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

Chunbo He,Xiangmin Lv,Cong Huang,Peter C Angeletti,Guohua Hua,Jixin Dong,Jin Zhou,Zhengfeng Wang,Bowen Ma,Xingcheng Chen,Paul F Lambert,Bo R Rueda,John S Davis,Cheng Wang

doi:10.1016/j.celrep.2019.02.004

Abstract

SUMMARYHPV 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.

Highlights

Cervical cancer is the most common gynecologic cancer and the fourth leading cause of cancer-related death in women worldwide
We successfully developed several transgenic mouse models indicating that the Hippo/YAP1 pathway is at the center of cervical carcinogenesis
We found that hyperactivation of YAP1 in the cervical epithelial cells is sufficient to induce cervical squamous cell carcinoma (CVSCC)

Summary

Introduction

Cervical cancer is the most common gynecologic cancer and the fourth leading cause of cancer-related death in women worldwide. According to the latest statistics of the International Agency for Research on Cancer (IARC), approximately 527,000 women are diagnosed with cervical cancer, and an estimated 265,000 women die of this disease each year, equal to almost one-tenth of global cancer deaths in women (Torre et al, 2015). The increased use of the Pap test and intensive implementation of health education programs have reduced cervical cancer death by more than 50% in the United States over the past 40 years. The National Cancer Institute estimates that 250,000 women are living with cervical cancer in the United States (Howlader et al, 2018). The survival rates of advanced-stage and recurrent cervical cancer patients are still very low. Cervical cancers of advanced stages and distant recurrence are currently considered to be incurable. Effective new therapeutic options are currently not available, because the detailed mechanism or mechanisms underlying cervical cancer development and progression are unclear at present

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