Garrido Maritza P, Bruneau Nicole, Vega Margarita, Selman Alberto, Tapia Julio C, Romero Carmen
Laboratory of Endocrinology and Reproductive Biology, Clinical Hospital University of Chile, Santiago, Chile.
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Chile, Santiago, Chile.
Histol Histopathol. 2020 Sep;35(9):961-971. doi: 10.14670/HH-18-226. Epub 2020 May 5.
Ovarian cancer is the first cause of death for gynecological malignances in developed countries and around 80% correspond to Epithelial Ovarian Cancer (EOC). Overexpression of Nerve Growth Factor (NGF) and its high affinity receptor TRKA are involved in EOC progression, modulating several oncogenic processes such as angiogenesis by the increase of Vascular Endothelial Growth Factor (VEGF). FSH receptors (FSH-R) are present in EOC, but their changes and contribution during EOC progression are still not thoroughly known. The aims of this study were to evaluate the abundance of FSH receptors during EOC differentiation and to determine whether FSH modulates oncoproteins such as NGF and VEGF in ovarian cells. FSH-R expression in EOC tissues and cell lines (A2780, poorly differentiated EOC cells and HOSE, non-tumoral ovarian surface epithelial cells) were measured by RT-PCR and laser capture of epithelial cells from EOC samples by qPCR. FSH-R protein levels were evaluated by immunohisto/cytochemistry. Additionally, ovarian explants and ovarian cell lines were stimulated with FSH and/or FSH-R inhibitor to assess NGF and VEGF mRNA and protein levels. The results showed that FSH-R levels decreased during EOC progression, nevertheless these receptors are still present in poorly differentiated EOC. FSH increased NGF expression in ovarian cells, which was prevented using a FSH-R inhibitor. Similarly, in ovarian cancer explants, FSH increased NGF and VEGF mRNA, as well as NGF protein levels. These results suggest that FSH would display a key role not only in initial stages of EOC, but also in late stages of this disease, by modulation of NGF and VEGF levels in EOC cells.
在发达国家，卵巢癌是妇科恶性肿瘤的首要死因，约80%的病例为上皮性卵巢癌（EOC）。神经生长因子（NGF）及其高亲和力受体TRKA的过表达与EOC进展有关，通过增加血管内皮生长因子（VEGF）来调节多种致癌过程，如血管生成。EOC中存在促卵泡激素受体（FSH-R），但其在EOC进展过程中的变化和作用仍未完全明确。本研究旨在评估EOC分化过程中FSH受体的丰度，并确定FSH是否调节卵巢细胞中的NGF和VEGF等癌蛋白。通过RT-PCR检测EOC组织和细胞系（A2780，低分化EOC细胞；HOSE，非肿瘤性卵巢表面上皮细胞）中的FSH-R表达，并通过qPCR对EOC样本中的上皮细胞进行激光捕获。通过免疫组织/细胞化学评估FSH-R蛋白水平。此外，用FSH和/或FSH-R抑制剂刺激卵巢外植体和卵巢细胞系，以评估NGF和VEGF的mRNA和蛋白水平。结果显示，在EOC进展过程中FSH-R水平下降，但这些受体仍存在于低分化EOC中。FSH增加了卵巢细胞中NGF的表达，而使用FSH-R抑制剂可阻止这种增加。同样，在卵巢癌外植体中，FSH增加了NGF和VEGF的mRNA以及NGF蛋白水平。这些结果表明，FSH不仅在EOC的初始阶段，而且在该疾病的晚期，通过调节EOC细胞中的NGF和VEGF水平发挥关键作用。
