A Human Papillomavirus-Independent Cervical Cancer Animal Model Reveals Unconventional Mechanisms of Cervical Carcinogenesis

Authors

Chunbo He, Massachusetts General Hospital & University of Nebraska Medical Center & Huazhong Agricultural University
Xiangmin Lv, Massachusetts General Hospital & University of Nebraska Medical Center
Cong Huang, Massachusetts General Hospital
Peter C. Angeletti, University of Nebraska-LincolnFollow
Guohua Hua, University of Nebraska Medical Center & Huazhong Agricultural University
Jixin Dong, University of Nebraska Medical Center
Jin Zhou, University of Nebraska Medical Center & Sun Yat-Sen University
Zhengfeng Wang, University of Nebraska Medical Center & Zhengzhou University
Bowen Ma, University of Nebraska Medical Center
Xingcheng Chen, University of Nebraska Medical Center
Paul F. Lambert, University of Wisconsin-MadisonFollow
Bo R. Rueda, Massachusetts General Hospital
John S. Davis, University of Nebraska Medical Center & Omaha Veterans Affairs Medical Center
Cheng Wang, Massachusetts General Hospital & University of Nebraska Medical CenterFollow

Document Type

Article

Date of this Version

3-5-2019

Citation

Cell Reports 26, 2636–2650, March 5, 2019 https://doi.org/10.1016/j.celrep.2019.02.004

Comments

2019 The Author(s).

Abstract

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.