title: High Glucose Stimulates Tumorigenesis in Hepatocellular Carcinoma Cells Through AGER-Dependent O-GlcNAcylation of c-Jun.
abstract: Epidemiologic studies suggest that hepatocellular carcinoma (HCC) has a strong relationship with diabetes. However, the underlying molecular mechanisms still remain unclear. Here, we demonstrated that high glucose (HG), one of the main characteristics of diabetes, was capable of accelerating tumorigenesis in HCC cells. Advanced glycosylation end product-specific receptor (AGER) was identified as a stimulator during this process. Mechanistically, AGER activated a hexosamine biosynthetic pathway, leading to enhanced O-GlcNAcylation of target proteins. Notably, AGER was capable of increasing activity and stability of proto-oncoprotein c-Jun via O-GlcNAcylation of this protein at Ser73. Interestingly, c-Jun can conversely enhance AGER transcription. Thereby, a positive autoregulatory feedback loop that stimulates diabetic HCC was established. Finally, we found that AG490, an inhibitor of Janus kinase, has the ability to impair AGER expression and its functions in HCC cells. In conclusion, AGER and its functions to stimulate O-GlcNAcylation are important during liver tumorigenesis, when high blood glucose levels are inadequately controlled.
authors.affiliation: School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Faculty of Medical Laboratory Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China sunfenyong@126.com karajan2@163.com.
authors.forename: Fenyong
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China Tongji University Advanced Institute of Translational Medicine, Shanghai, China sunfenyong@126.com karajan2@163.com.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
mesh_terms: D000215:Acylation; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D008401:Gas Chromatography-Mass Spectrometry; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D016755:Proto-Oncogene Proteins c-jun; D000067759:Receptor for Advanced Glycation End Products; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase