title: The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression.
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.
authors.affiliation: 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.
authors.forename: Chunbo
authors.initials: C
authors.lastname: He
authors.affiliation: 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.
authors.forename: Dagan
authors.initials: D
authors.lastname: Mao
authors.affiliation: 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.
authors.forename: Guohua
authors.initials: G
authors.lastname: Hua
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Lv
authors.affiliation: Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Xingcheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Angeletti
authors.affiliation: Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Jixin
authors.initials: J
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Remmenga
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Rodabaugh
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: John S
authors.initials: JS
authors.lastname: Davis
authors.affiliation: 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 chengwang@unmc.edu.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D002583:Uterine Cervical Neoplasms / Q000473:pathology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: EGFR; HPV; Hippo; YAP; cervical cancer