ArticlePloS one2014
FOXL2, GATA4, and SMAD3 co-operatively modulate gene expression, cell viability and apoptosis in ovarian granulosa cell tumor cells.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 61 citations in OpenAlex.
- Efficient differentiation of gonadal somatic cell-like cells (GSCLCs) using magnetic nanoparticles from mouse embryonic stem cells.American journal of translational research · 2026Article
- FOXL2 + cancer-associated fibroblasts enhances epithelial ovarian cancer development via TGFβ/Smad signaling.BMC cancer · 2025Article
- Metabolic characteristics of granulosa cell tumor: role of PPARγ signaling†.Biology of reproduction · 2024Article
- Incidental FOXL2 mutated adult granulosa cell tumour of the ovary with thecoma-like foci.Virchows Archiv : an international journal of pathology · 2023Article
- Forkhead box L2 is a target of miR-133b and plays an important role in the pathogenesis of non-small cell lung cancer.Cancer medicine · 2023Article
- Immunohistochemical markers of prognosis in adult granulosa cell tumors of the ovary - a review.Journal of ovarian research · 2023Review
- FOXO1 mitigates the SMAD3/FOXL2Journal of translational medicine · 2021Article
- GATA-4, a potential novel therapeutic target for high-grade meningioma, regulates miR-497, a potential novel circulating biomarker for high-grade meningioma.EBioMedicine · 2020Article
- Mutant FOXL2Cancer research · 2020Article
- Article
- FOXO1 Negates the Cooperative Action of FOXL2Journal of the Endocrine Society · 2019Article
- RUNX3 Promotes the Tumorigenic Phenotype in KGN, a Human Granulosa Cell Tumor-Derived Cell Line.International journal of molecular sciences · 2019Article
- Review
- A random forest classifier predicts recurrence risk in patients with ovarian cancer.Molecular medicine reports · 2018Article
- FOXL2C134W-Induced CYP19 Expression via Cooperation With SMAD3 in HGrC1 Cells.Endocrinology · 2018Article
- Endogenous c-Jun N-terminal kinase (JNK) activity marks the boundary between normal and malignant granulosa cells.Cell death & disease · 2018Article
- The molecular mechanism of ovarian granulosa cell tumors.Journal of ovarian research · 2018Review
- Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors.Reproduction (Cambridge, England) · 2017Article
- Granulosa Cell Tumors: Novel Predictors of Recurrence in Early-stage Patients.International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists · 2017Article
- Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant ovarian granulosa cell proliferation and apoptosis may lead to granulosa cell tumors (GCT), the pathogenesis of which involves transcription factors GATA4, FOXL2, and SMAD3. FOXL2 gene harbors a point mutation (C134W) in a vast majority of GCTs. GATA4 is abundantly expressed in GCTs and its expression correlates with poor prognosis. The TGF-β mediator SMAD3 promotes GCT cell survival through NF-κB activation, and interacts with FOXL2. Here, we find that the expression patterns of these factors overlap in the normal human ovary and 90 GCTs, and positively correlate with each other and with their mutual target gene CCND2, which is a key factor for granulosa cell proliferation. We have explored the molecular interactions of FOXL2, GATA4, and SMAD3 and their roles in the regulation of CCND2 using co-immunoprecipitation, promoter transactivation, and cell viability assays in human GCT cells. We found that not only SMAD3, but also GATA4 physically interact with both wild type and C134W-mutated FOXL2. GATA4 and SMAD3 synergistically induce a 8-fold increase in CCND2 promoter transactivation, which is 50% reduced by both FOXL2 types. We confirmed that wild type FOXL2 significantly decreases cell viability. Interestingly, GATA4 and SMAD3 caused a marked reduction of GCT cell apoptosis induced by wild type FOXL2. Thus, the effects of GATA4 and SMAD3 on both cell viability and apoptosis are distinct from those of wild type FOXL2; a perturbation of this balance due to the oncogenic FOXL2 mutation is likely to contribute to GCT pathogenesis.
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