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.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics*
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Carcinogenesis / genetics*
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Cell Movement / genetics
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Cell Proliferation / genetics
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Cystadenocarcinoma, Serous / drug therapy
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Cystadenocarcinoma, Serous / genetics*
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Cystadenocarcinoma, Serous / pathology
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Fallopian Tube Neoplasms / drug therapy
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Fallopian Tube Neoplasms / genetics*
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Fallopian Tube Neoplasms / pathology
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Fallopian Tubes / metabolism
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Fallopian Tubes / pathology
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Female
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Fibroblast Growth Factors / antagonists & inhibitors
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Fibroblast Growth Factors / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Neoplasm Grading
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / pathology
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Phenylurea Compounds / administration & dosage
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / genetics*
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Porphyrins / administration & dosage
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Pyrimidines / administration & dosage
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Signal Transduction / genetics
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Transcription Factors
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Verteporfin
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Phenylurea Compounds
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Phosphoproteins
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Porphyrins
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Pyrimidines
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Transcription Factors
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YAP-Signaling Proteins
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YAP1 protein, human
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Verteporfin
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Fibroblast Growth Factors
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infigratinib