Dataset Information

FOXO1 mitigates the SMAD3/FOXL2^C134W transcriptomic effect in a model of human adult granulosa cell tumor.

ABSTRACT:

Background

Adult granulosa cell tumor (aGCT) is a rare type of stromal cell malignant cancer of the ovary characterized by elevated estrogen levels. aGCTs ubiquitously harbor a somatic mutation in FOXL2 gene, Cys134Trp (c.402C?C134W, its partner SMAD3 and its antagonist FOXO1 in cellular models of aGCT.

Methods

In this work, seeking more comprehensive profiling of FOXL2^C134W transcriptomic effects, we performed an RNA-seq analysis comparing the effect of FOXL2^WT/SMAD3 and FOXL2^C134W/SMAD3 overexpression in an established human GC line (HGrC1), which is not luteinized, and bears normal alleles of FOXL2.

Results

Our data shows that FOXL2^C134W/SMAD3 overexpression alters the expression of 717 genes. These genes include known and novel FOXL2 targets (TGFB2, SMARCA4, HSPG2, MKI67, NFKBIA) and are enriched for neoplastic pathways (Proteoglycans in Cancer, Chromatin remodeling, Apoptosis, Tissue Morphogenesis, Tyrosine Kinase Receptors). We additionally expressed the FOXL2 antagonistic Forkhead protein, FOXO1. Surprisingly, overexpression of FOXO1 mitigated 40% of the altered genome-wide effects specifically related to FOXL2^C134W, suggesting it can be a new target for aGCT treatment.

Conclusions

Our transcriptomic data provide novel insights into potential genes (FOXO1 regulated) that could be used as biomarkers of efficacy in aGCT patients.

SUBMITTER: Secchi C

PROVIDER: S-EPMC7913442 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

FOXO1 mitigates the SMAD3/FOXL2<sup>C134W</sup> transcriptomic effect in a model of human adult granulosa cell tumor.

Secchi Christian C Benaglio Paola P Mulas Francesca F Belli Martina M Stupack Dwayne D Shimasaki Shunichi S

Journal of translational medicine 20210227 1

<h4>Background</h4>Adult granulosa cell tumor (aGCT) is a rare type of stromal cell malignant cancer of the ovary characterized by elevated estrogen levels. aGCTs ubiquitously harbor a somatic mutation in FOXL2 gene, Cys134Trp (c.402C < G); however, the general molecular effect of this mutation and its putative pathogenic role in aGCT tumorigenesis is not completely understood. We previously studied the role of FOXL2<sup>C134W</sup>, its partner SMAD3 and its antagonist FOXO1 in cellular models ...[more]

PMID: 33639972

Similar Datasets

Project description:The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.

Dataset Information

FOXO1 mitigates the SMAD3/FOXL2^C134W transcriptomic effect in a model of human adult granulosa cell tumor.

Background

Methods

Results

Conclusions

Publications

FOXO1 mitigates the SMAD3/FOXL2<sup>C134W</sup> transcriptomic effect in a model of human adult granulosa cell tumor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor.

Background

Methods

Results

Conclusions

Publications

FOXO1 mitigates the SMAD3/FOXL2<sup>C134W</sup> transcriptomic effect in a model of human adult granulosa cell tumor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

FOXO1 mitigates the SMAD3/FOXL2^C134W transcriptomic effect in a model of human adult granulosa cell tumor.