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 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.

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.

Adult ovarian granulosa cell tumor: Role of systemic chemotherapy and surgical treatment.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18083-e18083
Author(s):  
Anna Beliaeva ◽  
Elena Bakhidze
Keyword(s):  
Surgical Treatment ◽  
Adjuvant Chemotherapy ◽  
Drug Treatment ◽  
Granulosa Cell ◽  
Critical Role ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Low Grade ◽  
Significant Difference

e18083 Background: Granulosa cell tumor (GCT) are rare sex cord-stromal tumours. Their frequency is approximately 3% - 5% of all malignant ovarian tumors, and the incidence is from 0.6 to 2.1 cases per 100 000 women per year. According to the histological features, GCT are divided into two types: adult and juvenile. In the 2014 WHO histological classification, GCT were divided into borderline, which included the GCT of the juvenile type, and the malignant GCT of the adult type (AGCT). Despite the definition of AGCT not as borderline, but as low-grade malignant tumors, there are no specific recommendations for the surgical and drug treatment in such patients. Main method of treatment is surgical. Role of systemic treatment due to rarity of AGCT and late recurrence still has not determined. Methods: Data of 93 patients in our institution who were diagnosed with AGCT I-IV stage of the disease between 1980 and 2017 were evaluated. The data were obtained from the files of the patients, electronic database of the gynecologic oncology clinic, operation notes, and pathology records. Results: Stage of the disease, the spread of the tumor beyond the capsule and the number of mitoses of more than 10 significantly influenced the OS rates (p < 0.05). The average time before the onset of the first relapse in IA, IB stage was 134.5 months, in IC stage - 67.4 months, in II-IV stage - 34.3 months. Stage of the disease is an independent prognostic factor for the occurrence of a relapse of the disease. In stage I disease there was no influence of the volume of surgical treatment and adjuvant chemotherapy on DFS and the duration of disease-free period (p > 0.05). The duration of the non-progressive period was some, but not significantly more when performing optimal cytoreduction for the recurrence of the disease, and did not depend on the implementation regimen and adjuvant chemotherapy. Conclusions: There were not found significant difference in the overall and relapse-free survival of patients with ovarian AGCT, depending on the options of surgical and drug treatment they underwent. Studies showed that hormones play a critical role in the pathogenesis and treatment of GCT, especially in some ineffective cases for radiotherapy and chemotherapy. Additional multicenter randomized trials are needed to clarify the effectiveness of the various options for surgical and drug treatment of adult GCT patients.

scholarly journals Identification of SWI2/SNF2-Related 1 Chromatin Remodeling Complex (SWR1-C) Subunits in Pineapple and the Role of Pineapple SWR1 COMPLEX 6 (AcSWC6) in Biotic and Abiotic Stress Response

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 364 ◽  
Author(s):  
Jakada ◽  
Aslam ◽  
Fakher ◽  
Greaves ◽  
Li ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Chromatin Remodeling ◽  
Sequence Similarity ◽  
Rna Seq ◽  
Abiotic Stress Response ◽  
Biotic And Abiotic Stress ◽  
Enhanced Resistance ◽  
Chromatin Remodeling Complex ◽  
Genome Wide

Chromatin remodeling complex orchestrates numerous aspects of growth and development in eukaryotes. SWI2/SNF2-Related 1 chromatin remodeling complex (SWR1-C) is a member of the SWI/SNF ATPase-containing chromatin remodeling complex responsible for the exchange of H2A for H2A.Z. In plants, SWR1-C plays a crucial role by transcriptionally regulating numerous biological and developmental processes. However, SWR1-C activity remains obscure in pineapple. Here, we aim to identify the SWR1-C subunits in pineapple. By genome-wide identification, we found a total of 11 SWR1-C subunits in the pineapple. The identified SWR1-C subunits were named and classified based on the sequence similarity and phylogenetic analysis. RNA-Seq analysis showed that pineapple SWR1-C subunits are expressed differentially in different organs and at different stages. Additionally, the qRT-PCR of pineapple SWR1-C subunits during abiotic stress exposure showed significant changes in their expression. We further investigated the functions of pineapple SWR1 COMPLEX 6 (AcSWC6) by ectopically expressing it in Arabidopsis. Interestingly, transgenic plants ectopically expressing AcSWC6 showed susceptibility to fungal infection and enhanced resistance to salt and osmotic stress, revealing its involvement in biotic and abiotic stress. Moreover, the complementation of mutant Arabidopsis swc6 by pineapple SWC6 suggested the conserved function of SWC6 in plants.

scholarly journals Role of Anti-Müllerian Hormone in Diagnosing Granulosa Cell Tumor: A Case Report

2012 ◽  
Vol 5 (2) ◽  
pp. 94-96
Author(s):  
Aarti Umranikar ◽  
Mili Saran ◽  
Nick Brook ◽  
Neeta Singh ◽  
Darren Fowler ◽  
...  
Keyword(s):  
Case Report ◽  
Granulosa Cell ◽  
Granulosa Cell Tumor ◽  
Cell Tumor

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 Is There a Way to Predict Granulosa Cell Tumor of the Ovary? The Role of Peripheral Blood Test Parameters

2020 ◽  
Author(s):  
Muzaffer Seyhan Cikman ◽  
İsmet Gün ◽  
Önder Sakin ◽  
Kazibe Koyuncu ◽  
Ali Doğukan Anğın ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Peripheral Blood ◽  
Blood Test ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Test Parameters

scholarly journals LncRNA gas5 regulates granulosa cell apoptosis and viability following radiation by x-ray via sponging miR-205- 5p and Wnt/β-catenin signaling pathway in granulosa cell tumor of ovary

2020 ◽  
Vol 19 (6) ◽  
pp. 1153-1159
Author(s):  
Yan Li ◽  
Xing Ma ◽  
Jun Li ◽  
Saifei He ◽  
Juhua Zhuang ◽  
...  
Keyword(s):  
Western Blot ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Granulosa Cell ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
X Ray ◽  
Qrt Pcr ◽  
Lncrna Gas5

Purpose: To investigate the role of lncRNA gas5 in ovarian granulosa cells exposed to x-ray in granulosa cell tumor of ovary (GCTO). Methods: KGN cell line was exposed to X-ray to mimic the radiotherapy for GCSO patients in vitro, cell viability was checked by CCK8 assays. RNA expression of apoptosis-related genes was determined by quantitative reverse transcriptase-polymerase reaction (qRT-PCR) while Western Blot for biomarkers in wnt/β-catenin signaling. Differential expressions of lncRNA gas5 were examined after cells were exposed to a ray for 0,24,48hs. We over expressed gas5 and assessed resultant cell viability, apoptosis and signaling. The sponging between gas5 and miR-205-5p was verified by luciferase assay. CCK8, qRT-PCR and Western blot were applied to investigate the correlation between miR-205-5p, cell viability, and apoptosis after miR-205-5p augmentation. Similarly, interaction between gas5 and miR-205-5p was assessed after co-transfection of miR-205-5p mimics and oe-gas5. Finally, wnt inhibitor was used to study the role of signaling pathway in KGN cells. Results: Exposure of KGN to x-ray reduced cell viability and increased apoptosis. Gas5showed reduced expression in the cells, while miR-205-5p  expression increased. Gas5 upregulation protected the cells against apoptosis and contributed to cell viability and activation of wnt//β-catenin signaling. lncRNA gas5 targeted miR-205-5p and miR-205-5p mimics counteracted the functions of up-regulated lncRNA gas5, regulating Wnt/β-catenin signaling pathway. Inactivation of Wnt/β-catenin suppressed cell viability. Conclusions: lncRNA gas5 regulates cell apoptosis and viability following cellular radiation, thus presenting a potential therapeutic target for the application radiotherapy in GCTO patients. Keywords: Ovary, Proliferation, Apoptosis, lncRNA gas5, Radiotherapy, β-catenin signaling

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