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Human papillomavirus targets the YAP1-LATS2 feedback loop to drive cervical cancer development

Oncogene volume 41, pages 3761–3777 (2022)Cite this article

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Abstract

Human papillomavirus (HPV) infection is very common in sexually active women, but cervical cancer only develops in a small fraction of HPV-infected women, suggesting that unknown intrinsic factors associated with the unique genetic/genomic background of the high-risk population play a critical role in cervical carcinogenesis. Although our previous studies have identified the hyperactivated YAP1 oncogene as a critical contributor to cervical cancer, the molecular mechanism by which YAP1 drives cervical cancer is unknown. In the present study, we found that although the hyperactivated YAP1 caused a malignant transformation of immortalized cervical epithelial cells, it induced cellular senescence in cultures of primary human cervical epithelial cells (HCvECs). However, the hyperactivated YAP1 induced malignant transformation of HCvECs in the presence of high-risk HPV E6/E7 proteins, suggesting that the hyperactivated YAP1 synergizes with HPV to initiate cervical cancer development. Our mechanistic studies demonstrate that YAP1, via up-regulating LATS2, formed a YAP1-LATS2 negative feedback loop in cervical epithelial cells to maintain homeostasis of cervical tissue. Intriguingly, we found that high-risk HPV targets LATS2 to disrupt the feedback loop leading to the malignant transformation of cervical epithelial cells. Finally, we report that mitomycin C, an FDA-approved drug that could upregulate LATS2 and drive cellular senescence in vitro and in vivo, induced a regression of cervical cancer in a pre-clinial animal model. Thus, high-risk HPV targeting the YAP1-LATS2 feedback loop represents a new mechanism of cervical cancer development.

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Fig. 1: Hyperactivation of YAP1 induced senescence of cultured primary human cervical epithelial cells (HCvECs).
Fig. 2: HPV rescued HCvECs from YAP1-induced senescence.
Fig. 3: Synergistic combination of HPV infection and YAP1 hyperactivation induced tumorigenesis.
Fig. 4: Hyperactivated YAP1-induced overexpression of LATS2 in HCvEC cells contributes to the observed senescent phenotype.
Fig. 5: LATS2 is involved in the replication-induced senescence of human cervical epithelial cell.
Fig. 6: HPV E6/E7 target LATS2 in cervical epithelial cells.
Fig. 7: Overexpression of LATS2 also inhibited proliferation of cancerous cervical epithelial cells.
Fig. 8: Mitomycin (MMC) up-regulated LATS2 to induce senescence in cervical cancer cells.
Fig. 9: MMC up-regulated LATS2 expression and blocked cervical cancer progression in vivo.

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Acknowledgements

This work was supported by the National Cancer Institute/National Institute of Health (1R01CA197976, 1R01CA201500), the Vincent Memorial Hospital Foundation/Vincent Center for Reproductive Biology, Colleen’s Dream Foundation (no number), and the Ruggles Family Foundation. JSD is the recipient of a Veterans Administration Senior Research Career Scientist Award. BR was supported by the Nile Albright Research Foundation.

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Author notes

  1. Cong Huang

    Present address: Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China

  2. These authors contributed equally: Cong Huang, Xiangmin Lv, Peichao Chen, Jiyuan Liu.

Authors and Affiliations

  1. Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Cong Huang, Xiangmin Lv, Peichao Chen, Jiyuan Liu, Chunbo He, Li Chen, Hongbo Wang, Madelyn L. Moness, Bo R. Rueda & Cheng Wang

  2. College of Life and Environmental Science, Wenzhou University, Wenzhou, Zhejiang, 325035, China

    Peichao Chen

  3. Fred & Pamela Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Chunbo He, Jixin Dong & John S. Davis

  4. Key Laboratory of Animal Ecology and Conservation Biology, Chinese Academy of Sciences, Beijing, 100101, China

    Li Chen

  5. Olson Center for Women’s Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    John S. Davis

  6. Veterans Administration Nebraska-Western Iowa Healthcare System, Omaha, NE, 68105, USA

    John S. Davis

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Contributions

CH contributed to the experimental design, performance, data collection/analysis, and manuscript preparation. XLv contributed to experimental design and performed tumorigenic experiments. PC and JL contribute to experimental design, establishment of new cellular models, RNA-sequencing, and bioinformatic analyses. CHe contributed to experimental design and establishment of new cellular models. JD contributes to the construction of YAP1-expressing vectors. LC, MLM, and HW conducted IHC and real-time PCR analyses. JSD and BRR contributed to results discussion and manuscript review. CW conceived the original idea, supervised the studies, and contributed to experimental design, data analysis, and manuscript preparation.

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Correspondence to Cheng Wang.

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Huang, C., Lv, X., Chen, P. et al. Human papillomavirus targets the YAP1-LATS2 feedback loop to drive cervical cancer development. Oncogene 41, 3761–3777 (2022). https://doi.org/10.1038/s41388-022-02390-y

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