Novel mechanism of the cervical carcinogenesis
Department of Obstetrics and Gynecology, Massacusetts General Hospital/Harvard Medical School, Boston, MA 02114 USA.
HPV infections are common in healthy women but only rarely cause cervical cancer, suggesting that individual genetic susceptibility may play a critical role in the establishment of persistent HPV infection and development of cervical cancer.
We provide convincing in vitro and in vivo evidence showing that disruption of the Hippo pathway and subsequent hyperactivation of YAP1 oncogene is a critical pathological event that determines individual susceptibility to HPV infection and cervical carcinogenesis.
We found that hyperactivation of YAP1 in mouse cervical epithelium was sufficient to induce malignant transformation of cervical epithelial cells and promote development of invasive cervical cancer. Cervical epithelial cell-specific HPV16 E6/E7 and YAP1 double knock-in mouse model demonstrated that 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 via increasing the putative HPV receptor molecules and disrupting the host cell innate immunity. Our finding challenges the dogma that HPV is a necessary agent for the development of cervical cancer, uncovers a novel mechanism for the cervical carcinogenesis, and provides new targets for developing strategies to improve prevention and treatment of cervical cancer.