The Hippo Signaling Pathway in High Grade Serous Ovarian Carcinoma

高级别浆液性卵巢癌中的 Hippo 信号通路

• 批准号: 10211391
• 负责人: Cheng Wang
• 金额: $ 32.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211391
• 关键词: Achievement; Animal Model; Artificial Insemination; Award; Carcinoma; Cell Aging; Cell Cycle Arrest; Cells; Data; Development; Early Diagnosis; Epithelial; Epithelial Cells; Etiology; Fallopian Tube Carcinoma; Fluorescence; Funding; HPV-High Risk; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Image; Imaging technology; Immunization; In Vitro; Lead; Malignant - descriptor; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Modeling; Molecular; Mus; Natural Immunity; Oncogenes; Oncogenic; Oncoproteins; Ovarian; Ovarian Serous Adenocarcinoma; Ovary; Papillomavirus; Pathologic; Pathway interactions; Pelvic cavity structure; Pharmaceutical Preparations; Physiological; Play; Predisposition; Prevention; Process; Proteins; Protocols documentation; Publications; Publishing; Reporter; Research; Retrograde Menstruation; Risk Factors; Role; Serous; Signal Pathway; Solid; Survival Rate; Testing; Transgenic Animals; Transgenic Mice; Tumor-Derived; Vaccination; Virion; base; cancer imaging; carcinogenesis; carcinogenicity; clinical application; design; experimental study; exposed human population; improved; in vivo Model; mouse model; neglect; neoplastic cell; novel; novel chemoprevention; novel strategies; preclinical study; prevent; receptor; role model; screening; senescence; sperm cell; tool; transmission process; tumorigenesis

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.

项目摘要：卵巢高级浆液性癌（HGSC）是最致命的妇科癌。 卵巢HGSC的病因在很大程度上是未知的。尽管最近的研究（包括我们的）已经确定了 输卵管上皮细胞（FTEC）作为卵巢HGSC的原始细胞，即精确的分子机制（S） FTEC的HGSC的基本启动仍不清楚。在第一个资助时期，我们的研究结果提供了 可靠的证据表明，河马/YAP信号通路的破坏在恶性肿瘤中起着关键作用 永生的FTEC的转化以及从永生的输卵管和 卵巢上皮细胞。尽管有这些发现，我们发现从鼠标诱导HGSC是一项挑战 卵形上皮通过过度活化YAP1的细胞特异性表达。我们的机械研究意外 证明在培养的原代FTEC诱导的细胞衰老中，单独过度激活YAP1。 这一令人惊讶的发现表明，其他因素可能会阻止FTEC在YAP1引起的衰老。 恶性转化过程。帮助过度活化YAP1诱导恶性肿瘤的因素 FTEC的转换是未知的。我们的大规模筛查研究表明，人类感染 乳头瘤病毒（HPV）足以防止经过培养的原代FTEC诱导的YAP1诱导 衰老。一致地，我们以前的研究表明，HPV16 E6癌蛋白抑制了河马 途径和稳定的YAP1蛋白来促进YAP1的致癌作用。有趣的是，我们的初步 研究表明，YAP1通过增加的表达来促进培养的FTEC的HPV感染 HPV受体分子并抑制先天免疫。重要的是，HPV病毒体可以到达FTEC 生理（精子传播）和病理（通过逆行月经）均均均均既有。基于 上述证据，我们假设通过上调假定的HPV受体来假设YAP1过度活化 分子和抑制先天免疫，采用HPV克服癌基因诱导的衰老和 形成YAP1-HPV致癌联盟，以推动输卵管上皮的HGSC的启动。在这个项目中， 我们设计了三个特定的目标来检验我们的假设。在特定的目标1中，我们将建模致癌作用 输卵管上皮细胞中的Yap1-HPV联盟使用独特的转基因动物模型和新的 孤立的小鼠乳头瘤病毒（MMUPV1）。在特定的目标2中，我们设计了实验以揭示分子 YAP1-HPV联盟驱动输卵管癌变的机制。在特定的目标3中，我们 设计了临床前研究，以评估靶向HPV和YAP1的联合临床应用 在预防和早期发现HGSC衍生的FTEC中。实现拟议的研究可能 将HPV识别为被忽视的卵巢癌危险因素。识别功能 输卵管上皮的致癌作用中YAP1-HPV致癌轴的机理将提供 开发策略以改善FTEC衍生的HGSC的策略的新线索。