LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary
| Autor: | 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 |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 4, Pp 811-828 (2020) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|