The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression

Chunbo He; Dagan Mao; Guohua Hua; Xiangmin Lv; Xingcheng Chen; Peter C Angeletti; Jixin Dong; Steven W Remmenga; Kerry J Rodabaugh; Jin Zhou; Paul F Lambert; Peixin Yang; John S Davis; Cheng Wang

doi:10.15252/emmm.201404976

The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression

EMBO Mol Med. 2015 Nov;7(11):1426-49. doi: 10.15252/emmm.201404976.

Authors

Chunbo He¹, Dagan Mao², Guohua Hua¹, Xiangmin Lv³, Xingcheng Chen⁴, Peter C Angeletti⁵, Jixin Dong⁴, Steven W Remmenga⁶, Kerry J Rodabaugh³, Jin Zhou⁷, Paul F Lambert⁸, Peixin Yang⁹, John S Davis¹⁰, Cheng Wang¹¹

Affiliations

¹ Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.
² Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
³ Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA.
⁴ Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
⁵ Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA.
⁶ Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
⁷ Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA Department of Obstetrics and Gynecology, Urumqi General Hospital of Lanzhou Military Region, Urumqi, China.
⁸ Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁹ Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰ Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA Omaha Veterans Affairs Medical Center, Omaha, NE, USA.
¹¹ Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA [email protected].

Abstract

The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.

Keywords: EGFR; HPV; Hippo; YAP; cervical cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Line
Cell Movement
Cell Proliferation
Disease Progression
Female
Hippo Signaling Pathway
Humans
Mice
Mice, Transgenic
Oncogene Proteins, Viral / metabolism*
Phosphoproteins / metabolism*
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction*
Transcription Factors
Uterine Cervical Neoplasms / pathology*
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Oncogene Proteins, Viral
Phosphoproteins
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding