γ-aminobutyric acid B2 receptor:A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus  

作　　者：Charupong Saengboonmee Supannika Sorin Sakkarn Sangkhamanon Surang Chomphoo Somsiri Indramanee Wunchana Seubwai Kanyarat Thithuan Ching-Feng Chiu Seiji Okada Marie-Claude Gingras Sopit Wongkham 

机构地区：[1]Department of Biochemistry,Faculty of Medicine,Khon Kaen University,Khon Kaen 40002,Thailand [2]Center for Translational Medicine,Faculty of Medicine,Khon Kaen University,Khon Kaen 40002,Thailand [3]Cholangiocarcinoma Research Institute,Khon Kaen University,Khon Kaen 40002,Thailand [4]Department of Pathology,Faculty of Medicine,Khon Kaen University,Khon Kaen 40002,Thailand [5]Department of Anatomy,Faculty of Medicine,Khon Kaen University,Khon Kaen 40002,Thailand [6]Department of Forensic Medicine,Faculty of Medicine,Khon Kaen University,Khon Kaen 40002,Thailand [7]Graduate Institute of Metabolism and Obesity Sciences,Taipei Medical University,Taipei 11031,Taiwan [8]Division of Hematopoiesis,Joint Research Center for Human Retrovirus Infection,Kumamoto University,Kumamoto 860-0811,Japan [9]Human Genome Sequencing Center,Department of Human and Molecular Genetics,Baylor College of Medicine,Houston,TX 77030,United States [10]Michael E.DeBakey Department of Surgery,Baylor College of Medicine,Houston,TX 77030,United States

出　　处：《World Journal of Gastroenterology》2023年第28期4416-4432,共17页世界胃肠病学杂志（英文版）

基　　金：the Research Grant for Young Talented Scholars,National Research Council of Thailand,No.N41A640108.

摘　　要：BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying mechanisms.Previous studies showed thatγ-aminobutyric acid(GABA)B2 receptor(GABBR2)was upregulated in CCA cells cultured in high glucose(HG)conditions.Roles of GABA receptors in CCA progression have also been studied,but their association with DM and hyperglycemia in CCA remains unclarified.AIM To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.METHODS CCA cells,KKU-055 and KKU-213A,were cultured in Dulbecco Modified Eagle’s Medium supplemented with 5.6 mmol/L(normal glucose,NG)or 25 mmol/L(HG)glucose and assigned as NG and HG cells,respectively.GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot.Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence.GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry,and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis.Effects of baclofen,a GABA-B receptor agonist,on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays.Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment,and the candidate signaling molecules were validated using the public transcriptomic data and western blot.RESULTS GABBR2 expression in CCA cells was induced by HG in a dose-and time-dependent manner.CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia(P<0.01).High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors(P<0.05).HG cells of both tested CCA cell lines wer

关 键 词：BACLOFEN CHOLANGIOCARCINOMA Diabetes mellitus Drug repurposing HYPERGLYCEMIA Gamma-aminobutyric acid 

分 类 号：R735.8[医药卫生—肿瘤]