 protein were all significantly related to the poor histological grades and prognosis (all P<0.05). In multivariate analysis, RBMS3 and SFRP1 co-expression status was independent prognostic factor for GC patients. Finally, the positive correlation between expression levels (mRNA and protein) of RBMS3 and SFRP1 was observed. Overall, RBMS3 and SFRP1 are both aberrantly low expressed in GC, and RBMS3 and SFRP1 co-expression is a potential prognosis predictor of GC.}, keywords = {Gastric cancer Rbms3 Sfrp1 biomarker co-expression prognosis}, ISSN = {2156-6976 (Print) 2156-6976}, year = {2016}, type = {Journal Article} } @article{ author = {Zhou, C. and Chen, G. and Huang, Y. and Zhou, J. and Lin, L. and Feng, J. and Wang, Z. and Shu, Y. and Shi, J. and Hu, Y. and Wang, Q. and Cheng, Y. and Wu, F. and Chen, J. and Lin, X. and Wang, Y. and Huang, J. and Cui, J. and Cao, L. and Liu, Y. and Zhang, Y. and Pan, Y. and Zhao, J. and Wang, L. and Chang, J. and Chen, Q. and Ren, X. and Zhang, W. and Fan, Y. and He, Z. and Fang, J. and Gu, K. and Dong, X. and Jin, F. and Gao, H. and An, G. and Ding, C. and Jiang, X. and Xiong, J. and Zhou, X. and Hu, S. and Lu, P. and Liu, A. and Guo, S. and Huang, J. and Zhu, C. and Zhao, J. and Gao, B. and Chen, Y. and Hu, C. and Zhang, J. and Zhang, H. and Zhao, H. and Wang, Z. and Ma, X. and Shi, W.}, title = {Camrelizumab plus carboplatin and pemetrexed as first-line therapy for advanced non-squamous non-small-cell lung cancer: 5-year outcomes of the CameL randomized phase 3 study}, journal = {J Immunother Cancer}, volume = {12}, number = {11}, note = {2051-1426 Zhou, Caicun Chen, Gongyan Huang, Yunchao Zhou, Jianying Lin, LiZhu Feng, Jifeng Wang, Zhehai Shu, Yongqian}, abstract = {BACKGROUND: CameL phase 3 study demonstrated the superiority of camrelizumab plus chemotherapy over chemotherapy alone for progression-free survival in patients with previously untreated advanced non-squamous non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations. Here, we present the 5-year outcomes. METHODS: Patients were randomized (1:1) and received 4-6 cycles of camrelizumab plus carboplatin and pemetrexed (n=205) or carboplatin and pemetrexed (n=207) every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only. Crossover from chemotherapy group to camrelizumab monotherapy was permitted after disease progression. RESULTS: Median time from randomization to data cut-off was 65.2 months (range, 59.7-72.2). HR for overall survival (OS) was 0.74 (95% CI 0.58 to 0.93; one-sided p=0.0043), and was 0.62 (95% CI 0.49 to 0.79; one-sided p<0.0001) after adjustment for crossover. Five-year OS rates were 31.2% (95% CI 24.7% to 37.9%) with camrelizumab plus chemotherapy versus 19.3% (95% CI 13.9% to 25.3%) with chemotherapy alone. Among the 33 patients who completed 2 years of camrelizumab, 5-year OS rate was 84.3% (95% CI 66.4% to 93.2%), and 5-year duration of response rate was 46.5% (95% CI 24.9% to 65.6%) in the 32 responders. No new safety signals were noted. CONCLUSIONS: Camrelizumab plus carboplatin and pemetrexed as first-line therapy continued to demonstrate long-term OS benefit over carboplatin and pemetrexed, with manageable toxicity. Patients who completed 2 years of camrelizumab had enduring response and impressive OS. Current 5-year updated analysis further supports camrelizumab plus carboplatin and pemetrexed as a standard-of-care for previously untreated advanced non-squamous NSCLC without EGFR/ALK alterations. TRIAL REGISTRATION NUMBER: NCT03134872.}, ISSN = {2051-1426}, DOI = {10.1136/jitc-2024-009240}, year = {2024}, type = {Journal Article} } @article{ author = {Zhou, Y. and Liang, Z. and Xia, Y. and Li, S. and Liang, J. and Hu, Z. and Tang, C. and Zhao, Q. and Gong, Q. and Ouyang, Y.}, title = {Disruption of RBMS3 suppresses PD-L1 and enhances antitumor immune activities and therapeutic effects of auranofin against triple-negative breast cancer}, journal = {Chem Biol Interact}, volume = {369}, pages = {110260}, note = {1872-7786 Zhou, Yuting Liang, Zhongping Xia, Yingjie Li, Shuai Liang, Jiali Hu, Zhixiang Tang, Chengbin Zhao, Qing Gong, Qing Ouyang, Yongchang Journal Article Ireland Chem Biol Interact. 2023 Jan 5;369:110260. doi: 10.1016/j.cbi.2022.110260. Epub 2022 Nov 19.}, abstract = {Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction exerts a vital role in tumor-associated immune evasion. While strategies disrupting PD-1/PD-L1 axis have shown clinical benefits in various cancers, the limited response rate prompts us to investigate the complex mechanisms underlying the molecular regulation of PD-L1. Here, we identify the RNA binding protein RBMS3 as a crucial PD-L1 regulator in triple-negative breast cancer (TNBC). Correlation analysis shows that Rbms3 significantly correlates with immunosuppressive CD274, Rbms1, NT5E and ENTPD1. RBMS3 protein binds to CD274 mRNA specifically in TNBC cells to increase PD-L1 levels. Mechanistically, RBMS3 stabilizes CD274 mRNA by interacting with its 3'UTR, which represents as an intrinsic cancer cell mechanism for driving PL-D1 upregulation in TNBC. RBMS3 depletion not only destabilizes the mRNA stability and protein expression of PD-L1, but also suppresses the migratory abilities of TNBC MDA-MB-231 cells. Importantly, combination of RBMS3 ablation with auranofin (AUF), an FDA-approved thioredoxin reductase inhibitor, facilitates anti-tumor T-cell immunity in vivo and improves AUF-mediated anti-cancer effect. Taken together, our findings reveal RBMS3 as a key post-transcriptional regulator of PD-L1 and how they contribute to immune escape in TNBC, which could lead to novel combinatorial therapeutic strategies to enhance the efficacy of cancer immunotherapy.}, keywords = {Humans *Triple Negative Breast Neoplasms/drug therapy/pathology Auranofin/pharmacology/therapeutic use Programmed Cell Death 1 Receptor/metabolism/therapeutic use B7-H1 Antigen/genetics Antibodies RNA, Messenger/genetics Cell Line, Tumor DNA-Binding Proteins/metabolism RNA-Binding Proteins Trans-Activators/metabolism}, ISSN = {0009-2797}, DOI = {10.1016/j.cbi.2022.110260}, year = {2023}, type = {Journal Article} } @article{ author = {Zhu, L. and Xi, P. W. and Li, X. X. and Sun, X. and Zhou, W. B. and Xia, T. S. and Shi, L. and Hu, Y. and Ding, Q. and Wei, J. F.}, title = {The RNA binding protein RBMS3 inhibits the metastasis of breast cancer by regulating Twist1 expression}, journal = {J Exp Clin Cancer Res}, volume = {38}, number = {1}, pages = {105}, note = {1756-9966 Zhu, Lei Xi, Pei-Wen Li, Xiao-Xia Sun, Xi Zhou, Wen-Bin Xia, Tian-Song Shi, Liang Hu, Yue Ding, Qiang Wei, Ji-Fu 81572595/National Natural Science Foundation of China/ 81602336/Young Scientists Fund/ 81802644/Young Scientists Fund/ Journal Article England J Exp Clin Cancer Res. 2019 Feb 28;38(1):105. doi: 10.1186/s13046-019-1111-5.}, abstract = {BACKGROUND: Metastasis remains the biggest obstacle for breast cancer treatment. Therefore, identification of specific biomarker of metastasis is very necessary. The RNA binding protein 3 (RBMS3) acts as a tumor suppressor in various cancers. Whereas, its role and underlying molecular mechanism in breast cancer is far from elucidated. METHODS: Quantitative real-time PCR and western blots were carried out to determine the expression of RBMS3 in breast cancer cells and tissues. Transwell and in vivo metastasis assay were conducted to investigate the effects of RBMS3 on migration, invasion and metastasis of breast cancer cells. Transcriptome sequencing was applied to screen out the differential gene expression affected by RBMS3. RNA immunoprecipitation assay combined with luciferase reporter assay were performed to explore the direct correlation between RBMS3 and Twist1 mRNA. RESULTS: RBMS3 was downregulated in breast cancer and ectopic expression of RBMS3 contributed to inhibition of cell migration, invasion in vitro and lung metastasis in vivo. Furthermore, RBMS3 negatively regulated Twsit1 expression via directly binding to 3'-UTR of Twist1 mRNA, and thereby decreased Twist1-induced expression of matrix metalloproteinase 2 (MMP2). Additionally, Twist1-induced cell migration, invasion and lung metastasis could be reversed by the upregulation of RBMS3. CONCLUSIONS: In summary, our study revealed a novel mechanism of the RBMS3/Twsit1/MMP2 axis in the regulation of invasion and metastasis of breast cancer, which may become a potential molecular marker for breast cancer treatment.}, keywords = {Animals Breast Neoplasms/metabolism/*pathology Cell Movement/physiology Female Gene Expression Regulation, Neoplastic/*physiology Heterografts Humans Matrix Metalloproteinase 2/biosynthesis Mice, Inbred BALB C Neoplasm Invasiveness/pathology Nuclear Proteins/*biosynthesis RNA-Binding Proteins/*metabolism Trans-Activators/*metabolism Twist-Related Protein 1/*biosynthesis Breast cancer Mmp2 Metastasis Rbms3 Twist1 mRNA stability Core Facility of Nanjing Medical University (Nanjing, China), was approved by Institutional Animal Care and Use Committee for animal use. All samples were used according to the ethical guidelines of the 1975 Declaration of Helsinki. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.}, ISSN = {0392-9078 (Print) 0392-9078}, DOI = {10.1186/s13046-019-1111-5}, year = {2019}, type = {Journal Article} }