Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA; College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Cell Rep. 2019 Mar 5;26(10):2636-2650.e5. doi: 10.1016/j.celrep.2019.02.004.
HPV infections are common in healthy women and only rarely cause cervical cancer, suggesting that individual genetic susceptibility may play a critical role in the establishment of persistent HPV infection and the development of cervical cancer. Here, we provide convincing in vitro and in vivo evidence showing that differential expression and activation of YAP1 oncogene determine individual susceptibility to HPV infection and cervical carcinogenesis. We found that hyperactivation of YAP1 in mouse cervical epithelium was sufficient to induce invasive cervical cancer. Cervical epithelial cell-specific HPV16 E6/E7 and YAP1 double-knockin mouse model demonstrated that high-risk HPV synergized with hyperactivated YAP1 to promote the initiation and progression of cervical cancer. Our mechanistic studies indicated that hyperactivation of YAP1 in cervical epithelial cells facilitated HPV infection by increasing the putative HPV receptor molecules and disrupting host cell innate immunity. Our finding reveals an unconventional mechanism for cervical carcinogenesis.
HPV 感染在健康女性中很常见，很少导致宫颈癌，这表明个体遗传易感性可能在持续性 HPV 感染和宫颈癌的发展中起着关键作用。在这里，我们提供了令人信服的体外和体内证据，表明 YAP1 癌基因的差异表达和激活决定了个体对 HPV 感染和宫颈癌发生的易感性。我们发现，YAP1 在小鼠宫颈上皮中的过度激活足以诱导侵袭性宫颈癌。宫颈上皮细胞特异性 HPV16 E6/E7 和 YAP1 双敲入小鼠模型表明，高危型 HPV 与过度激活的 YAP1 协同作用，促进宫颈癌的发生和发展。我们的机制研究表明，YAP1 在宫颈上皮细胞中的过度激活通过增加潜在的 HPV 受体分子和破坏宿主细胞固有免疫来促进 HPV 感染。我们的发现揭示了宫颈癌发生的一种非传统机制。
