title: The four and a half LIM domains 2 (FHL2) regulates ovarian granulosa cell tumor progression via controlling AKT1 transcription.
abstract: The four and a half LIM domains 2 (FHL2) has been shown to play important roles in the regulation of cell proliferation, survival, adhesion, motility and signal transduction in a cell type and tissue-dependent manner. However, the function of FHL2 in ovarian physiology and pathology is unclear. The aim of this study was to determine the role and functional mechanism of FHL2 in the progression of ovarian granulosa cell tumors (GCTs). Immunohistochemical analysis indicated that FHL2 was overexpressed in GCT tissues. Cellular localization of FHL2 in GCT cells was cell cycle dependent. Knockdown of FHL2 suppressed GCT cell growth, reduced cell viability and inhibited cell migration. Consistently, ectopic expression of FHL2 in GCT cells with very low endogenous FHL2 promoted cell growth, improved cell viability and enhance cell migration. Importantly, overexpression of FHL2 promoted GCT progression in vivo. Mechanistic studies indicated that FHL2 regulates AKT1 gene expression in vitro and in vivo. Knockdown of FHL2 or AKT1 in GCT cell lines induced very similar phenotypes. Ectopic expression of constitutively active AKT1 rescued FHL2 knockdown-induced arrest of GCT cell growth and reduction of GCT cell viability, suggesting that FHL2 regulates GCT cell growth and viability through controlling AKT1 expression. Finally, co-immunoprecipitation and chromatin immunoprecipitation analyses indicated that FHL2 functions as a co-activator of NFκB and AP-1 to regulate AKT1 gene transcription. In conclusion, results from the present study indicate that FHL2 exerts its oncogenic action in GCT cells via controlling AKT1 gene expression. FHL2 is a promising target for the development of novel drugs against ovarian granulosa cell tumor.
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics/Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei province 430070, China.
authors.forename: G
authors.initials: G
authors.lastname: Hua
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics/Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei province 430070, China.
authors.forename: C
authors.initials: C
authors.lastname: He
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics/Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lv
authors.affiliation: Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei province 430070, China.
authors.forename: L
authors.initials: L
authors.lastname: Fan
authors.affiliation: Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei province 430070, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics/Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Remmenga
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics/Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Rodabaugh
authors.affiliation: Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei province 430070, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Lele
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Karpf
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics/Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Omaha Veterans Affairs Medical Center, Omaha, NE 68105, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Davis
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics/Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006106:Granulosa Cell Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D008156:Luciferases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt