LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary
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...
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Format: | Article |
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Elsevier
2020-01-01
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Series: | Cellular and Molecular Gastroenterology and Hepatology |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20300989 |
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doaj-60459d05658743638ce517d4ed82da20 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yin-Xin Zhu Chi Han Li Guolin Li Huiyi Feng Tian Xia Chi Hin Wong Frederic Khe Cheong Fung Joanna Hung-Man Tong Ka-Fai To Rufu Chen Yangchao Chen |
spellingShingle |
Yin-Xin Zhu Chi Han Li Guolin Li Huiyi Feng Tian Xia Chi Hin Wong Frederic Khe Cheong Fung Joanna Hung-Man Tong Ka-Fai To Rufu Chen Yangchao Chen LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary Cellular and Molecular Gastroenterology and Hepatology Pancreatic Cancer Gemcitabine Oncostatin M Receptor SP1 Signaling |
author_facet |
Yin-Xin Zhu Chi Han Li Guolin Li Huiyi Feng Tian Xia Chi Hin Wong Frederic Khe Cheong Fung Joanna Hung-Man Tong Ka-Fai To Rufu Chen Yangchao Chen |
author_sort |
Yin-Xin Zhu |
title |
LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary |
title_short |
LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary |
title_full |
LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary |
title_fullStr |
LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary |
title_full_unstemmed |
LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummary |
title_sort |
llgl1 regulates gemcitabine resistance by modulating the erk-sp1-osmr pathway in pancreatic ductal adenocarcinomasummary |
publisher |
Elsevier |
series |
Cellular and Molecular Gastroenterology and Hepatology |
issn |
2352-345X |
publishDate |
2020-01-01 |
description |
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). |
topic |
Pancreatic Cancer Gemcitabine Oncostatin M Receptor SP1 Signaling |
url |
http://www.sciencedirect.com/science/article/pii/S2352345X20300989 |
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doaj-60459d05658743638ce517d4ed82da202020-11-25T03:41:14ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-01104811828LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal AdenocarcinomaSummaryYin-Xin Zhu0Chi Han Li1Guolin Li2Huiyi Feng3Tian Xia4Chi Hin Wong5Frederic Khe Cheong Fung6Joanna Hung-Man Tong7Ka-Fai To8Rufu Chen9Yangchao Chen10School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong KongDepartment of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, ChinaSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong KongDepartment of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong KongDepartment of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong KongGuangdong Provincial People's Hospital, Guangzhou, Guangdong Province, China; Rufu Chen, Department of Hepatobiliary Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China; Correspondence Address correspondence to: Yangchao Chen, PhD, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong. fax: (852) 26035123.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).http://www.sciencedirect.com/science/article/pii/S2352345X20300989Pancreatic CancerGemcitabineOncostatin M ReceptorSP1 Signaling |