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: The HT3 cancer cell line, which is HPV negative (Fogh et al, 1977; Yee et al, 1985), was used to determine the mechanism underlying HPV16 E6 regulation of YAP protein level. Treatment of HT3 cells with HPV16 E6 increased YAP protein (Fig9B and D), but HPV16 E6 did not affect YAP mRNA expression (Fig10A and B). This suggests that HPV16 E6 may regulate YAP protein turnover. Treatment of HT3 cells with MG132, a potent proteasome inhibitor, for 4 h or 8 h drastically increased YAP and EGFR protein levels (Fig10C). In contrast, treatment of HT3 cells with cycloheximide (CHX), an inhibitor of eukaryotic gene translation, for 4 h or 8 h significantly reduced EGFR and YAP protein levels (Fig10C and D). This evidence suggests that YAP and EGFR proteins are continuously synthesized and degraded in a proteasome-dependent mechanism in cervical cancer cells. The addition of HPV16 E6 prevented the degradation of YAP protein in CHX-treated cells, but had little or no effect on the degradation of EGFR (Fig10D and E). These observations clearly indicate that HPV16 E6 stabilizes the YAP protein in cervical cancer cells.
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.