FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor
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Published on: December 26, 2016
Christian Secchi1, Paola Benaglio2, Francesca Mulas2
1Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093, USA. chsecchi@health.ucsd.edu.
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.
Insights
The FOXL2 Cys134Trp mutation in adult granulosa cell tumors alters 717 genes. Overexpressing the antagonist FOXO1 partially reversed these changes, suggesting FOXO1 as a potential therapeutic target for ovarian cancer.
Area of Science:
- Genomics
- Molecular Biology
- Oncology
Background:
- Adult granulosa cell tumor (aGCT) is a rare ovarian cancer characterized by high estrogen levels.
- The FOXL2 Cys134Trp mutation is common in aGCTs, but its precise role in tumorigenesis is unclear.
- Previous studies explored FOXL2, SMAD3, and FOXO1 in aGCT cellular models.
Purpose of the Study:
- To comprehensively profile the transcriptomic effects of the FOXL2 Cys134Trp mutation in aGCT.
- To investigate the potential of FOXO1 as a therapeutic target in aGCT.
Main Methods:
- RNA-sequencing was performed comparing FOXL2 wild-type (WT)/SMAD3 and FOXL2 Cys134Trp (C134W)/SMAD3 overexpression in a human granulosa cell line (HGrC1).
- The impact of overexpressing the FOXL2 antagonist, FOXO1, was also assessed.
Main Results:
- FOXL2 C134W/SMAD3 overexpression altered 717 genes, including known and novel FOXL2 targets.
- Affected genes were enriched in cancer-related pathways like chromatin remodeling and apoptosis.
- FOXO1 overexpression mitigated 40% of the FOXL2 C134W-specific transcriptomic alterations.
Conclusions:
- The FOXL2 Cys134Trp mutation drives significant transcriptomic changes in aGCT.
- FOXO1 acts as an antagonist to FOXL2 C134W, showing potential as a therapeutic target.
- FOXO1-regulated genes may serve as biomarkers for treatment efficacy in aGCT patients.
