title: High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation.
abstract: Epidemiological studies have indicated diabetes mellitus (DM) as a risk of cholangiocarcinoma (CCA), however, the effects and mechanisms of high glucose on progression of CCA remain unclear. This study reports for the first time of the enhancing effects of high glucose on aggressive phenotypes of CCA cells via STAT3 activation. CCA cells cultured in high glucose media exerted significantly higher rates of cell proliferation, adhesion, migration and invasion than those cultured in normal glucose. The phosphokinase array revealed STAT3 as the dominant signal activated in response to high glucose. Increased nuclear STAT3, p-STAT3 and its downstream target proteins, cyclin D1, vimentin and MMP2, were shown to be underling mechanisms of high glucose stimulation. The link of high glucose and STAT3 activation was confirmed in tumor tissues from CCA patients with DM that exhibited higher STAT3 activation than those without DM. Moreover, the levels of STAT3 activation were correlated with the levels of blood glucose. Finally, decreasing the level of glucose or using a STAT3 inhibitor could reduce the effects of high glucose. These findings suggest that controlling blood glucose or using a STAT3 inhibitor as an alternative approach may improve the therapeutic outcome of CCA patients with DM.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Charupong
authors.initials: C
authors.lastname: Saengboonmee
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Wunchana
authors.initials: W
authors.lastname: Seubwai
authors.affiliation: Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Chawalit
authors.initials: C
authors.lastname: Pairojkul
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Sopit
authors.initials: S
authors.lastname: Wongkham
mesh_terms: D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008867:Microtomy; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016610:Tissue Embedding; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014746:Vimentin; D019938:Cyclin D1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D005947:Glucose