Abstract
YAP is a key component of the Hippo signaling pathway and plays a critical role in the development and progression of multiple cancer types, including ovarian cancer. However, the effects of YAP on ovarian cancer development in vivo and its downstream effectors remain uncertain. In this study we found that strong YAP expression was associated with poor ovarian cancer patient survival. Specifically, we showed for the first time that high YAP expression levels were positively correlated with TEAD4 gene expression, and their co-expression was a prognostic marker for poor ovarian cancer survival. Hyperactivation of YAP by mutating its five inhibitory phosphorylation sites (YAP-5SA) increased ovarian cancer cell proliferation, resistance to chemotherapeutic drugs, cell migration, and anchorage-independent growth. In contrast, expression of a dominant negative YAP mutant reversed these phenotypes in ovarian cancer cells both in vitro and in vivo. Our results suggested that YAP caused these effects by promoting an epithelial-to-mesenchymal transition. Thus, YAP promotes ovarian cancer cell growth and tumorigenesis both in vitro and in vivo. Further, high YAP and TEAD4 expression is a prognostic marker for ovarian cancer progression and a potential target for ovarian cancer treatment.
Highlights
Epithelial ovarian cancers (EOCs) comprise the majority of malignant ovarian tumors in adult women and have the worst prognosis among female cancers based on their 5-year survival rates
YAP expression was positively correlated with TEAD4 expression and their co-expression was closely associated with poor ovarian cancer patient survival. These findings indicate that YAP is a key ovarian cancer oncogene and that YAP/TEAD4 co-expression may be a predictor of a poor prognosis for human ovarian cancer
When total YAP expression levels were taken into account, these were significantly associated with a poor prognosis (Figure 1B). These results suggested that high YAP expression levels rather than its subcellular distributions were associated with ovarian cancer patient survival
Summary
Epithelial ovarian cancers (EOCs) comprise the majority of malignant ovarian tumors in adult women and have the worst prognosis among female cancers based on their 5-year survival rates. These patients often present with non-specific pelvic or abdominal symptoms. The core components of the Hippo pathway, including MST1/2, LATS, Sav, and YAP, are highly conserved from the fruit fly (Drosophila) to mammals [1,2,3,4,5,6]. Activated LATS1/2, in turn, phosphorylate and inhibit YAP and TAZ transcription co-activator [7,8]. YAP is closely associated with tumorigenesis as a critical transcription coactivator in the Hippo pathway
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