Yan Yan, Jiang Xueli, Zhao Ying, Wen Haixia, Liu Guoyi
Laboratory of Reproductive Endocrinology, Department of Physiology, Harbin Medical University, Harbin, China.
Cell Biochem Funct. 2015 Dec;33(8):552-9. doi: 10.1002/cbf.3154. Epub 2015 Nov 3.
G protein-coupled estrogen receptor (GPER) is identified as a critical estrogen receptor, in addition to the classical estrogen receptors ERα and ERβ. In ERα-negative ovarian cancer cells, our previous studies have found that estrogen stimulated cell proliferation and metastasis via GPER. However, the ligand-independent function of GPER in ovarian cancer cells is still not clear. Herein, we describe that GPER has a co-expression with ERα and ERβ, which are first determined in SKOV3 ovarian cancer cell line. In the absence of estrogen, GPER depletion by specific siRNA inhibits the proliferation, migration and invasion of SKOV3 cells. Whereas abrogation of ERα or ERβ by specific antagonist MPP and PHTPP has the opposite effects for stimulation of cell growth. Markedly, GPER knockdown attenuates MPP or PHTPP-induced cell proliferation, migration and invasion. Furthermore, GPER modulates protein expression of the cell cycle critical components, c-fos and cyclin D1 and factors for cancer cell invasion and metastasis, matrix metalloproteinase 2 (MMP-2) and MMP-9. These findings establish that GPER ligand-independently stimulates the proliferation, migration and invasion of SKOV3 cells. Knockdown of GPER attenuates the progression of ovarian cancer that caused by functional loss of ERα or ERβ. Targeting GPER provides new aspect as a potential therapeutic strategy in ovarian cancer.
除了经典的雌激素受体ERα和ERβ外，G蛋白偶联雌激素受体（GPER）被鉴定为一种关键的雌激素受体。在ERα阴性的卵巢癌细胞中，我们之前的研究发现雌激素通过GPER刺激细胞增殖和转移。然而，GPER在卵巢癌细胞中的非配体依赖性功能仍不清楚。在此，我们描述了GPER与ERα和ERβ共表达，这是首次在SKOV3卵巢癌细胞系中确定的。在没有雌激素的情况下，通过特异性siRNA耗尽GPER可抑制SKOV3细胞的增殖、迁移和侵袭。而用特异性拮抗剂MPP和PHTPP消除ERα或ERβ对细胞生长的刺激则具有相反的效果。值得注意的是，敲低GPER可减弱MPP或PHTPP诱导的细胞增殖、迁移和侵袭。此外，GPER调节细胞周期关键成分c-fos和细胞周期蛋白D1的蛋白表达以及癌细胞侵袭和转移相关因子基质金属蛋白酶2（MMP-2）和MMP-9。这些发现表明，GPER非配体依赖性地刺激SKOV3细胞的增殖、迁移和侵袭。敲低GPER可减弱由ERα或ERβ功能丧失引起的卵巢癌进展。靶向GPER为卵巢癌的潜在治疗策略提供了新的方向。
