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.
Highlights
Hepatocellular carcinoma (HCC) is one of common cancers worldwide, especially in Asia and south Africa
Immunoblot analysis demonstrated that treatment of hepatoma cell line HepG2 with Aflatoxin B1 (AFB1) resulted in an increase in IGF-I receptor (IGF-IR) phosphorylation, while the levels of total IGF-IR were unchanged
To examine the possibility that AFB1 might affect the turnover rate of IRS1 and IRS2 protein, HepG2 and SMMC-7721 cells were treated with cycloheximide to inhibit new protein synthesis for the times indicated, and extracts assessed by western blotting for IRS1, IRS2 and b-actin to control for loading
Summary
Hepatocellular carcinoma (HCC) is one of common cancers worldwide, especially in Asia and south Africa. Aflatoxin B1 (AFB1), an ubiquitous contaminant of the human foods in developing world, is a known carcinogen that may increase the risk of HCC. Aflatoxin exposure synergistically increases the risk of liver cancers in people chronically infected with hepatitis virus, another important risk factor in the etiology of HCC [1]. Once taken by liver cells, AFB forms adducts with hepatic DNA, ribosomal RNA, and proteins. Hepatic AFB1-DNA adducts correlate with hepatic cancer risk [2]. Cytochrome P450 enzymes can oxidize AFB1 into several products thereby either activating or detoxicating AFB1. One of these metabolites, AFB1-8,9-exoepoxide is mutagenic through reacting with DNA [3]. AFB-N7-guanine adduct in urine may serve as a biomarker of the biologically active AFB
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