PMID- 26417066 OWN - NLM STAT- MEDLINE DCOM- 20160811 LR - 20220410 IS - 1757-4684 (Electronic) IS - 1757-4676 (Print) IS - 1757-4676 (Linking) VI - 7 IP - 11 DP - 2015 Nov TI - The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. PG - 1426-49 LID - 10.15252/emmm.201404976 [doi] AB - 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-alpha 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-alpha, 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. CI - (c) 2015 The Authors. Published under the terms of the CC BY 4.0 license. FAU - He, Chunbo AU - He C AD - 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. FAU - Mao, Dagan AU - Mao D AD - 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. FAU - Hua, Guohua AU - Hua G AD - 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. FAU - Lv, Xiangmin AU - Lv X AD - Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA. FAU - Chen, Xingcheng AU - Chen X AD - Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. FAU - Angeletti, Peter C AU - Angeletti PC AD - Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA. FAU - Dong, Jixin AU - Dong J AD - Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. FAU - Remmenga, Steven W AU - Remmenga SW AD - 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. FAU - Rodabaugh, Kerry J AU - Rodabaugh KJ AD - Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA. FAU - Zhou, Jin AU - Zhou J AD - 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. FAU - Lambert, Paul F AU - Lambert PF AD - Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. FAU - Yang, Peixin AU - Yang P AD - Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Davis, John S AU - Davis JS AD - 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. FAU - Wang, Cheng AU - Wang C AD - 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. LA - eng GR - R00 HD059985/HD/NICHD NIH HHS/United States GR - 5R00HD059985/HD/NICHD NIH HHS/United States GR - R01 CA201500/CA/NCI NIH HHS/United States GR - 5P01AG029531/AG/NIA NIH HHS/United States GR - P30 CA036727/CA/NCI NIH HHS/United States GR - R01 GM109066/GM/NIGMS NIH HHS/United States GR - P01 AG029531/AG/NIA NIH HHS/United States GR - R01 DK083243/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - EMBO Mol Med JT - EMBO molecular medicine JID - 101487380 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Oncogene Proteins, Viral) RN - 0 (Phosphoproteins) RN - 0 (Transcription Factors) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Adaptor Proteins, Signal Transducing/*metabolism MH - Animals MH - Cell Line MH - Cell Movement MH - Cell Proliferation MH - Disease Progression MH - Female MH - Hippo Signaling Pathway MH - Humans MH - Mice MH - Mice, Transgenic MH - Oncogene Proteins, Viral/*metabolism MH - Phosphoproteins/*metabolism MH - Protein Serine-Threonine Kinases/*metabolism MH - *Signal Transduction MH - Transcription Factors MH - Uterine Cervical Neoplasms/*pathology MH - YAP-Signaling Proteins PMC - PMC4644376 OTO - NOTNLM OT - EGFR OT - HPV OT - Hippo OT - YAP OT - cervical cancer EDAT- 2015/09/30 06:00 MHDA- 2016/08/12 06:00 PMCR- 2015/11/01 CRDT- 2015/09/30 06:00 PHST- 2015/09/30 06:00 [entrez] PHST- 2015/09/30 06:00 [pubmed] PHST- 2016/08/12 06:00 [medline] PHST- 2015/11/01 00:00 [pmc-release] AID - emmm.201404976 [pii] AID - 10.15252/emmm.201404976 [doi] PST - ppublish SO - EMBO Mol Med. 2015 Nov;7(11):1426-49. doi: 10.15252/emmm.201404976.