基于PI3K／Akt信号靶向预防和治疗HPV E7癌基因诱导肿瘤的研究

Human Papillomavirus (HPV) infection is the most prevalent factor in many human cancers such as cervical cancer. An estimated, 5% of human cancers are caused by infections with HPV. The cancer cervical vaccines against HPVs have enormously prevented HPV-associated cervical cancer. However, cervical cancer and other HPV-caused cancers still remain a major health problem worldwide because of no therapeutic HPV vaccines. Furthermore, epidemiological surveys and molecular mechanism studies indicate that HPV infection itself is necessary, but insufficient for completing transformation of the human epithelial cells in vivo to induce carcinogenesis. A few published studies and our preliminary experiments have clearly shown that PI3K/AKT/mTOR signaling pathway plays an important role in HPV-induced carcinogenesis. We hypothesize that HPV E6/E7 oncoproteins in HPV-infected or-transformed cells not only knock down tumor suppressors p53 and pRb, but also importantly alter multiple cellular and molecular events, particularly, activating the PI3K/AKT/mTOR signaling pathway leading to the induction of carcinogenesis. We aim to systematically study the mechanisms of HPV 16 E7 oncogene expression in primary keratinocytes and, especially, its role in activating PI3K/AKT signaling to induce development of cancerous cells and tumour in our newly established keratinocytes/E7-EL4 cell co-culture model, together with the well established primary keratinocyte culture system and animal model. Then we propose to target the PI3K/AKT signaling to prevent and treat HPV-induced cancers.

HPV感染是致宫颈癌的主要因素，其E6/E7癌基因蛋白可通过抑制降解抑癌蛋白(p53和Rb)诱发肿瘤，但研究表明在其诱发肿瘤过程中尚有宿主细胞信号转导因素参与。近来研究报道及我们的前期实验均提示，PI3K/Akt/mTOR信号在HPV致癌过程中发挥着关键作用。我们推测，在HPV感染或转化的细胞中E6/E7既降解p53和Rb，同时激活PI3K/Akt/mTOR信号从而诱发宫颈癌的发生。因此，本项目拟用我们最近首创的角质形成细胞(KC)/E7-淋巴瘤细胞(E7-EL4)共培养新模型，及已建立的角质形成细胞培养系统和小鼠实验模型，以及基因密码修饰技术，系统研究HPV16E7癌基因在角质形成细胞（KCs）中的表达，激活PI3K/AKT信号的分子机制，上皮细胞的转化及其肿瘤上发生和发展过程中的关键作用，从而为通过以PI3K/AKT信号分子为靶点来预防和治疗HPV诱发的肿瘤提供理论基础和临床实践依据。

HPV感染是致宫颈癌的主要因素，其E6/E7癌基因蛋白可通过抑制降解抑癌蛋白(p53和Rb)诱发肿瘤，但研究表明在其诱发肿瘤过程中尚有宿主细胞信号转导因素参与。本项目采用我们首创的角质形成细胞(KC)/E7-淋巴瘤细胞(E7-EL4)共培养新模型，及已建立的角质形成细胞培养系统和小鼠实验模型，以及基因密码修饰技术，系统研究了HPV16E7癌基因在角质形成细胞（KCs）中的表达，激活PI3K/AKT信号的分子机制，上皮细胞的转化及其肿瘤上发生和发展过程中的关键作用。结果表明，在HPV感染或转化的细胞中E6/E7既降解p53和Rb，同时激活PI3K/Akt/mTOR信号从而诱发宫颈癌的发生。从而为通过以PI3K/AKT信号分子为靶点来预防和治疗HPV诱发的肿瘤提供理论基础和临床实践依据。