The Hippo Pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo Pathway is of prognostic significance to cancer patients. Here we show that Yap, the human homolog of the key transcriptional target of the Hippo pathway, plays a conserved role in promoting tumorigenesis in both the fly ovary and human ovarian cancer. While studies linking Yap to cancer in other tissues have focused on overall Yap levels, we demonstrate for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap, or low levels of cytoplasmic phosphorylated-Yap, associated with poor survival from ovarian cancer. Patients with both high nuclear Yap and low cytoplasmic phosphorylated-Yap had approximately 50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. Further, overexpression of Yap and phosphorylation-defective Yap-5A in immortalized ovarian surface epithelium cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage independent growth, while Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Together, our results indicate that Hippo signaling is likely to define a novel pathway in ovarian cancer.

PMID: 20947521 [PubMed - as supplied by publisher] Source: National Library of Medicine.