抑癌基因LKB1及其新靶标INPP4B在宫颈癌细胞中的功能与调控

人乳头瘤病毒感染是宫颈癌的首要致病因素，在宫颈癌发生发展过程中，许多细胞信号通路异常推进了细胞恶性转化。抑癌蛋白LKB1在宫颈癌组织中表达缺失率较高，目前宫颈癌中LKB1抑癌的分子机制尚不完全清楚。我们首次发现LKB1可上调宫颈癌细胞中新型抑癌蛋白INPP4B的表达，而LKB1对INPP4B的调控以及INPP4B在宫颈癌中的功能尚未见报道。本项目将在细胞和组织水平系统研究LKB1及其新靶标INPP4B在宫颈癌中的功能与调控：①在细胞水平探究LKB1对INPP4B表达的调控机制、两者对PI3K/Akt/mTOR信号通路的调节及对细胞增殖的抑制作用。②在组织层面确定临床宫颈癌组织中LKB1、INPP4B的表达状况及两者的相关性、HPV癌蛋白E6、E7与LKB1、INPP4B蛋白表达的相关性；探讨LKB1蛋白表达缺失和启动子高甲基化的关系。通过上述工作为宫颈癌的治疗干预提供新的靶点与理论依据。

Human papillomavirus (HPV) infection is the major cause of cervical cancer. Many cell signaling pathways are involved in cervical carcinogenesis. LKB1 is an important tumor-suppressor that is frequently lost in cervical cancer tissues. At present, the molecule mechanism of LKB1 tumor suppressor function in cervical cancer is not well understood. We have identified the tumor-suppressor INPP4B as a novel target for LKB1 in cervical cancer cells. The regulation of INPP4B by LKB1 has not been reported and the function of INPP4B in cervical cancer is not known. This project will investigate the function and regulation of LKB1 and its new target INPP4B in cervical cancer in vitro and in vivo: ① to explore the mechanism by which INPP4B is regulated by LKB1 in cervical cancer cell lines, and their impact on PI3K/Akt/mTOR signaling pathways and cell proliferation. ② to determine the expression and correlation of LKB1 and INPP4B in clinical cervical cancer tissues; the expression and correlation of HPV oncoprotein E6, E7 and LKB1 will also be analyzed in tissue samples. Moreover, we will investigate the correlation between lack of LKB1 expression and promoter methylation in cervical cancer tissues. Our work will identify new targets and provide novel insights for the treatment and intervention of cervical cancer.