The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression.
Bottom Line: The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP).Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer.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.
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.Show MeSH
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Mentions: We found that TGF-α treatment and YAP overexpression significantly increased AREG mRNA level (Fig6). Since AREG is a member of the family of the EGF-like ligands and we have shown that the EGFR pathway interacts with the Hippo pathway to regulate cervical cancer cell growth, we infer that AREG may also be involved in the regulation of cervical cancer cell proliferation. Treatment of ME180 cells with recombinant human AREG increased phosphorylation of EGFR at Tyr1173 and reduced phosphorylation of YAP (at Ser127 and Ser397), LATS1 (Ser 909), and MOB1 (Thr35) within 30 min (Fig7A, Appendix Fig S13). Treatment of ME180 cells with AREG induced elongated cell morphology (within 24 h) and significantly increased cell proliferation (72 h) (Fig7B). Moreover, AREG potently stimulated ME180 cell migration, as indicated by the significant increase in the wound closure in the wound-healing assay (Fig7C). Most interestingly, we found that the AREG mRNA expression was induced by AREG itself in cultured ME180 cervical cancer cells (Fig7D). Knockdown of YAP with YAP siRNA significantly suppressed AREG-stimulated AREG mRNA expression (P < 0.0001) (Fig7E).
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.