gga-miR-221/222-ERK/NF-кB信号轴促进J亚群禽白血病病毒致瘤作用的分子机制

Avian leukosis virus subgroup J (ALV-J) is one of the most important oncogenic pathogen. Recent research indicated that expression of gga-miR-221/222 were up-regulated and ERK/NF-кB signaling pathway was activated in tumor cells caused by ALV-J. Our previous research had found that gga-miR-221/222 suppressed ADAMTS6 which was the inhibitor of extracellular signal regulated kinase (ERK) signaling pathway, and ERK/NF-кB signaling pathway was closely related to the expression of gga-miR-221/222. The project focus on analysis and confirmation of the regulation of gga-miR-221/222 by NF-кB-p65 and other regulator, illustrate the feedback regulation of gga-miR-221/222 and ERK/NF-кB via the biological effect of ADAMTS6 in vivo and in vitro. Combined with the changes of protein related to cell proliferation and apoptosis, the role of gga-miR-221/222-ERK/NF-кB signaling axis in the tumorigenesis of ALV-J is elucidated finally. These research results will reveal the regulation pattern of ALV-J based on host miRNAs, facilitate in understanding the tumorigenesis mechanism of ALV-J.

J亚群禽白血病病毒（ALV-J）是危害养鸡业的重要致肿瘤病原之一。已有研究表明，ALV-J致肿瘤细胞中存在gga-miR-221/222的高度表达和ERK/NF-кB通路的激活。课题组在前期研究中发现gga-miR-221/222可抑制ERK通路的负调控因子ADAMTS6，而ERK/NF-кB通路与gga-miR-221/222的转录水平密切相关。本项目拟分析和确定NF-кB-p65等分子对gga-miR-221/222的调控，基于ADAMTS6的生物学功能分别从细胞和在体水平论证gga-miR-221/222对ERK/NF-кB通路的反馈调控。结合细胞增殖、凋亡和肿瘤转移等蛋白的变化，最终阐明gga-miR-221/222-ERK/NF-кB信号轴在ALV-J致瘤过程中的作用。研究结果有助于揭示ALV-J调控宿主miRNAs转录的模式，以利于深入理解ALV-J的致瘤机理。

J亚群禽白血病病毒（ALV-J）是危害养鸡业的重要致肿瘤病原之一，已有的研究表明其致瘤机制与miRNAs的异常表达密切相关。本项目系统论述了ALV-J感染后的细胞和肿瘤组织高表达的gga-miR-221/222联合ERK/NF-кB通路的促进ALV-J的致瘤过程，验证了ERK信号通路的负调控因子ADAMTS6为gga-miR-221/222的靶基因，分析了高表达的gga-miR-221/222通过ADAMTS6进一步激活ERK及其下游的NF-кB通路信号通路从而促进细胞增殖、阻滞凋亡和增强肿瘤转移；同时运用体外细胞实验论述了NF-кB通路磷酸化的关键效应分子p65蛋白可通过结合gga-miR-221/222启动子区域进一步增强其转录，并证实gga-miR-221/222可促进ALV-J的复制。本项目系统剖析了ALV-J、gga-miR-221/222与ERK-NF-кB信号轴相互影响的“正反馈”调控模式，可从新的角度助益于理解ALV-J的致瘤机理。