Ovarian granulosa cell tumors: The role of GATA4 in predicting tumor behavior

Excessive cell proliferation and decreased apoptosis have been implicated in the pathogenesis of ovarian granulosa cell tumors (GCTs). We hypothesized that transcription factor GATA-4 controls expression of the antiapoptotic factor Bcl-2 and the cell cycle regulator cyclin D2 in normal and neoplastic granulosa cells. To test this hypothesis, a tissue microarray based on 80 GCTs was subjected to immunohistochemistry for GATA-4, Bcl-2, and cyclin D2, and the data were correlated to clinical and histopathological parameters. In addition, quantitative RT-PCR for GATA-4, Bcl-2, and cyclin D2 was performed on 21 human GCTs. A mouse GCT model was used to complement these studies. The role of GATA-4 in the regulation of Bcl2 and ccdn2 (coding for cyclin D2) was studied by transactivation assays, and by disrupting GATA-4 function with dominant negative approaches in mouse and human GCT cell lines. We found that GATA-4 expression correlated with Bcl-2 and cyclin D2 expression in human and murine GCTs. Moreover, GATA-4 enhanced Bcl-2 and cyclin D2 promoter activity in murine GCT cells. Whereas GATA-4 overexpression up-regulated and dominant negative GATA-4 suppressed Bcl-2 expression in human GCT cells, the effects on cyclin D2 were negligible. Our results reveal a previously unknown relationship between GATA-4 and Bcl-2 in mammalian granulosa cells and GCTs, and suggest that GATA-4 influences granulosa cell fate by transactivating Bcl-2.

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Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors

Acta Endocrinologica ◽

10.1530/eje-10-0849 ◽

2011 ◽

Vol 164 (1) ◽

pp. 115-122 ◽

Cited By ~ 21

Author(s):

Anniina Färkkilä ◽

Mikko Anttonen ◽

Jurate Pociuviene ◽

Arto Leminen ◽

Ralf Butzow ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Granulosa Cell ◽

Biologically Active ◽

Treatment Modalities ◽

Vascular Endothelial ◽

Granulosa Cell Tumors ◽

Ovarian Granulosa Cell ◽

Endothelial Growth Factor

ObjectiveOvarian granulosa cell tumors (GCTs) are hormonally active sex cord stromal tumors accounting for 3–5% of all ovarian cancers. These tumors are generally diagnosed at an early stage but there is a high risk of recurrence, associated with high mortality. Treatment of recurrent GCTs is difficult, and biologically targeted treatment modalities are lacking. GCTs are highly vascularized, and angiogenic factors most probably play a role in their pathology. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, but in GCTs, the role of VEGF and its receptors VEGFR-1 (FLT1) and VEGFR-2 (KDR) remains largely unknown. Our objective is to study the expression of VEGF and its receptors in human GCTs.MethodsWe analyzed GCTs from 106 patients for the expressions of VEGF and its receptors utilizing tumor tissue microarray, tumor mRNA, and patient serum samples.ResultsWe found that VEGF and its main biologically active receptor VEGFR-2 were highly expressed in primary and recurrent GCTs, when compared with normal granulosa-lutein cells. The expression of VEGF correlated positively to tumor microvessel density and to VEGFR-2 expression at the protein (P<0.05) and mRNA (P<0.05) levels. In contrast to VEGFR-2, the expression of VEGFR-1 was weak. Tumor VEGF protein expression was not prognostic for recurrence, however, we found high levels of circulating VEGF in the serum of patients with primary GCT.ConclusionsThe results suggest an important role of VEGF and VEGFR-2 in GCT pathology and support the possibility of applying novel VEGF- or VEGFR-2-targeted treatments to patients with GCT.

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8 Role of Expression of Estrogen Receptor β, Proliferating Cell Nuclear Antigen, and p53 in Ovarian Granulosa Cell Tumors

Molecular Genetics, Gastrointestinal Carcinoma, and Ovarian Carcinoma - Handbook of Immunohistochemistry and in Situ Hybridization of Human Carcinomas ◽

10.1016/s1874-5784(05)80094-7 ◽

2005 ◽

pp. 371-379

Author(s):

Stefania Staibano ◽

Gaetano De Rosa

Keyword(s):

Estrogen Receptor ◽

Granulosa Cell ◽

Proliferating Cell Nuclear Antigen ◽

Estrogen Receptor Β ◽

Nuclear Antigen ◽

Granulosa Cell Tumors ◽

Ovarian Granulosa Cell ◽

Proliferating Cell

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Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22042047 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2047

Author(s):

Nina Schmid ◽

Kim-Gwendolyn Dietrich ◽

Ignasi Forne ◽

Alexander Burges ◽

Magdalena Szymanska ◽

...

Keyword(s):

Cell Proliferation ◽

Granulosa Cell ◽

Granulosa Cells ◽

Drug Targets ◽

Growth Regulation ◽

Sirtuin 1 ◽

Ki 67 ◽

Granulosa Cell Tumors ◽

Novel Drug

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1–7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.

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