Novel Mechanisms of Cervical Cancer Development and Progression

 描述（申请人提供）：宫颈癌是世界范围内第二大最常见的女性癌症，每年约有520，000例新发病例。高危型人乳头瘤病毒（hrHPV）在几乎所有宫颈癌中都有检出，被认为是宫颈癌的主要危险因素。然而，流行病学研究表明，感染HPV的女性中只有不到4%会发展为浸润性癌症。大多数受感染的妇女在其一生中从未患上癌症。因此，个体宿主特有的未知因素似乎有助于异型增生转化和疾病进展。控制宫颈癌发生和发展的分子机制知之甚少。据报道，Hippo通路在包括卵巢癌在内的几种癌症的肿瘤发生中起关键作用。然而，Hippo信号通路在宫颈癌发病机制中的作用尚未研究。我们的初步研究清楚地表明，雅普，Hippo信号通路的主要效应子，在宫颈癌中过表达，并与患者生存率低相关。野生型雅普或组成型活性雅普的过表达促进宫颈癌细胞的增殖并驱动永生化宫颈上皮细胞的转化。敲低雅普可抑制宫颈癌细胞增殖。此外，雅普刺激人宫颈癌裸鼠移植瘤的生长。有趣的是，我们发现HPV 16 E6蛋白与雅普相互作用以调节宫颈癌细胞的增殖。我们假设Hippo通路在宫颈癌的发生和发展中起着重要作用。在拟议项目中，我们将 系统地研究Hippo/雅普通路在宫颈癌发生发展中的作用;使用转基因小鼠模型确定Hippo/雅普通路与hrHPV癌蛋白之间的潜在相互作用，并探索Hippo通路与hrHPV癌蛋白相互作用调节宫颈癌发生的潜在信号机制。该项目的成功实现将确定Hippo/雅普途径作为宫颈致瘤过程的新的关键调节因子。这些发现不仅将大大扩展我们对宫颈癌发生的认识，而且还将为宫颈癌的预防和治疗提供新的靶点。此外，这项研究的完成也将为预防和治疗其他HPV相关癌症打开新的窗口。

 DESCRIPTION (provided by applicant): Cervical cancer is the second most commonly diagnosed cancer in women worldwide, with ~520, 000 new cases diagnosed every year. High risk human papillomavirus (hrHPVs) have been detected in almost all cervical carcinomas and are thought to be major risk factors for cervical cancer. However, epidemiological studies show that fewer than 4% of women infected with HPV develop invasive cancer. The majority of infected women never develop cancer in their lifetime. Therefore, unknown factors unique to individual hosts appear to contribute to the dysplastic transformation and disease progression. The molecular mechanisms controlling the initiation and progression of cervical cancer are poorly understood. The Hippo pathway has been reported to play critical roles in tumorigenesis in several cancers, including in ovarian cancer. However, the role of the Hippo signaling pathway in the pathogenesis of cervical cancer has not been examined. Our preliminary studies clearly indicate that YAP, the major effector of the Hippo signaling pathway, is overexpressed in cervical cancer and is associated with poor patient survival. Overexpression of wild type YAP or constitutively active YAP promotes proliferation of cervical cancer cells and drives transformation of immortalized cervical epithelial cells. Knockdown of YAP suppressed cervical cancer cell proliferation. Moreover, YAP stimulated growth of human cervical cancer xenografts in athymic nude mice. Intriguingly, we found that the HPV16 E6 protein interacts with YAP to regulate proliferation of cervical cancer cells. We hypothesize that the Hippo pathway plays a central role in the initiation and progression of cervical cancer. In the proposed project, we will systematically examine the role of the Hippo/YAP pathway in the initiation and progression of cervical cancer; determine the potential interaction between the Hippo/YAP pathway and hrHPV oncoproteins using transgenic mouse models, and explore the potential signaling mechanism by which the Hippo pathway interacts with hrHPV oncoproteins to regulate cervical carcinogenesis. Successful achievement of this project will identify the Hippo/YAP pathway as a novel and key regulator of the tumorigenic process in the cervix. These findings will not only significantly expand our knowledge on cervical carcinogenesis, but will also provide new targets for the prevention and treatment of cervical cancer. Moreover, accomplishment of the proposed study will also open new windows for the prevention and treatment of other HPV-associated cancers.