The molecular mechanism of ovarian granulosa cell tumors

Li et al. Journal of Ovarian Research (2018) 11:13 https://doi.org/10.1186/s13048-018-0384-1 REVIEW Open Access The molecular mechanism of ovarian granulosa cell tumors Jiaheng Li1, Riqiang Bao1, Shiwei Peng2 and Chunping Zhang3* Abstract Over these years, more and more sex cord-stromal tumors have been reported. Granulosa cell tumor (GCT) is a rare tumor in ovaries, accounts for 2% to 5% of ovarian cancers. The main different feature of GCTs from other ovarian cancers is that GCTs can lead to abnormally secreted hormones (estrogen, inhibin and Müllerian inhibiting substance). The GCT is divided into two categories according to the age of patients, namely AGCT (adult granulosa cell tumor) and JGCT (Juvenile granulosa cell tumor). AGCT patients accounts for 95%. Although the pathogenesis is not clear, FOXL2 (Forkhead box L2) mutation was considered as the most critical factor in AGCT development. The current treatment is dominated by surgery. Target therapy remains in the adjuvant therapy stage, such as hormone therapy. During these years, other pathogenic factors were also explored, such as PI3K/AKT (phosphatidylinositol-3-kinase; serine/threonine kinase), TGF-β (Transforming growth factor beta) signaling pathway, Notch signaling pathway, GATA4 and VEGF (vascular endothelial growth factor). These factors and signaling pathway play important roles in GCT cell proliferation, apoptosis, or angiogenesis. The purpose of this review is to summarize the possible pathogenic factors and signaling pathways, which may shed lights on developing potential therapeutic targets for GCT. Keywords: GCT, FOXL2, PI3K/AKT signaling, TGF-β signaling, Notch signaling Background Granulosa cell tumor (GCT) is the most common sex cord-stromal tumor that stem from granulosa cells. GCT accounts for 2% to 5% of all ovarian cancers and can be divided into two subtypes according to the differences of the age of patients, clinical and histopathologic features [1]. About 95% of GCT belong to the adult granulosa cell tumors (AGCTs), and others are juvenile granulosa cell tumors (JGCTs). JGCT only occurs in people who are younger than 30 years old with the features of hypoestrogenism and abnormal abdominal mass [2, 3]. Clinical features of AGCT include abnormal uterine bleeding in postmenopausal patients and menometrorrhagia in youngers. Some reports also indicated that patients were with stopping ovulating symptom [4]. The incidence of GCT is around 0.47 to 1.6 per 100,000. The main risk factors of GCT include nulliparity, fatness, oral contraceptives and family cancer history. From the cancer databases in Finland, Iceland, Norway and Sweden, the GCT onset * Correspondence: 3 Department of Cell Biology, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, People’s Republic of China Full list of author information is available at the end of the article showed scattered feature. There was no increasing trend over the 60 years [5]. Abnormal cell cycle is related to the occurrence and development of cancers. The recent studies provided powerful evidences that fork head box protein L2 (FOXL2), PI3K/AKT signaling pathway, TGF-β signaling pathway, Notch signaling pathway and etc. were involved in granulosa cell tumor through influencing cell proliferation and apoptosis [6–10]. In the development of GCT, a variety of cell signaling pathways, such as TGF-β, Notch and PI3K/AKT, are involved. In fact, these signal pathways are not isolated, but make up a complex network and contribute to the formation and development of GCT. FOXL2 is the most important mutant gene in GCT formation. Studies showed that FOXL2 is involved in the TGF-β pathway. For example, FOXL2 mutation has negative effect on SMAD3 (drosophila mothers against decapentaplegic protein) activation by interacting with BMPs, follistatin and activin A [11]. FOXO1/3 (forkhead box O1/3) also inhibited SMAD3 [12]. The interaction between Notch signaling and PI3K/AKT were also proved [13]. In the following sections, we will summarize the influence of different cell signaling network on GCT. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. Journal of Ovarian Research (2018) 11:13 Page 2 of 8 FOXL2 Notch signaling pathway Forkhead transcription factor 2 (FOXL2) is a transcription factor. The gene is 2.7 kb long and encodes 376 amino acids, which locates at human chromosome 3q23. The sequence of FOXL2 is highly conserved. It is mainly expressed in ovarian granulosa cell and pituitarium. FOXL2 is the first confirmed autosomal gene that maintains normal function of ovary, and it is also a marker of sexual selection and development. FOXL2 knockout mouse model showed sex reversal [14]. Further studies showed that FOXL2 regulated the ovarian granulosa cell proliferation, follicle development and ovarian hormones synthesis [14]. In 2009, a breakthrough of AGCT, using the wholetranscriptome paired-end RNA sequencing, showed that a somatic missense mutation (402C»G) occurred in four different AGCT samples at C134W (amino acid position 134) [15]. From the published results, the mutation exists in more than 97% of AGCT, and it is rarely detected in other ovarian cancer [16]. Some reports showed that the expression of FOXL2 was also downregulated in aggressive JGCT [17, 18]. These studies make FOXL2 as one possible pathognomonic defining feature. The mechanism of mutant FOXL2 in GCT was also widely explored. Some studies showed that prominent serine 33 (S33) phosphorylation of FOXL2, which is induced by GSK3β, was detected in C134W mutation. The phosphorylation modification of FOXL2 contributes to the growths of GCTs [19, 20]. The growth of GCT was proportional to the S33 phosphorylation status, and GSK3β inhibitor might serve as an effective intervention for GCT therapy [19]. Some studies examined the transcriptional targets of mutant FOXL2. Wile-type FOXL2 plays a key role in inhibiting granulosa cell proliferation and promoting apoptosis [21]. However, mutant FOXL2 downregulated the INHA, one of a proliferative signaling ligand [22]. Death signaling mediators, TNF-R1 (Tumor necrosis factor receptor 1) and FAS, were also decreased [23]. Caspase 8, BID and BAK determine the FOXL2 depended granulosa cell apoptotic pathway, but mutant FOXL2 was unable to elicit the apoptotic signaling responses [24]. In addition, mutant FOXL2 has been shown to reduce GnRH receptor expression, thus conf (...truncated)