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

• Published in: Cell reports (Cambridge) 2019-03, Vol.26 (10), p.2636-2650.e5
• Main Authors: He, Chunbo, Lv, Xiangmin, Huang, Cong, Angeletti, Peter C., Hua, Guohua, Dong, Jixin, Zhou, Jin, Wang, Zhengfeng, Ma, Bowen, Chen, Xingcheng, Lambert, Paul F., Rueda, Bo R., Davis, John S., Wang, Cheng
• Format: Article
• Language: English
• Subjects: cervical cancer mouse model; cervical carcinogenesis; Hippo pathway; HPV infection; HPV receptor molecules; innate immunity; interferon-stimulated genes; molecular mechanism; type I interferon; YAP1 oncogene
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Human papillomavirus is not necessary for the development of cervical cancer•Hyperactivated YAP1 in cervical epithelia is sufficient to drive cervical carcinogenesis•Synergism between HPV and YAP1 accelerates cervical cancer initiation and progression•Combined targeting of YAP1 and HPV may improve cervical cancer prevention and treatment HPV infections are common in healthy women and only rarely cause cervical cancer. He et al. provide evidence that hyperactivation of the YAP1 oncogene can drive cervical cancer initiation and progression. YAP1 hyperactivation in cervical epithelial cells increases the HPV receptors and disrupts host cell innate immunity, facilitating HPV infection.