title: Gene Network Analysis of Glucose Linked Signaling Pathways and Their Role in Human Hepatocellular Carcinoma Cell Growth and Survival in HuH7 and HepG2 Cell Lines.
abstract: Cancer progression may be affected by metabolism. In this study, we aimed to analyze the effect of glucose on the proliferation and/or survival of human hepatocellular carcinoma (HCC) cells. Human gene datasets regulated by glucose were compared to gene datasets either dysregulated in HCC or regulated by other signaling pathways. Significant numbers of common genes suggested putative involvement in transcriptional regulations by glucose. Real-time proliferation assays using high (4.5 g/L) versus low (1 g/L) glucose on two human HCC cell lines and specific inhibitors of selected pathways were used for experimental validations. High glucose promoted HuH7 cell proliferation but not that of HepG2 cell line. Gene network analyses suggest that gene transcription by glucose could be mediated at 92% through ChREBP in HepG2 cells, compared to 40% in either other human cells or rodent healthy liver, with alteration of LKB1 (serine/threonine kinase 11) and NOX (NADPH oxidases) signaling pathways and loss of transcriptional regulation of PPARGC1A (peroxisome-proliferator activated receptors gamma coactivator 1) target genes by high glucose. Both PPARA and PPARGC1A regulate transcription of genes commonly regulated by glycolysis, by the antidiabetic agent metformin and by NOX, suggesting their major interplay in the control of HCC progression.
authors.affiliation: Lyon University, INSERM, UMR1060, INRA1397, CarMeN Laboratory, INSA, HCL, 69008 Lyon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Berger
authors.affiliation: Lyon University, INSERM, UMR1060, INRA1397, CarMeN Laboratory, INSA, HCL, 69008 Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vega
authors.affiliation: Lyon University, Centre de Génétique et de Physiologie Moléculaire et Cellulaire (CGPhiMC), CNRS UMR5534, 69622 Lyon, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Weiss-Gayet
authors.affiliation: Lyon University, INSERM, UMR1060, INRA1397, CarMeN Laboratory, INSA, HCL, 69008 Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Géloën
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000008:administration & dosage; D047493:PPAR alpha / Q000096:biosynthesis / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D047493:PPAR alpha; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose