化学致癌过程中STAT3通路介导DNA损伤信号参与抑癌基因FHIT表观遗传调控的作用和机制

致癌物暴露后关键基因的异常调控和作用与肿瘤发生发展密切相关。近年研究表明表观遗传改变参与肿瘤发生和重要基因调控，但其上游连接致癌物损伤到表观遗传系统的信号调节网络及具体机制仍然不明。本实验室对亚硝胺类化学致癌物的系列研究证明：致癌物可引起DNA损伤相关信号通路异常；致癌物诱导细胞恶性变过程中抑癌基因FHIT为早期下调关键基因，其调控受表观遗传修饰重要影响、且与STAT3通路活化紧密相关。为明确致癌物损伤后STAT3通路介导FHIT相关表观遗传改变的具体机制，本项目拟进一步研究致癌物致细胞恶性变过程中STAT3通路与DNA损伤应答的交互作用、及其早期调控FHIT下调的生物学意义，解析参与FHIT低表达的表观遗传修饰，进而阐明STAT3通路负调控FHIT转录的表观遗传机制。本研究将为深入理解化学致癌过程中“信号调节通路介导下游关键基因的表观遗传异常机制”提供重要线索，并为预警和治疗提供新依据。

The dysregulation of key genes after carcinogen exposure is closely related to tumor development. Recent studies have shown that epigenetic changes are involved in tumorigenesis and important gene regulation. However, the signaling pathways connecting carcinogen damage and epigenetic systems remain unclear. Series studies in our lab revealed that the exposure of N-nitroso carcinogens can trigger DNA damage and related signal pathway abnormalities, and thus affect the genetic and epigenetic dysregulation of various genes. The malignant transformation cell model after long-time carcinogen exposure further shows that the tumor suppressor gene FHIT is an early down-regulated key genes affected by epigenetic modifications which is closely related to STAT3 pathway activation. Therefore, the aims of this study are: investigate the interaction between STAT3 pathway and DNA damage responses in the process of malignant transformation, and their role in the early down-regulation of FHIT; the epigenetic modification regulation of FHIT; and further clarify the regulatory mechanisms of STAT3 pathway in the epigenetic regulation of FHIT transcription. Our results will bring benefits to the understanding of important pathway networks modulating gene epigenetic regulations in chemical carcinogenesis, and provide molecular bases for cancer monitoring and therapy.