| RRC ID |
56654
|
| Author |
Hua G, He C, Lv X, Fan L, Wang C, Remmenga SW, Rodabaugh KJ, Yang L, Lele SM, Yang P, Karpf AR, Davis JS, Wang C.
|
| Title |
The four and a half LIM domains 2 (FHL2) regulates ovarian granulosa cell tumor progression via controlling AKT1 transcription.
|
| Journal |
Cell Death Dis
|
| 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.
|
| Volume |
7(7)
|
| Pages |
e2297
|
| Published |
2016-7-14
|
| DOI |
10.1038/cddis.2016.207
|
| PII |
cddis2016207
|
| PMID |
27415427
|
| PMC |
PMC4973349
|
| MeSH |
Animals
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Female
Gene Expression Regulation, Neoplastic*
Genes, Reporter
Granulosa Cell Tumor / genetics*
Granulosa Cell Tumor / metabolism
Granulosa Cell Tumor / pathology
Humans
LIM-Homeodomain Proteins / antagonists & inhibitors
LIM-Homeodomain Proteins / genetics*
LIM-Homeodomain Proteins / metabolism
Luciferases / genetics
Luciferases / metabolism
Mice
Mice, Nude
Muscle Proteins / antagonists & inhibitors
Muscle Proteins / genetics*
Muscle Proteins / metabolism
NF-kappa B / genetics
NF-kappa B / metabolism
Neoplasm Transplantation
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Transcription Factor AP-1 / genetics
Transcription Factor AP-1 / metabolism
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription, Genetic
|
| IF |
5.959
|
| Times Cited |
13
|
| Resource |
| Human and Animal Cells |
KGN(RCB1154) |
