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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404976 |
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| _version_ | 1849332228741398528 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chunbo He |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ae338b6989054d0abc04d54d4ce31d6a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-ae338b6989054d0abc04d54d4ce31d6a2025-08-20T03:46:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-09-017111426144910.15252/emmm.201404976The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progressionChunbo He0Dagan Mao1Guohua Hua2Xiangmin Lv3Xingcheng Chen4Peter C Angeletti5Jixin Dong6Steven W Remmenga7Kerry J Rodabaugh8Jin Zhou9Paul F Lambert10Peixin Yang11John S Davis12Cheng Wang13Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterFred & Pamela Buffett Cancer Center, University of Nebraska Medical CenterNebraska Center for Virology, School of Biological Sciences, University of Nebraska‐LincolnFred & Pamela Buffett Cancer Center, University of Nebraska Medical CenterOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterDepartment of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public HealthDepartment of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of MedicineOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterOlson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical CenterAbstract 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.https://doi.org/10.15252/emmm.201404976cervical cancerEGFRHippoHPVYAP |
| spellingShingle | 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 The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression EMBO Molecular Medicine cervical cancer EGFR Hippo HPV YAP |
| title | The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression |
| title_full | The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression |
| title_fullStr | The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression |
| title_full_unstemmed | The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression |
| title_short | The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression |
| title_sort | hippo yap pathway interacts with egfr signaling and hpv oncoproteins to regulate cervical cancer progression |
| topic | cervical cancer EGFR Hippo HPV YAP |
| url | https://doi.org/10.15252/emmm.201404976 |
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