Novel Mechanisms of Cervical Cancer Development and Progression

 描述(申请人提供)：宫颈癌是全球第二大最常见的女性癌症，每年约有52万例新诊断病例。高危人乳头瘤病毒(HrHPV)在几乎所有的宫颈癌中都被检测到，并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的女性患浸润性癌症的比例不到4%。大多数受感染的女性在她们的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发育异常转化和疾病进展。控制宫颈癌发生和发展的分子机制还知之甚少。据报道，河马途径在包括卵巢癌在内的几种癌症的发生发展中起关键作用。然而，HIPPO信号通路在宫颈癌发病机制中的作用尚未被研究。我们的初步研究清楚地表明，河马信号通路的主要效应者YAP在宫颈癌中过度表达，并与患者预后不良有关。野生型YAP或成分活性YAP的过表达促进宫颈癌细胞的增殖，并驱动永生化的宫颈上皮细胞的转化。YAP基因敲除可抑制宫颈癌细胞的增殖。此外，YAP还能刺激裸鼠移植人宫颈癌的生长。有趣的是，我们发现HPV16E6蛋白与YAP相互作用，调节宫颈癌细胞的增殖。我们假设河马通路在宫颈癌的发生和发展中起核心作用。在拟议的项目中，我们将 系统研究HIPPO/YAP通路在宫颈癌发生发展中的作用；利用转基因小鼠模型确定HIPPO/YAP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。该项目的成功完成将确定Hippo/YAP通路是宫颈肿瘤发生过程中的一个新的和关键的调节因子。这些发现不仅将大大扩展我们对宫颈癌发生的认识，也将为宫颈癌的预防和治疗提供新的靶点。此外，这项拟议研究的完成还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.