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.
Highlights
Of ovarian sex-cord/stromal tumors and are the most poorly understood ovarian neoplasms.[1,2] granulosa cell tumor (GCT) grow relatively slow, these tumors are characterized by their high frequency of recurrence, malignant potential and metastatic capacity.[2]
It is reported that four and a half LIM domains 2 (FHL2) serves as a transcriptional co-activator of several transcription factors, including androgen receptor, activator protein 1 (AP-1), CAMP responsive element-binding protein (CREB), BRCA1 and Wilms tumor 1 (WT-1).13-16 Interestingly, FHL2 is able to function as a transcriptional co-repressors of ERK2, promyelocytic leukemia zinc finger (PLZF), Nur[77], E4F transcription factor 1 (E4F1) and FOXO1.17–19 FHL2 is expressed in a wide range of organs
We found that FHL2 is overexpressed in the GCT tissues
Summary
Of ovarian sex-cord/stromal tumors and are the most poorly understood ovarian neoplasms.[1,2] GCTs grow relatively slow, these tumors are characterized by their high frequency of recurrence, malignant potential and metastatic capacity.[2]. FOXL2 has been identified as a potential driver in the pathogenesis of adult-type GCTs.[8,9,10] Our previous studies indicated that the Hippo/YAP pathway may play an important role in the regulation of GCT cell proliferation, migration and steroidogenesis.[11] Despite this progress, the molecular mechanisms underlying GCT development are largely unknown. The four and a half LIM domains 2 (FHL2) contains four and a half highly conserved cysteine-rich LIM homeodomains. This unique structure enables FHL2 to interact with many different proteins.[12] It is reported that FHL2 serves as a transcriptional co-activator of several transcription factors, including androgen receptor, AP-1, CREB, BRCA1 and WT-1.13-16 Interestingly, FHL2 is able to function as a transcriptional co-repressors of ERK2, PLZF, Nur[77], E4F1 and FOXO1.17–19 FHL2 is expressed in a wide range of organs. The exact mechanism underlying its differential actions in different type of cancers is unclear
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