Role of the YAP1-LATS2 negative feedback loop in cervical carcinogenesis

摘要：全球每年约有57万名妇女被诊断为宫颈癌(CVC)，导致 每年有310,000多名妇女死于与CVC有关的死亡。在美国，国家癌症研究所 据估计，目前约有29万名妇女患有CVC。五年总体存活率 复发或转移的CVC低于20%。尽管之前的研究发现高危人类 人乳头瘤病毒(HrHPV)作为CVC的病原体，绝大多数由HPV引起的癌前病变 最终消退，表明仅有HPV不足以引起CVC。未知内在因素(S) 与高危人群的遗传/基因组改变相关的可能在 HPV诱导宫颈上皮内瘤变(CIN)与宫颈癌的研究进展我们最近 初步研究表明，YAP1(河马信号通路的主要效应者)和LATS2(一个关键的 KK和上游YAP1抑制子)形成YAP1-LATS2负反馈 环，以维持宫颈上皮的动态平衡。重要的是，我们观察到尽管HPV16E6/E7 未能诱导原代人宫颈上皮细胞恶性转化，成功 通过YAP-LATS2反馈环中断诱导HcerECs恶变，导致 宫颈鳞状细胞癌的发生发展。基于这些观察，我们假设 一个功能正常的YAP1-LATS2负反馈环对于维持宫颈的内稳态是必不可少的 上皮细胞，而被破坏的YAP1-LATS2反馈环是以前从未见过的 人乳头瘤病毒诱导宫颈上皮内瘤变的研究进展在这个拟议的项目中，我们将创造新的 转基因小鼠模型YAP1-LATS2负反馈环中断在形成和修复中的作用 HPV诱导的CIN的进展(目标1)，检查中断的YAP1-LATS2环的机制 推动癌前病变进展(AIM 2)，并测试靶向中断的YAP1-LATS2环路是否具有 改进CSCC预防和治疗的潜力(目标3)。拟议研究的成果 预计将认识到中断的YAP1-LATS2反馈环路是一种前所未有的机制 宫颈癌变和宫颈上皮癌变的潜在机制。组合在一起 新技术，如单细胞RNA测序，与我们独特的生理/病理相关 转基因动物模型有望识别参与形成和发展的关键基因和途径。 人乳头瘤病毒癌前病变的进展与宫颈癌的发生发展研究成果 从拟议的临床前研究得出的结论将为开发新药和策略提供坚实的基础 提高人类口腔鳞癌的防治水平。

Summary: Globally, around 570,000 women are diagnosed with cervical cancer (CVC) each year, resulting in more than 310,000 CVC-related deaths in women annually. In the United States, the National Cancer Institute estimates that approximately 290,000 women are currently living with CVC. The five-year overall survival rate for recurrent or metastatic CVC is lower than 20%. Although previous studies identify high-risk human papillomavirus (hrHPV) as a causative agent of CVC, the vast majority of HPV-induced pre-cancer lesions eventually regress, suggesting that HPV alone is insufficient to cause CVC. Unknown intrinsic factor(s) associated with the genetic/genomic alterations of the high-risk population likely play a critical role in the progression of HPV-induced cervical intraepithelial neoplasia (CIN) and cervical carcinogenesis. Our recent preliminary studies demonstrate that YAP1 (a major effector of the Hippo signaling pathway) and LATS2 (a key kinase and upstream YAP1 suppressor in the Hippo signaling cascade) form a YAP1-LATS2 negative feedback loop to maintain homeostasis of the cervical epithelium. Importantly, we observed that although HPV16 E6/E7 failed to induce malignant transformation of primary human cervical epithelial cells (HcerECs), they successfully induced malignant transformation of HcerECs with a disrupted YAP-LATS2 feedback loop, leading to the development of cervical squamous cell carcinoma (CSCC). Based on these observations, we hypothesize that a functional YAP1-LATS2 negative feedback loop is essential for maintaining the homeostasis of the cervical epithelium, and the disrupted YAP1-LATS2 feedback loop is a previously unprecedented mechanism underlying the progression of hrHPV-induced cervical intraepithelial neoplasia. In this proposed project, we will create novel transgenic mice to model the role of the disrupted YAP1-LATS2 negative feedback loop in the formation and progression of HPV-induced CINs (Aim 1), examine the mechanisms by which the disrupted YAP1-LATS2 loop drives pre-cancer lesion progression (Aim 2), and test whether targeting the disrupted YAP1-LATS2 loop has the potential to improve the prevention and treatment of CSCC (Aim 3). The achievement of the proposed studies is expected to recognize the disrupted YAP1-LATS2 feedback loop as a previously unprecedented mechanism underlying the progression of cervical neoplasia and carcinogenesis of the cervical epithelium. The combination of new technologies such as single-cell RNA sequencing with our unique physiological/pathological relevant transgenic animal models is expected to identify key genes and pathways involved in the formation and progression of HPV-induced pre-cancer lesions and the development of cervical cancer. Research results derived from the proposed preclinical studies will provide a solid base for developing new drugs and strategies to improve the prevention and treatment of human CSCC.