Abstract LB-A01: Yes-associated protein 1 regulates cervical cancer initiation and progression via suppressing innate immunity and increasing cell susceptibility to human papillomavirus infection
Authors: He Chunbo , Lv Xiangmin , Huang Cong , Hua Guohua , Zhou Jin , Wang Zhengfeng , Dong Jixin , Angeletti Peter C , Lambert Paul F. , Rueda Bo R , Davis John S , Wang Cheng 
Published: August 2018

Introduction: Although human Papillomavirus (HPV) has been identified as a causative reagent for cervical cancer (CVC), accumulating evidence indicates that HPV alone is insufficient to induce CVC. The molecular mechanisms underlying CVC development are largely unknown. Our previous in vitro studies indicated that YAP1, the major effector of the Hippo pathway, interacts with HPV to drive the progression of CVC. However, whether the Hippo/YAP1 pathway also regulates cervical carcinogenesis in vivo is unknown.

Aims: To examine the molecular mechanism(s) by which the Hippo/YAP pathway interacts with HPV to regulate the cervical carcinogenesis.

Methods: The cBioportal for Cancer Genomics, an online tool developed to visualize The Cancer Genomic Atlas (TCGA) studies, was used to analyze alterations of the Hippo pathway in human CVC. Primary cervical epithelial cells and cervical cancer cell lines were used to determine effects of YAP1 on cell susceptibility to HPV infection. KRT14-YAPS127A mice, which express constitutively active YAP1 (YAPS127A) in cervical epithelial cells under doxycycline (Dox) induction, and KRT14-E6/E7-YAPS127A mice, which express both HPV E6/E7 and YAPS127A in cervical epithelial cells under Dox induction, were used to examine the role of YAP1 gene in cervical carcinogenesis.

Results: Multidimensional cancer genomic data showed that disruption of the Hippo signaling pathway is a common event in human CVC, which is featured by frequent amplification and up-regulation of oncogenes and deletion/mutation of tumor suppressors. Moreover, the disrupted Hippo pathway is associated with poor prognosis of CVC patients. Dox-induced expression of

YAPS127A in KRT14-YAPS127A mouse cervical epithelial cells resulted in neoplasia of cervical epithelium within 2 months. Most KRT14-YAPS127A mice developed invasive CVC after induction with dox for 6 months. Metastatic spread of CVC induced urethral and outlet obstruction in some KRT14-YAPS127A mice. Around 50% of KRT14-YAPS127A mice died of CVC within 16 months of Dox induction. Histological analysis revealed that KRT14-YAPS127A mice developed squamous cell carcinomas (SCC). Although KRT14-E6/E7 mice (only expressing E6/E7) rarely developed CVC after induction with Dox for 12 months, KRT14-E6/E7-YAPS127A mice developed cervical cancer within 4 months of Dox induction. Compared to KRT14-YAPS127A mice, cancer cells in the cervical tissue of KRT14-E6/E7-YAPS127A mice were more proliferative and invasive. Mechanistic studies showed that ectopic expression of YAPS127A in human cervical epithelial cells resulted in a significant increase in cell susceptibility to HPV infection, while inhibition of YAP1 activity reduced the acceptability of cervical epithelial cells to HPV infection. Intriguingly, we found that activation of YAP induced up-regulation of the putative HPV cellular receptor and disrupted innate immunity in cervical epithelial cells.

Conclusion: Our research demonstrates that constitutive activation of YAP1 is sufficient to induce cervical SCC. Hyper-activation of YAP increases the susceptibility of cervical epithelial cells to HPV infection. HPV, in turn, synergistically promotes YAP1-induced initiation and progression of cervical cancer. The Hippo/YAP signaling pathway may represent a promising target for developing novel strategies to prevent and treat cervical cancer.

[C.H., X.L., and C.H. contributed equally to this work.]

Citation Format: Chunbo He, Xiangmin Lv, Cong Huang, Guohua Hua, Jin Zhou, Zhengfeng Wang, Jixin Dong, Peter C Angeletti, Paul F. Lambert, Bo R Rueda, John S Davis, Cheng Wang. Yes-associated protein 1 regulates cervical cancer initiation and progression via suppressing innate immunity and increasing cell susceptibility to human papillomavirus infection [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A01.