Aflatoxin B1 up-regulates insulin receptor substrate 2 and stimulates hepatoma cell migration.
Aflatoxin B1 up-regulates insulin receptor substrate 2 and stimulates hepatoma cell migration.
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黄曲霉毒素 B1 上调胰岛素受体底物 2 并刺激肝癌细胞迁移
DOI：
10.1371/journal.pone.0047961
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Ma Y;Kong Q;Hua H;Luo T;Jiang Y
黄曲霉毒素B1(AFB1)是一种强致癌物，可诱发肝细胞癌。黄曲霉毒素1-8，9-外环氧化物是黄曲霉毒素B_1的代谢物之一，作为诱变剂与DNA反应并诱导基因突变，包括抑癌基因P53。此外，据报道，AFB1刺激IGF受体激活。胰岛素样生长因子-I受体(IGF-IR)信号的异常激活与多种人类肿瘤密切相关。在本研究中，我们研究了AFB1对IGF-IR信号通路中关键元件的影响，以及AFB1对肝癌细胞迁移的影响。结果表明，AFB1可诱导肝癌细胞株HepG2、SMMC-7721和永生化人肝细胞株Chang liver的IGF-IR、Akt和ERK1/2的磷酸化。AFB1还下调胰岛素受体底物(IRS)1，但矛盾的是，通过阻止蛋白酶体降解上调IRS2。IGF-IR抑制剂处理肝癌细胞和常肝细胞可阻断AFB1诱导的Akt和ERK1/2磷酸化。此外，IRS2基因敲除抑制了AFB1诱导的Akt和ERK1/2的磷酸化。最后，黄曲霉毒素B_1刺激肝癌细胞迁移。IGF-IR抑制剂或IRS2基因敲除可抑制AFB1诱导的肝癌细胞迁移。这些数据表明，AFB1通过IGF-IR/IRS2轴刺激肝癌细胞迁移。
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.
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影响因子：
3.8
作者：
Kensler, Thomas W.;Roebuck, Bill D.;Groopman, John D.
通讯作者：
Groopman, John D.
DOI：
10.1073/pnas.102167699
发表时间：
2002-05-14
影响因子：
11.1
作者：
Smela, ME;Hamm, ML;Essigmann, JM
通讯作者：
Essigmann, JM
影响因子：
5.3
作者：
Shaw, LM
通讯作者：
Shaw, LM
影响因子：
3.8
作者：
Woo, Leslie L.;Egner, Patricia A.;Wogan, Gerald N.
通讯作者：
Wogan, Gerald N.
影响因子：
8
作者：
Kim, B;van Golen, CM;Feldman, EL
通讯作者：
Feldman, EL