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

引用

World Journal of Gastroenterology 2023年第28期29卷 4416-4432页

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 Department of Biochemistry Faculty of MedicineKhon Kaen UniversityKhon Kaen 40002Thailand Center for Translational Medicine Faculty of MedicineKhon Kaen UniversityKhon Kaen 40002Thailand Cholangiocarcinoma Research Institute Khon Kaen UniversityKhon Kaen 40002Thailand Department of Pathology Faculty of MedicineKhon Kaen UniversityKhon Kaen 40002Thailand Department of Anatomy Faculty of MedicineKhon Kaen UniversityKhon Kaen 40002Thailand Department of Forensic Medicine Faculty of MedicineKhon Kaen UniversityKhon Kaen 40002Thailand Graduate Institute of Metabolism and Obesity Sciences Taipei Medical UniversityTaipei 11031Taiwan Division of Hematopoiesis Joint Research Center for Human Retrovirus InfectionKumamoto UniversityKumamoto 860-0811Japan Human Genome Sequencing Center Department of Human and Molecular GeneticsBaylor College of MedicineHoustonTX 77030United States Michael E.DeBakey Department of Surgery Baylor College of MedicineHoustonTX 77030United States

BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying *** studies showed thatγ-aminobutyric acid(GABA)B2 receptor(GABBR2)was upregulated in CCA cells cultured in high glucose(HG)*** of GABA receptors in CCA progression have also been studied,but their association with DM and hyperglycemia in CCA remains *** To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic *** 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,***2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western *** and localization of GABBR2 in CCA cells were determined using ***2 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 *** of baclofen,a GABA-B receptor agonist,on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic ***-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 *** GABBR2 expression in CCA cells was induced by HG in a dose-and time-dependent *** 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<0.0

关键词： Baclofen Cholangiocarcinoma Diabetes mellitus Drug repurposing Hyperglycemia Gamma-aminobutyric acid

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