Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China.
Oncogene. 2022 Jul;41(30):3761-3777. doi: 10.1038/s41388-022-02390-y. Epub 2022 Jun 27.
Human papillomavirus (HPV) infection is very common in sexually active women, but cervical cancer only develops in a small fraction of HPV-infected women, suggesting that unknown intrinsic factors associated with the unique genetic/genomic background of the high-risk population play a critical role in cervical carcinogenesis. Although our previous studies have identified the hyperactivated YAP1 oncogene as a critical contributor to cervical cancer, the molecular mechanism by which YAP1 drives cervical cancer is unknown. In the present study, we found that although the hyperactivated YAP1 caused a malignant transformation of immortalized cervical epithelial cells, it induced cellular senescence in cultures of primary human cervical epithelial cells (HCvECs). However, the hyperactivated YAP1 induced malignant transformation of HCvECs in the presence of high-risk HPV E6/E7 proteins, suggesting that the hyperactivated YAP1 synergizes with HPV to initiate cervical cancer development. Our mechanistic studies demonstrate that YAP1, via up-regulating LATS2, formed a YAP1-LATS2 negative feedback loop in cervical epithelial cells to maintain homeostasis of cervical tissue. Intriguingly, we found that high-risk HPV targets LATS2 to disrupt the feedback loop leading to the malignant transformation of cervical epithelial cells. Finally, we report that mitomycin C, an FDA-approved drug that could upregulate LATS2 and drive cellular senescence in vitro and in vivo, induced a regression of cervical cancer in a pre-clinial animal model. Thus, high-risk HPV targeting the YAP1-LATS2 feedback loop represents a new mechanism of cervical cancer development.
人乳头瘤病毒（HPV）感染在性活跃女性中非常普遍，但宫颈癌仅在一小部分 HPV 感染女性中发展，这表明与高危人群独特的遗传/基因组背景相关的未知内在因素在宫颈癌发生中起着关键作用。尽管我们之前的研究已经确定了过度激活的 YAP1 癌基因是宫颈癌的一个关键贡献者，但 YAP1 驱动宫颈癌的分子机制尚不清楚。在本研究中，我们发现尽管过度激活的 YAP1 导致永生化宫颈上皮细胞发生恶性转化，但它在原代人宫颈上皮细胞（HCvEC）的培养物中诱导了细胞衰老。然而，在高危型 HPV E6/E7 蛋白存在的情况下，过度激活的 YAP1 诱导了 HCvEC 的恶性转化，这表明过度激活的 YAP1 与 HPV 协同作用引发宫颈癌的发展。我们的机制研究表明，YAP1 通过上调 LATS2，在宫颈上皮细胞中形成 YAP1-LATS2 负反馈回路，以维持宫颈组织的稳态。有趣的是，我们发现高危型 HPV 靶向 LATS2 以破坏反馈回路，导致宫颈上皮细胞的恶性转化。最后，我们报告说丝裂霉素 C，一种已获得 FDA 批准的药物，可以上调 LATS2 并在体外和体内诱导细胞衰老，可在临床前动物模型中诱导宫颈癌消退。因此，高危型 HPV 靶向 YAP1-LATS2 反馈回路代表了宫颈癌发展的新机制。
