Abstract B31: YAP1-induced cervical carcinogenesis challenges the HPV dogma

Abstract

Abstract Aims: HPV infections are common in 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. The molecular mechanisms underlying cervical cancer development remain unclear. Although our previous in vitro studies have shown that YAP1 plays a role in the malignant transformation of cervical epithelial cells, whether YAP1 contributes to the cervical carcinogenesis in vivo is unknown. This study aims to determine whether YAP1, alone or interacting with HPV, contributes to cervical carcinogenesis in vivo. Methods: Cellular and transgenic mouse models were developed to evaluate the role of YAP1 in cervical carcinogenesis. Results: Keratin-14 promoter-driven expression of constitutively active YAP1 (YAPS127A) in mouse cervical epithelial cells induced invasive cervical cancer, suggesting that hyperactivation of YAP1 is sufficient to induce cervical cancer development. Cervical epithelial cell-specific HPV and YAP1 double knockin mouse models showed that HPV synergizes with YAP1 to promote the initiation and progression of cervical carcinogenesis. Our mechanistic studies demonstrated that hyperactivation of YAP1 in cervical epithelium not only increased the putative HPV receptor molecules and cellular susceptibility to HPV infection, but also disrupted the host cell innate immune system, resulting in failure of HPV viral recognition, suppression of type I IFN production, inhibition of the IFNRs/JAKs/STATs pathway, and blockage of production of antiviral interferon-stimulated genes. Conclusion: Our results indicated that the YAP1 oncogene plays a central role in cervical cancer development. The synergism between hyperactivated YAP1 and high-risk HPV may be a key driver of cervical cancer initiation and progression. 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. Note: This abstract was not presented at the conference. Citation Format: Cheng Wang. YAP1-induced cervical carcinogenesis challenges the HPV dogma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B31.