Chevalier Nicolas, Hinault Charlotte, Clavel Stephan, Paul-Bellon Rachel, Fenichel Patrick
Université Côte d'Azur, CHU, INSERM U1065, C3M, Nice, France.
Université Côte d'Azur, INSERM U1065, C3M, Nice, France.
Front Endocrinol (Lausanne). 2021 Jan 26;11:600404. doi: 10.3389/fendo.2020.600404. eCollection 2020.
The G protein-coupled estrogen receptor (GPER), also known as GPR30, is a widely conserved 7-transmembrane-domain protein which has been identified as a novel 17β-estradiol-binding protein that is structurally distinct from the classic oestrogen receptors (ERα and ERβ). There are still conflicting data regarding the exact role and the natural ligand of GPER/GPR30 in reproductive tracts as both male and female knock-out mice are fertile and have no abnormalities of reproductive organs. Testicular germ cell cancers (TGCCs) are the most common malignancy in young males and the most frequent cause of death from solid tumors in this age group. Clinical and experimental studies suggested that estrogens participate in the physiological and pathological control of male germ cell proliferation. In human seminoma cell line, while 17β-estradiol (E2) inhibits cell proliferation through an ERβ-dependent mechanism, an impermeable E2 conjugate (E2 coupled to BSA), cell proliferation is stimulated by activating ERK1/2 and protein kinase A through a membrane GPCR that we further identified as GPER/GPR30. The same effect was observed with low but environmentally relevant doses of BPA, an estrogenic endocrine disrupting compound. Furthermore, GPER/GPR30 is specifically overexpressed in seminomas but not in non-seminomas and this overexpression is correlated with an ERβ-downregulation. This GPER/GPR30 overexpression could be linked to some genetic variations, as single nucleotide polymorphisms, which was also reported in other hormone-dependent cancers. We will review here the implication of GPER/GPR30 in TGCCs pathophysiology and the arguments to consider GPER/GPR30 as a potential therapeutic target in humans.
G蛋白偶联雌激素受体（GPER），也称为GPR30，是一种广泛保守的7跨膜结构域蛋白，已被鉴定为一种新型的17β-雌二醇结合蛋白，其结构与经典雌激素受体（ERα和ERβ）不同。关于GPER/GPR30在生殖道中的具体作用和天然配体仍存在相互矛盾的数据，因为雄性和雌性基因敲除小鼠都具有生育能力且生殖器官无异常。睾丸生殖细胞癌（TGCC）是年轻男性中最常见的恶性肿瘤，也是该年龄组实体瘤死亡的最常见原因。临床和实验研究表明，雌激素参与雄性生殖细胞增殖的生理和病理控制。在人精原细胞瘤细胞系中，虽然17β-雌二醇（E2）通过依赖ERβ的机制抑制细胞增殖，但一种不可渗透的E2偶联物（E2与牛血清白蛋白偶联），通过激活ERK1/2和蛋白激酶A，通过一种我们进一步鉴定为GPER/GPR30的膜GPCR刺激细胞增殖。在低剂量但与环境相关的双酚A（一种雌激素内分泌干扰化合物）中也观察到了相同的效果。此外，GPER/GPR30在精原细胞瘤中特异性过表达，而在非精原细胞瘤中则不过表达，这种过表达与ERβ下调相关。这种GPER/GPR30过表达可能与一些遗传变异有关，如单核苷酸多态性，这在其他激素依赖性癌症中也有报道。我们将在此回顾GPER/GPR30在TGCC病理生理学中的意义，以及将GPER/GPR30视为人类潜在治疗靶点的依据。
