| Epithelial ovarian cancers (EOCs) comprise the majority of malignant ovarian tumors in adult women and have the worst prognosis among female cancers based on their5-year survival rates. Due to the lack of specific symptoms and effective screening methods, patients are often diagnosed when at an advanced stage and their prognosis is even worse than with other cancers. Recent evidence suggests that some solid tumors include ovarian cancer contain distinct populations of cells that are responsible for tumor initiation, maintenance, growth, chemo-resistance and recurrence which termed cancer stem cell or cancer initiated stem cell. One hypothesis is that tumourigenic cancer cells with stem cell properties can propagate tumor initiation, progression, metastasis and drug resistance.The Hippo pathway is a recently discovered signal transduction pathway. The core components of the Hippo pathway including YAP are highly conserved from the fruit fly (Drosophila) to mammals. YAP is closely associated with tumorigenesis as a critical transcription co-activator in the Hippo pathway. TEAD family transcription factors are important for the growth-promoting function of YAP. Previous studies showed that YAP was highly expressed in human ovarian cancer tissues and that high YAP activity promoted the proliferation and survival of cultured ovarian cancer cells. However, the role of YAP in ovarian cancer development in vivo and the association of YAP/TEAD with ovarian cancer patient survival have not been thoroughly investigated.In this study we show that continuous YAP activation induces increased ovarian cancer cell proliferation, resistance to cisplatin-induced cellular apoptosis, loss of contact inhibition, increased cell migration, and anchorage-independent growth both in vitro and in vivo. High YAP expression was associated with poor ovarian cancer patient survival. Further, TEAD family members were also expressed in ovarian cancer tissues. Interestingly, YAP expression was positively correlated with TEAD4expression and their co-expression was closely associated with poor ovarian cancer patient survival. Hyperactivation of YAP increased ovarian cancer cell proliferation and resistance to chemotherapeutic drugs. In contrast, expression of a dominant negative YAP mutant reversed these phenotypes. Thus, YAP promotes ovarian tumorigenesis both in vitro and in vivo.We also demonstrated a role of YAP in promoting the self-renewal of ovarian cancer stem-like cells. From primary ovarian cancer tissues, I identified ovarian cancer initiating cells (OCICs) possess cancer stem cell properties. The identified sphere-forming cells have strong tumorigenic capability as other reported epithelial cancer initiating cells. YAP and TEAD family members, except TEAD2, were all expressed at significantly higher levels in OCICs than in differentiated ovarian cancer cells. Importaintly, YAP/TEAD co-activator is required for OCICs pluripotency maintenance. In addition, YAP-TEAD confers OCICs’resistance to chemotherapeutic drugs. Genes in Wnt and MAPK pathways are involved in YAP-maintained pluripotency and chemoresistance in OCICs. These results supported our observation that YAP-TEAD determined ovarian cancer malignancy levels, and provided more mechanistic insights about the role of YAP and TEAD in ovarian cancers. |
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