Secchi Christian, Benaglio Paola, Mulas Francesca, Belli Martina, Stupack Dwayne, Shimasaki Shunichi
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Department of Pediatrics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
J Transl Med. 2021 Feb 27;19(1):90. doi: 10.1186/s12967-021-02754-0.
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, its partner SMAD3 and its antagonist FOXO1 in cellular models of aGCT.
In this work, seeking more comprehensive profiling of FOXL2 transcriptomic effects, we performed an RNA-seq analysis comparing the effect of FOXL2/SMAD3 and FOXL2/SMAD3 overexpression in an established human GC line (HGrC1), which is not luteinized, and bears normal alleles of FOXL2.
Our data shows that FOXL2/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, suggesting it can be a new target for aGCT treatment.
Our transcriptomic data provide novel insights into potential genes (FOXO1 regulated) that could be used as biomarkers of efficacy in aGCT patients.
成人颗粒细胞瘤（aGCT）是一种罕见的卵巢基质细胞恶性肿瘤，其特征是雌激素水平升高。aGCT普遍存在FOXL2基因的体细胞突变，即Cys134Trp（c.402C < G）；然而，这种突变的一般分子效应及其在aGCT肿瘤发生中的假定致病作用尚未完全明确。我们之前在aGCT细胞模型中研究了FOXL2、其伙伴SMAD3及其拮抗剂FOXO1的作用。
在这项研究中，为了更全面地分析FOXL2转录组效应，我们进行了RNA测序分析，比较了FOXL2/SMAD3和FOXL2/SMAD3过表达在已建立的未黄体化且携带FOXL2正常等位基因的人颗粒细胞系（HGrC1）中的作用。
我们的数据表明，FOXL2/SMAD3过表达改变了717个基因的表达。这些基因包括已知和新发现的FOXL2靶点（TGFB2、SMARCA4、HSPG2、MKI67、NFKBIA），并且在肿瘤相关通路（癌症中的蛋白聚糖、染色质重塑、细胞凋亡、组织形态发生、酪氨酸激酶受体）中富集。我们还表达了FOXL2拮抗蛋白叉头蛋白FOXO1。令人惊讶的是，FOXO1过表达减轻了40%与FOXL2特异性相关的全基因组改变效应，这表明它可能是aGCT治疗的新靶点。
我们的转录组数据为潜在基因（FOXO1调控的）提供了新的见解，这些基因可作为aGCT患者疗效的生物标志物。
