Abstract
Accumulating evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from fallopian tube secretory epithelial cells (FTSECs). However, the molecular mechanisms underlying the initiation and progression of HGSC derived from FTSECs remains unclear. In this study, we found that the Hippo/Yes-associated protein (YAP) signaling pathway has a critical role in the initiation and progression of fallopian tube and ovarian HGSC. Importantly, YAP was overexpressed in inflammatory and cancerous fallopian tube tissues. Further, overexpression of wild-type YAP, or constitutively active YAP in immortalized FTSECs, induced cell proliferation, migration, colony formation and tumorigenesis. Moreover, the Hippo/YAP and the fibroblast growth factor (FGF) signaling pathways formed an autocrine/paracrine-positive feedback loop to drive the progression of the FTSEC-derived HGSC. Evidence in this study strongly suggests that combined therapy with inhibitors of YAP (such as verteporfin) and FGF receptors (such as BGJ398) can provide a novel therapeutic strategy to treat fallopian tube and ovarian HGSC.
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Acknowledgements
We thank Dr Adam Karpf (The Pamela and Fred Cancer Center, University of Nebraska Medical Center) for providing ovarian HGSC cell lines. We acknowledge the cBioPortal for Cancer Genomics (http://cbioportal.org) for providing data sets and online analyzing tools. We also acknowledge the TCGA research Network (http://cancergenome.nih.gov) for providing data sets. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R00HD059985, 5P01AG029531); the Olson Center for Women’s Health (no number); the Fred and Pamela Buffett Cancer Center (LB595), the Colleen’s Dream Foundation (no number), the Omaha Veterans Administration Medical Center (5I01BX000512) and the National Institute of Food and Agriculture (2011-67015-20076). We thank Melody Montgomery at the University of Nebraska Medical Center (UNMC) Research Editorial Office for the professional editing of the manuscript.
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Hua, G., Lv, X., He, C. et al. YAP induces high-grade serous carcinoma in fallopian tube secretory epithelial cells. Oncogene 35, 2247–2265 (2016). https://doi.org/10.1038/onc.2015.288
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DOI: https://doi.org/10.1038/onc.2015.288
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