Institut National de la Santé et de la Recherche Médicale UMR U1065/UNS, Centre Méditerranéen de Médecine Moléculaire, Equipe 5 Environnement, Reproduction et Cancers Hormono-Dépendants, Nice, France.
PLoS One. 2012;7(4):e34672. doi: 10.1371/journal.pone.0034672. Epub 2012 Apr 4.
Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation.
We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation.
These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas.
睾丸生殖细胞肿瘤是全世界年轻男性中最常见的癌症，发病率呈上升趋势。其发病机制和原因尚不清楚，但流行病学和临床数据表明，胎儿暴露于具有雌激素作用的环境内分泌干扰物（EEDs）中，可能参与睾丸生殖细胞癌的发生。然而，这些 EEDs（如双酚 A）通常是经典核雌激素受体的弱配体。最近，一些研究小组表明，非经典膜 G 蛋白偶联雌激素受体（GPER/GPR30）通过快速非基因组激活信号转导途径，介导雌激素和几种外源性雌激素对各种人雌激素依赖性癌细胞（乳腺、卵巢、子宫内膜）的作用。本研究旨在证明 GPER 在睾丸肿瘤中过度表达，并能够触发 JKT-1 精原细胞瘤细胞增殖。
我们在这里首次报道了 GPER 在正常和恶性人睾丸生殖细胞中的完整形态和功能特征。在正常成年人类睾丸中，GPER 由体细胞（Sertoli 细胞）和生殖细胞（精原细胞和精母细胞）表达。GPER 仅在精原细胞瘤中过度表达，精原细胞瘤是最常见的睾丸生殖细胞癌，定位于细胞膜，并在体外触发 JKT-1 细胞的增殖效应，该效应完全被 G15（GPER 选择性拮抗剂）和 siRNA 无效化所消除。
这些结果表明，GPER 由人正常成年睾丸生殖细胞表达，在精原细胞瘤中特异性过表达，并能够在体外触发精原细胞瘤细胞增殖。因此，在评估睾丸生殖细胞癌中的外源性雌激素或其他内分泌干扰物时，应考虑 GPER 而不是经典 ERs。它也可能代表精原细胞瘤的预后标志物和/或治疗靶点。
