The Hippo Signaling Pathway in High Grade Serous Ovarian Carcinoma

项目简介：卵巢高级别浆液性癌(HGSC)是最致命的妇科癌症。 卵巢HGSC的病因在很大程度上尚不清楚。尽管最近的研究(包括我们的研究)已经发现 输卵管上皮细胞作为卵巢HGSC的起源细胞，其确切的分子机制(S) 从FTEC启动HGSC的基础仍不清楚。在第一个资助期内，我们的研究成果提供 确凿证据表明，河马/YAP信号通路的破坏在恶性疾病中起关键作用 永生化输卵管内皮细胞的转化及HGSC的发育 卵巢上皮细胞。尽管有这些发现，但我们发现从小鼠体内诱导hGSC是具有挑战性的。 输卵管上皮细胞特异性表达高活性YAP1。我们的机械研究，出乎意料的是， 结果表明，在原代培养的FTEC中，YAP1单独过度激活可诱导细胞衰老。 这一令人惊讶的发现表明，其他因素可能阻止FTECs在YAP1诱导的衰老过程中 恶变过程。协助YAP1过度激活的致癌因子S FTEC的转变是未知的。我们的大规模筛查研究表明，人类感染 人乳头瘤病毒(HPV)足以阻止YAP1诱导的原代FTECs的过度激活 衰老。我们之前的研究一直表明，HPV16E6癌蛋白对河马有抑制作用 途径和稳定的YAP1蛋白，促进YAP1的致癌作用。有趣的是，我们的初选 研究表明，YAP1通过增加HPV的表达促进培养的FTEC感染HPV。 HPV受体分子和抑制先天免疫。重要的是，HPV病毒粒子可以在以下条件下到达FTEC 生理(精子传递)和病理(通过逆行月经)两种情况。基于 以上证据，我们假设YAP1过度激活，通过上调假定的HPV受体 分子和抑制先天免疫，利用HPV克服癌基因诱导的衰老和 形成YAP1-HPV致癌联盟以驱动输卵管上皮细胞HGSC的启动。在这个项目中， 我们设计了三个具体目标来检验我们的假设。在特定目标1中，我们将模拟致癌作用 输卵管上皮细胞YAP1-HPV联盟的独特转基因动物模型和新的 分离的小鼠乳头瘤病毒(MmuPV1)。在特定的目标2中，我们设计了实验来揭示分子 YAP1-HPV联合促进输卵管癌变的机制(S)。在具体目标3中，我们 设计临床前研究评估联合靶向HPV和YAP1的潜在临床应用 在预防和早期检测FTECs来源的HGSC方面。完成拟议的研究可以 将HPV确定为卵巢癌的一个被忽视的可预防的危险因素。功能的识别 YAP1-HPV致癌轴在输卵管上皮癌变中的作用机制(S)将提供 为制定策略以改进FTEC来源的HGSC的预防和早期发现提供新线索。

PROJECT SUMMARY: Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological cancer. The etiology of ovarian HGSC is largely unknown. Although recent studies (including ours) have identified the fallopian tube epithelial cell (FTECs) as a cell-of-origin of ovarian HGSC, the exact molecular mechanism(s) underlying initiation of HGSC from FTECs are still unclear. In the first funded period, our research results provide solid evidence that the disruption of the Hippo/YAP signaling pathway plays a critical role in the malignant transformation of immortalized FTECs and the development of HGSC from the immortalized fallopian tube and ovarian epithelial cells. Despite these findings, we found that it is challenging to induce HGSC from mouse oviduct epithelium by cell-specific expression of hyperactivated YAP1. Our mechanistic studies, unexpectedly, demonstrated that hyperactivation of YAP1 alone in the cultured primary FTEC induced cellular senescence. This surprising finding suggested that other factors likely prevent FTECs from YAP1-induced senescence during the malignant transformation process. The factor(s) that aid hyperactivated YAP1 in the induction of malignant transformation of FTECs are unknown. Our large-scale screening studies showed that infection of human papillomavirus (HPV) was sufficient to prevent cultured primary FTECs from hyperactivated YAP1-induced senescence. Consistently, our previous studies have shown that HPV16 E6 oncoprotein suppressed the Hippo pathway and stabilized YAP1 protein to promote the oncogenic action of YAP1. Intriguingly, our preliminary studies demonstrated that YAP1 facilitated HPV infection of cultured FTECs by increasing the expression of HPV receptor molecules and suppressing the innate immunity. Importantly HPV virions could reach FTECs under both physiological (sperm-transmission) and pathological (via retrograde menstruation) conditions. Based on the above evidence, we hypothesize that hyperactivated YAP1, via upregulating the putative HPV receptor molecules and suppressing the innate immunity, employs HPV to overcome oncogene-induced senescence and forms a YAP1-HPV oncogenic alliance to drive the initiation of HGSC in fallopian tube epithelium. In this project, we designed three specific aims to test our hypothesis. In specific aim 1, we will model the carcinogenic action of the YAP1-HPV alliance in fallopian tube epithelial cells using unique transgenic animal models and newly isolated mouse papillomavirus (MmuPV1). In specific aim 2, we designed experiments to reveal the molecular mechanism(s) by which the YAP1-HPV alliance drives fallopian tube carcinogenesis. In specific aim 3, we designed preclinical studies to evaluate the potential clinical applications of combined targeting HPV and YAP1 in the prevention and early detection of HGSC-derived from FTECs. Achieving the proposed studies could identify HPV as a neglected preventable risk factor for ovarian cancer. Identification of the functioning mechanism (s) of the YAP1-HPV oncogenic axis in the carcinogenesis of fallopian tube epithelium will provide new clues for developing strategies to improve the prevention and early detection of FTEC-derived HGSC.