黄曲霉毒素B1对肿瘤细胞IGF1受体/IRS2信号通路及细胞迁移的影响

Aflatoxin is a well-known carcinogen which is involved in hepatocarcinogenesis. Aflatoxin also synergizes with hepatitis virus to induce hepatocelluar carcinoma. In addition, aflatoxin may induce lung cancer. After being metabolized, aflatoxin induces DNA damage, especially gene mutations. Aflatoxin can induce the mutation of tumor suppressor p53, which underlies hepatocarcinogenesis.Moreover, recent study demonstrate that aflatoxin can induce IGF2 expression thereby activating IGF1R. Our preliminary study show that aflatoxin may regulate several key elements in IGF1R signaling axis. In the current project, we will investigate the effects of aflatoxin on IGF1R signaling and roles of IGF1R/IRS2 signaling axis in aflatoxin-induced hepatoma cell and lung cancer cell migration. Also, we will investigate the effects of green tea polyphenol EGCG on aflatoxin regulation of IGF1R/IRS2 signaling axis and cell migration. Finally, we will study roles of SNCG, a protein which is frequently overexpressed in human tumors and associated with IGF1R signaling, in the induction of cancer cell migration by aflatoxin. These study will shed new light on uncovering the mechanisms underlying aflatoxin-induced carcinogenesis and tumor progression.

黄曲霉毒素是一种已知的致癌物，与肝癌发生关系密切，特别是可与慢性肝炎病毒感染协同诱发肝癌。此外，黄曲霉毒素也可诱发肺癌。黄曲霉毒素在代谢后可诱发DNA损伤，尤其是可引起基因突变。黄曲霉毒素可诱导抑癌基因P53突变，这是黄曲霉毒素的一个重要致癌机制。近来研究还发现黄曲霉毒素可诱导IGF2表达并活化IGF1R。我们前期工作也表明黄曲霉毒素可调节IGF1R信号通路的多个元件。本项目拟研究黄曲霉毒素对肝癌、肺癌细胞中IGF1R信号通路中几个主要元件的影响，深入研究IGF1R/IRS2信号通路在黄曲霉毒素诱导肝癌、肺癌细胞迁移中的作用，以及绿茶多酚EGCG对黄曲霉毒素影响IGF1R/IRS2通路及细胞迁移的干预作用。最后，我们还将研究SNCG这一与IGF1R信号转导有关的肿瘤相关蛋白在黄曲霉毒素诱导肿瘤细胞迁移中的作用。以上这些研究对深入了解黄曲霉毒素在肿瘤发生、发展中的作用机制具有重要意义。

黄曲霉毒素B1（AFB1）是一种毒性极强的致癌物,可诱发肝癌、肺癌等恶性肿瘤。目前已知AFB1致癌机理主要是其代谢产物可形成DNA加和物从而诱发基因突变，包括抑癌基因p53突变等。AFB1的作用机制可能较复杂，涉及多重效应，AFB1是否还通过其它作用机制促进肿瘤发生、发展还不清楚。本课题主要研究AFB1对肿瘤细胞中胰岛素样生长因子受体（IGF-IR）信号转导及肿瘤细胞迁移的影响。本研究发现AFB1可诱导肝癌、肺癌细胞中IGF-IR磷酸化及其下游的AKT、ERK磷酸化。此外，AFB1还下调IRS1表达水平，但上调IRS2蛋白水平。AFB1促进IRS1蛋白降解，却增强IRS2蛋白稳定性。AFB1可诱导SRC磷酸化，这是其稳定IRS2蛋白的原因。AFB1促进肝癌、肺癌细胞迁移，抑制IGF-IR、IRS2或SRC均可拮抗AFB1诱导的细胞迁移。天然产物EGCG可抑制AFB1诱导IGF-IR及SRC磷酸化，同时抑制AFB1诱导癌细胞迁移，表明EGCG可对拮抗AFB1的促癌作用。本研究揭示了AFB1不仅可诱发癌变，还可促进癌细胞迁移。同时，本研究还揭示了AFB1促癌作用的新机制，即促进IGF-IR信号转导。这些新发现将有助于设计化学预防AFB1的致癌或促癌作用的方案。