Hippo-YAP信号通路在人类T细胞白血病1型病毒致癌中的作用及其分子机制研究

人类T细胞白血病1型病毒（HTLV-1）的感染可导致成人T细胞白血病（ATL）的发生，但目前HTLV-1的致癌机制仍未完全阐明。研究表明Hippo-YAP信号通路的异常调控与肿瘤发生密切相关。然而Hippo-YAP通路在HTLV-1致癌中的功能尚未有报道。我们前期研究发现Hippo通路核心蛋白YAP在ATL细胞中异常高表达。沉默YAP后，白血病细胞的恶性增殖受到抑制。此外，HTLV-1编码的Tax蛋白能激活YAP的转录活性。因此我们推测“在ATL发生过程中，HTLV-1通过其编码的Tax蛋白调控Hippo通路及YAP蛋白功能，从而促进ATL的发生”。据此，本项目拟利用CRISPR、免疫沉淀和ChIP-Seq等技术，从体外细胞、体内临床病人及实验动物水平研究Hippo-YAP通路在HTLV-1致癌过程中的功能及机制。该研究将为阐明HTLV-1致癌机理提供新思路，并为治疗ATL提供新靶点。

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL), while the molecular mechanism of HTLV-1 mediated leukemogenesis is still unknown. Accumulating evidences show that dysregulation of Hippo-YAP signaling pathway plays a critical role in the development of multiple cancers. However, the function of Hippo-YAP pathway on HTLV-1-induced oncogenesis has not been elucidated. Our pilot study indicated that the expression level of YAP was elevated in HTLV-1-infected cell lines and clinical ATL samples. In addition, knockdown of YAP in ATL cells repressed cellular proliferation. Moreover, HTLV-1 encoded Tax protein enhanced YAP mediated transcriptional activation. Thus, we hypothesize that HTLV-1 may support proliferation of ATL cells by dysregulating Hippo-YAP signaling pathway. In this project, we will study the function of Hippo-YAP in ATL using various methods, such as CRISPR, immunoprecipitation, and ChIP-Seq etc, and clarify the molecular mechanism by which YAP promotes ATL cell proliferation and tumorigenesis in vitro and in vivo. This research may provide new insights into the mechanism of oncogenesis by HTLV-1, and implicate Hippo-YAP signaling as potential therapeutic target.