title: Possible role of visfatin in hepatoma progression and the effects of branched-chain amino acids on visfatin-induced proliferation in human hepatoma cells.
abstract: Obesity and related metabolic abnormalities, including adipocytokine dysbalance, are risk factors for hepatocellular carcinoma (HCC). Visfatin, an adipocytokine that is highly expressed in visceral fat, is suggested to play a role in the progression of human malignancies. Branched-chain amino acids (BCAA) reduce the incidence of HCC in obese patients with liver cirrhosis and prevent obesity-related liver carcinogenesis in mice. In this study, we investigated the possible role of visfatin on HCC progression and the effects of BCAA on visfatin-induced proliferation of HCC cells. In patients with HCCs, serum visfatin levels were significantly correlated with stage progression and tumor enlargement. Visfatin preferentially stimulated the proliferation of HepG2, Hep3B, and HuH7 human HCC cells compared with Hc normal hepatocytes. Visfatin phosphorylated extracellular signal-regulated kinase (ERK), Akt, and GSK-3β proteins in HepG2 cells. LY294002 [a phosphoinositide-3-kinase (PI3K) inhibitor], PD98059 [a MAP/ERK 1 kinase (MEK1) inhibitor], CHIR99021 (a GSK-3β inhibitor), and BCAA significantly inhibited visfatin-induced proliferation in HepG2 cells. BCAA also inhibited phosphorylation of GSK-3β, increased cellular levels of p21(CIP1), caused cell-cycle arrest in G(0)/G(1) phase, and induced apoptosis in HCC cells in the presence of visfatin. These findings suggest that visfatin plays a critical role in the proliferation of HCC cells and may be associated with the progression of this malignancy. In addition, BCAA might inhibit obesity-related liver carcinogenesis by targeting and, possibly, by overcoming the stimulatory effects of visfatin.
authors.affiliation: Department of Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Soranobu
authors.initials: S
authors.lastname: Ninomiya
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kenji
authors.initials: K
authors.lastname: Imai
authors.forename: Koji
authors.initials: K
authors.lastname: Takai
authors.forename: Makoto
authors.initials: M
authors.lastname: Shiraki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hara
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsurumi
authors.forename: Sonoko
authors.initials: S
authors.lastname: Ishizaki
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000597:Amino Acids, Branched-Chain; D054409:Nicotinamide Phosphoribosyltransferase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases