scholarly journals FOXO1 Negates the Cooperative Action of FOXL2C134W and SMAD3 in CYP19 Expression in HGrC1 Cells by Sequestering SMAD3

2019 ◽  
Vol 3 (11) ◽  
pp. 2064-2081 ◽  
Author(s):  
Martina Belli ◽  
Christian Secchi ◽  
Dwayne Stupack ◽  
Shunichi Shimasaki
Keyword(s):  
Granulosa Cell ◽  
Binding Assay ◽  
Granulosa Cell Tumor ◽  
Underlying Mechanism ◽  
Cell Tumor ◽  
Rare Type ◽  
Competitive Binding Assay ◽  
Cooperative Action ◽  
Estradiol Synthesis ◽  
Cyp19 Expression

Abstract Adult granulosa cell tumor (aGCT) is a rare type of ovarian cancer characterized by estrogen excess. Interestingly, only the single somatic mutation FOXL2C134W was found across virtually all aGCTs. We previously reported that FOXL2C134W stimulates CYP19 transcription synergistically with SMAD3, leading to elevated estradiol synthesis in a human granulosa cell line (HGrC1). This finding suggested a key role for FOXL2C134W in causing the typical estrogen overload in patients with aGCTs. We have now investigated the effect of FOXO1, a tumor suppressor, on CYP19 activation by FOXL2C134W in the presence of SMAD3. Intriguingly, FOXO1 antagonized the positive, synergistic effect of FOXL2C134W and SMAD3 on CYP19 transcription. Similar to FOXL2C134W, FOXO1 binds SMAD3 but not the proximal FOXL2C134W binding site (−199 bp) of the CYP19 promoter identified in our earlier studies. The results of a competitive binding assay suggested a possible underlying mechanism in which FOXO1 sequesters SMAD3 away from FOXL2C134W, thereby negating the cooperative action of FOXL2C134W and SMAD3 in inducing CYP19 expression. To our knowledge, this study is the first to demonstrate the ability of FOXO1 to restore an altered CYP19 expression by FOXL2C134W and SMAD3 and provides insight as to why FOXO1 deficiency promotes GCT development in mice.

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

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Christian Secchi ◽  
Paola Benaglio ◽  
Francesca Mulas ◽  
Martina Belli ◽  
Dwayne Stupack ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Chromatin Remodeling ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Rna Seq ◽  
Pathogenic Role ◽  
Rare Type ◽  
Cellular Models ◽  
Genome Wide

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 < 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 FOXL2C134W, its partner SMAD3 and its antagonist FOXO1 in cellular models of aGCT. Methods In this work, seeking more comprehensive profiling of FOXL2C134W transcriptomic effects, we performed an RNA-seq analysis comparing the effect of FOXL2WT/SMAD3 and FOXL2C134W/SMAD3 overexpression in an established human GC line (HGrC1), which is not luteinized, and bears normal alleles of FOXL2. Results Our data shows that FOXL2C134W/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 FOXL2C134W, 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.

scholarly journals FOXO1 Mitigation of FOXL2C143W/SMAD3 Transcriptomic Landscape in a Model of Granulosa Cell Tumor

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1018-A1019
Author(s):  
Christian Secchi ◽  
Paola Benaglio ◽  
Francesca Mulas ◽  
Martina Belli ◽  
Dwayne Stupack ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cell Tumor ◽  
Direct Consequence ◽  
Transcript Abundance ◽  
Cell Tumor ◽  
Gene Promoters ◽  
Rna Seq ◽  
Illumina Hiseq ◽  
Rare Type ◽  
Exact Test

Abstract Background: Adult granulosa cell tumor (aGCT) is a rare type of stromal cell malignant cancer of the ovary. Postmenopausal genital bleeding is the main aGCT clinical sign which is attributed to estrogen excess driven by CYP19 upregulation. Typically, aGCTs that are diagnosed at an initial stage can be treated with surgery. However, recurrences are mostly fatal1. Current studies are focused on finding new molecular markers and targets that aim to treat the aGCTs recurrence. Between 95-97% of aGCTs harbor a somatic mutation in the FOXL2 gene, Cys134Trp (c.402C&lt;G)2. A TGF-β pathway protein, SMAD3, was identified as an essential partner in FOXL2C134W transcriptional activity driving CYP19 upregulation3. Recently, the antitumoral FOXO1 gene has been recognized as a potential target for suppressing the FOXL2C134W pathogenic action4. Aim: The objective of this study was to examine whether FOXO1 upregulation affects the FOXL2C143W/SMAD3 transcriptomic landscape. Methods: RNA-seq analysis was performed comparing the effect of FOXL2WT/SMAD3 and FOXL2C143W/SMAD3 overexpression in presence of FOXO1 by transfection of an established human GC line (HGrC1). RNA-seq libraries were prepared using the illumina TrueSeq and sequenced using an illumina HiSeq Platform4000. To quantify transcript abundance for each sample we used salmon (1.1.0) with default parameters, using indexes from hg38. Data was subsequently imported in R using the tximport package and processed with the DESeq2 package. Results: RNA-seq data show that FOXL2C143W/SMAD3 significantly drives 717 genes compared with the WT and enabled us to identify targets (TGFB2, SMARCA4, HSPG2, MKI67, NFKBIA) and neoplastic pathways directly associated with the mutant. To provide evidence that the differences in gene expression were attributed to a direct consequence of FOXL2 binding, we annotated gene promoters with previously published FOXL2 ChIP-seq analysis. The majority (73-40%) of the differential expressed genes (DEGs) between FOXL2C134W and FOXL2WT had a FOXL2 binding site at their promoters, which was a significantly higher proportion than in non-DEGs (Fisher’s exact test, murine: p= 7.9x10-157; human, p= 9.9x10-39). Surprisingly, the number of DEGs between FOXL2C134W + FOXO1 and FOXL2WT was much lower (230) with respect to the number of DEGs between FOXL2C134W and FOXL2WT (717, of which 130 in common; linear regression slope ß = 0 .58), suggesting that the effect of FOXL2C134W compared with FOXL2WT is moderated by the addition of FOXO1. Conclusions: Our transcriptomic study provides the first evidence that FOXO1 can efficiently mitigate 40% of the altered genome-wide effect specifically related to FOXL2C134W in a model of human aGCT.1 Farkkila, A. et al. Ann Med (2017). 2 Jamieson, S. & Fuller, P. J. Endocr Rev (2012). 3 Belli, M. et al. Endocrinology (2018). 4 Belli, M et al. J Endocr Soc (2019).

Granulosa Cell Tumour – A Rare Presentation at Age Twenty

2020 ◽  
Author(s):  
Munazza Anis
Keyword(s):  
Granulosa Cell ◽  
Tertiary Care ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Care Hospital ◽  
Age Group ◽  
Rare Presentation ◽  
Rare Type ◽  
Juvenile Granulosa Cell Tumor ◽  
The Right

Granulosa cell tumor is a rare type of ovarian tumor, which arises from sex cord stroma. Histologically this tumor has two types and is named according to the common age group they affect; adult granulosa cell tumor (AGCT) and juvenile granulosa cell tumor. AGCT constitutes 2-5% of all ovarian cancers. Mostly present in women of age > 40 years. In this case report, we discussed the role of conservative surgery in young adult reported with granulosa cell tumor. An unmarried teenage girl presented at a private tertiary care hospital with abdominal pain and abdominal distention. Radiological examinations suggested a mass originating from the right ovary for which laparotomy was done and a ruptured cyst was found near the right ovary with a mass adherent to surrounding peritoneal viscera. Right ovarian cystectomy along with omental biopsy and left ovarian biopsy was performed. Rare presentation of this tumor will help clinicians to not categorize the type histologically with the age group.

scholarly journals FOXO1 mitigates the SMAD3/FOXL2C134W Transcriptomic Effect in a Model of Human Adult Granulosa Cell Tumor

2020 ◽  
Author(s):  
Christian Secchi ◽  
Paola Benaglio ◽  
Francesca Mulas ◽  
Martina Belli ◽  
Dwayne Stupack ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Chromatin Remodeling ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Rna Seq ◽  
Rare Type ◽  
Cellular Models ◽  
Genome Wide ◽  
Foxl2 Gene

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<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 FOXL2C134W, its partner SMAD3 and its antagonist FOXO1 in cellular models of aGCT. Methods: In this work, seeking more comprehensive profiling of FOXL2C134W transcriptomic effects, we performed an RNA-seq analysis comparing the effect of FOXL2WT/SMAD3 and FOXL2C143W/SMAD3 overexpression in an established human GC line (HGrC1), which is not luteinized, and bears normal alleles of FOXL2. Results: Our data shows that FOXL2C143W/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 FOXL2C134W, 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.

Postmenopausal hirsutism and hyperandrogenemia due to granulosa cell tumor of the ovary

2013 ◽  
Author(s):  
Cigdem Bahadir ◽  
Aysegul Atmaca ◽  
Hulusi Atmaca ◽  
Ramis Colak
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cell Tumor ◽  
Cell Tumor

Granulosa cell tumor of the ovary

2017 ◽  
Vol 2 (16) ◽  
pp. 48
Author(s):  
D. Oprescu ◽  
C. Herghelegiu ◽  
A. Moldoveanu
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cell Tumor ◽  
Cell Tumor

scholarly journals Right trisectionectomy for liver metastasis of granulosa cell tumor: a case report and literature review

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Itsuki Koganezawa ◽  
Koichi Tomita ◽  
Masashi Nakagawa ◽  
Yosuke Ozawa ◽  
Toshimichi Kobayashi ◽  
...  
Keyword(s):  
Case Report ◽  
Liver Metastasis ◽  
Literature Review ◽  
Granulosa Cell ◽  
Granulosa Cell Tumor ◽  
Cell Tumor

scholarly journals Juvenile granulosa cell tumor

2016 ◽  
Author(s):  
Geetanjali Tuteja ◽  
S. Unmesh ◽  
S. Shree ◽  
S. Rudra ◽  
Keyword(s):  
Granulosa Cell ◽  
Precocious Puberty ◽  
Early Stage ◽  
Pubertal Development ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Cell Tumour ◽  
Tumour Resection ◽  
Granulosa Cell Tumour ◽  
Juvenile Granulosa Cell Tumor

The differential diagnosis for precocious puberty in a young female includes peripheral causes. This case report documents a rare cause of isosexual precocious puberty, a juvenile granulosa cell tumour of the ovary–and a brief literature review. A one year-old baby girl presented with mass abdomen, vaginal discharge and rapid onset of pubertal development. She underwent an exploratory laparotomy for tumour resection. Pathology reported a juvenile granulosa cell tumour of the ovary. Early stage granulosa cell tumor surgically treated has good prognosis. Adjuvant chemotherapy is not indicated in this setting.

scholarly journals Adult‐type granulosa cell tumor of the ovary: a FOXL2 ‐centric disease

2021 ◽  
Author(s):  
Jessica A Pilsworth ◽  
Dawn R Cochrane ◽  
Samantha J Neilson ◽  
Bahar H Moussavi ◽  
Daniel Lai ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Adult Type
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