簇集蛋白（Clusterin）介导的衰老相关分泌表型（SASP）在六价铬[Cr(VI)] 诱导的肝细胞恶性转化中的作用研究

近年来“铬污染”事件频发，已知饮用水被六价铬[Cr(VI)]污染可致居民发生肝癌。本课题组证实长期低剂量Cr(VI)暴露诱导肝细胞早衰，簇集蛋白（CLU）在抑制早衰的同时刺激衰老相关分泌表型（SASP）的形成，后者与肿瘤发生发展相关，但Cr(VI)暴露后SASP在肝细胞恶性转化中的作用未见报道。本研究首次将SASP与Cr(VI)致癌作用结合，旨在证实CLU可能通过调节与肿瘤促进、抑制、清除相关的SASP成分而促进肝细胞恶性转化。拟构建过表达或沉默CLU基因的L02细胞模型，Cr(VI)诱导早衰后分析CLU通路与SASP成分；体外体内实验中分别观察各处理组早衰细胞分泌的SASP对正常L02、有恶性转化倾向的L02以及发生转化的L02细胞的作用，揭示Cr(VI)暴露后CLU介导的SASP对肝细胞恶性转化各阶段（转化前、过程中、后）的影响，为预防和靶向治疗Cr(VI)相关癌症提供新的思路和策略。

Cromium pollution events occurred frequently in recent years, and it is confirmed that drinking water contaminated with Hexavalent chromium [Cr(VI)] increased the incidence of liver cancer of the residents. Our research group demonstrated that low dose and long term exposure of Cr(VI) induced the premature senescence of the hepatocytes, and Clusterin (CLU) not only inhibited premature senescence but also stimulated the formation of senescence-associated secretory phenotype (SASP). It is known that SASP may play important role in the cancer progression, and the reports related to the role of SASP played in Cr(VI)-induced hepatocytes malignant transformation were not seen. For the first time the present research will combine the carcinogenic effects of Cr(VI) with SASP, and aim to confirm the high expressed CLU in the senescent cells may promote Cr(VI)-induced hepatocytes malignant transformation by regulating the SASP components associated with tumor promotion, inhibition, and clearance. The present study planned to over express and knock down CLU gene in the L02 hepatocytes, construct the Cr(VI)-induced senescent cell models, and then analyze the upstream and downstream pathways of CLU as well as the SASP components. The in vitro and in vivo studies will observe the effect of SASP from senescent cells of various groups on the normal L02 cells, the L02 cells with malignant transformation potential after Cr(VI) exposure, and the Cr(VI)-induced transformed L02 (T-L02). The present study will uncover the effect of CLU-mediated SASP on the various stages of hepatocytes malignant transformation (before, during, and after the transformation) after Cr(VI) exposure, which will provide new ideas and strategies for the prevention and targeted therapy for Cr(VI)-related cancers.