人类T淋巴细胞白血病1型病毒HBZ蛋白通过抑制C/EBPalpha信号通路促进肿瘤细胞生长的机制研究

人类T淋巴细胞白血病1型病毒（HTLV-1）是成人T细胞白血病（ATL）的致病病原。由HTLV-1反义链编码的HBZ蛋白在ATL发病过程中扮演重要角色。我们研究显示，HBZ具有促进肿瘤细胞生长的作用，但机制不详。申请人前期发现HBZ蛋白显著抑制C/EBPalpha信号传导途径。同时还发现，HBZ可抵消C/EBPalpha对T细胞生长的抑制作用。因此，我们推测"HBZ负向调节C/EBPalpha信号通路，从而解除C/EBPalpha对肿瘤细胞生长的抑制作用"是HBZ促进肿瘤细胞生长的机制。本项目拟应用荧光素酶报告系统，RT-PCR，siRNA，免疫沉淀，Western blot等技术，从体外细胞水平和体内实验动物水平，研究HBZ蛋白对C/EBPalpha信号通路的调控作用，进而揭示HBZ促进肿瘤细胞生长的分子机制。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). The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of HTLV-1 provirus, plays critical role in the leukemogenesis of ATL. Our previous studies have shown that the expression of HBZ in T-cells promotes T-cell proliferation, while the mechanism is still unknown. Our pre-study observed that HBZ suppressed C/EBPalpha signaling pathway. In addition, HBZ overcame C/EBPalpha-mediated cell proliferation block. Thus, we speculate that HBZ may support proliferation of ATL cells through inhibiting C/EBPalpha signaling. In this project, we will study the effect of HBZ on C/EBPalpha signaling pathway using different molecular methods, such as luciferase assay, RT-PCR, siRNA, immunoprecipitation, Western blot etc, and clarify the molecular mechanism by which HBZ promotes proliferation of T-cells in vitro and in vivo. This research may provide new insights into the mechanism of oncogenesis by HTLV-1, and implicate HBZ and C/EBPalpha as potential therapeutic targets.