title: YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors.
abstract: The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes-associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of the ovary, excess production of estrogen, a high frequency of recurrence, and the potential for malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild type YAP or a constitutively active YAP (YAP1) mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in the regulation of GCT cell proliferation, migration, and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT.
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, The Fred and Pamela Buffett Cancer Center, Department of Pathology, Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA Department of Pathology, Tianjin Medical University Cancer Hospital, Tianjin, China Omaha Veterans Affairs Medical Center, Omaha, Nebraska 68105, USA College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
authors.forename: David
authors.initials: D
authors.lastname: Fu
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Lv
authors.forename: Guohua
authors.initials: G
authors.lastname: Hua
authors.forename: Chunbo
authors.initials: C
authors.lastname: He
authors.forename: Jixin
authors.initials: J
authors.lastname: Dong
authors.forename: Subodh M
authors.initials: SM
authors.lastname: Lele
authors.forename: David Wan-Cheng
authors.initials: DW
authors.lastname: Li
authors.forename: Qiongli
authors.initials: Q
authors.lastname: Zhai
authors.forename: John S
authors.initials: JS
authors.lastname: Davis
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
mesh_terms: D000328:Adult; D000735:Androstenedione / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006106:Granulosa Cell Tumor / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D000735:Androstenedione; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: Hippo/YAP pathway; cell proliferation; granulosa cell tumor; migration; steroidogenesis