LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary
| العنوان: | LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary |
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| المؤلفون: | Yangchao Chen, Tian Xia, Guolin Li, Frederic Khe Cheong Fung, Ka Fai To, Joanna H.M. Tong, Chi Han Li, Yin-Xin Zhu, Chi Hin Wong, Huiyi Feng, Rufu Chen |
| المصدر: | Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 4, Pp 811-828 (2020) Cellular and Molecular Gastroenterology and Hepatology |
| بيانات النشر: | Elsevier, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, MAPK/ERK pathway, OSMR, oncostatin M receptor, ERK2, extracellular signal-regulated kinase 2, PDAC, pancreatic ductal adenocarcinoma, IC50, median inhibitory concentration, Deoxycytidine, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 0302 clinical medicine, RNA interference, Medicine, SP1 Signaling, Extracellular Signal-Regulated MAP Kinases, TGF, transforming growth factor, Original Research, Aged, 80 and over, Oncostatin M Receptor beta Subunit, Gene knockdown, Kinase, Gastroenterology, Oncostatin M receptor, Middle Aged, Sp1, specificity protein 1, Oncostatin M Receptor, ChIP, chromatin immunoprecipitation, HPDE, human pancreatic ductal epithelial, RNAi, RNA interference, hENT1, human equilibrative nucleoside transporter 1, Female, 030211 gastroenterology & hepatology, siLLGL1, small interfering lethal giant larvae homolog 1, EMT, epithelial-mesenchymal transition, IHC, immunohistochemistry, Carcinoma, Pancreatic Ductal, medicine.drug, Adult, Sp1 Transcription Factor, Young Adult, cDNA, complementary DNA, 03 medical and health sciences, Pancreatic Cancer, Cell Line, Tumor, SWH, Salvador/Warts/Hippo, Pancreatic cancer, Humans, Gene silencing, LLGL1, lethal giant larvae homolog 1, lcsh:RC799-869, Aged, Pol II, RNA polymerase II, Hepatology, business.industry, Lgl, lethal giant larvae, medicine.disease, CSC, cancer stem cell, Gemcitabine, qRT-PCR, quantitative reverse-transcription polymerase chain reaction, Pancreatic Neoplasms, Cytoskeletal Proteins, 030104 developmental biology, OSM, oncostatin M, Drug Resistance, Neoplasm, siRNA, small interfering RNA, Cancer research, lcsh:Diseases of the digestive system. Gastroenterology, Dlg, discs large protein, Transcriptome, business |
| الوصف: | Background & Aims Gemcitabine resistance is rapidly acquired by pancreatic ductal adenocarcinoma (PDAC) patients. Novel approaches that predict the gemcitabine response of patients and enhance gemcitabine chemosensitivity are important to improve patient survival. We aimed to identify genes as novel biomarkers to predict the gemcitabine response and the therapeutic targets to attenuate chemoresistance in PDAC cells. Methods Genome-wide RNA interference screening was conducted to identify genes that regulated gemcitabine chemoresistance. A cell proliferation assay and a tumor formation assay were conducted to study the role of lethal giant larvae homolog 1 (LLGL1) in gemcitabine chemoresistance. Levels of LLGL1 and its regulating targets were measured by immunohistochemical staining in tumor tissues obtained from patients who received gemcitabine as a single therapeutic agent. A gene-expression microarray was conducted to identify the targets regulated by LLGL1. Results Silencing of LLGL1 markedly reduced the gemcitabine chemosensitivity in PDAC cells. Patients had significantly shorter survival (6 months) if they bore tumors expressing low LLGL1 level than tumors with high LLGL1 level (20 months) (hazard ratio, 0.1567; 95% CI, 0.05966–0.4117). Loss of LLGL1 promoted cytokine receptor oncostatin M receptor (OSMR) expression in PDAC cells that led to gemcitabine resistance, while knockdown of OSMR effectively rescued the chemoresistance phenotype. The LLGL1-OSMR regulatory pathway showed great clinical importance because low LLGL1 and high OSMR expressions were observed frequently in PDAC tissues. Silencing of LLGL1 induced phosphorylation of extracellular signal-regulated kinase 2 and specificity protein 1 (Sp1), promoted Sp1 (pThr453) binding at the OSMR promoter, and enhanced OSMR transcription. Conclusions LLGL1 possessed a tumor-suppressor role as an inhibitor of chemoresistance by regulating OSMR–extracellular signal-regulated kinase 2/Sp1 signaling. The data sets generated and analyzed during the current study are available in the Gene Expression Omnibus repository (ID: GSE64681). Graphical abstract |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::522e00f260ff434833ed2e958f307cb5Test http://www.sciencedirect.com/science/article/pii/S2352345X20300989Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....522e00f260ff434833ed2e958f307cb5 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |