title: Aflatoxin B1 up-regulates insulin receptor substrate 2 and stimulates hepatoma cell migration.
abstract: Aflatoxin B1 (AFB1) is a potent carcinogen that can induce hepatocellular carcinoma. AFB1-8,9-exo-epoxide, one of AFB1 metabolites, acts as a mutagen to react with DNA and induce gene mutations, including the tumor suppressor p53. In addition, AFB1 reportedly stimulates IGF receptor activation. Aberrant activation of IGF-I receptor (IGF-IR) signaling is tightly associated with various types of human tumors. In the current study, we investigated the effects of AFB1 on key elements in IGF-IR signaling pathway, and the effects of AFB1 on hepatoma cell migration. The results demonstrated that AFB1 induced IGF-IR, Akt, and Erk1/2 phosphorylation in hepatoma cell lines HepG2 and SMMC-7721, and an immortalized human liver cell line Chang liver. AFB1 also down-regulated insulin receptor substrate (IRS) 1 but paradoxically up-regulated IRS2 through preventing proteasomal degradation. Treatment of hepatoma cells and Chang liver cells with IGF-IR inhibitor abrogated AFB1-induced Akt and Erk1/2 phosphorylation. In addition, IRS2 knockdown suppressed AFB1-induced Akt and Erk1/2 phosphorylation. Finally, AFB1 stimulated hepatoma cell migration. IGF-IR inhibitor or IRS2 knockdown suppressed AFB1-induced hepatoma cell migration. These data demonstrate that AFB1 stimulates hepatoma cell migration through IGF-IR/IRS2 axis.
authors.affiliation: State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Ma
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Kong
authors.forename: Hui
authors.initials: H
authors.lastname: Hua
authors.forename: Ting
authors.initials: T
authors.lastname: Luo
authors.forename: Yangfu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D016604:Aflatoxin B1 / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D056945:Hep G2 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002273:Carcinogens; D055504:Insulin Receptor Substrate Proteins; D016604:Aflatoxin B1; D017526:Receptor, IGF Type 1