GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions.
GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions.
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DOI：
10.18632/oncotarget.20653
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发表时间：
2017-10-13
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影响因子：
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通讯作者：
Harvey BJ
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文献类型：
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作者：
Bustos V;Nolan ÁM;Nijhuis A;Harvey H;Parker A;Poulsom R;McBryan J;Thomas W;Silver A;Harvey BJ
雌激素受体ERβ是正常高分化结肠上皮中主要表达的ER亚型。然而，随着结直肠癌（CRC）恶性进展，ERβ在缺氧微环境下表达缺失。这就提出了关于缺氧条件下雌激素17β-雌二醇（E2）通过其他雌激素受体（如ERα或g蛋白偶联雌激素受体（GPER, GPR30））在ERβ在结直肠癌进展中丢失后信号传导作用的问题。我们验证了E2或缺氧可通过GPER作用于CRC细胞表型改变的假设。在一组CRC细胞系中，GPER的表达在缺氧和E2的作用下被上调。e2调节基因共济失调毛细血管扩张突变（ATM）在缺氧时通过GPER信号被抑制。E2处理增强了缺氧诱导的HIF1-α和VEGFA的表达，但在常氧条件下抑制了HIF1-α和VEGFA的表达。E2对VEGFA的表达和抑制是通过gper依赖机制介导的。E2处理增强了缺氧诱导的CRC细胞迁移和增殖，而在常氧环境下，E2处理抑制了细胞迁移和增殖。E2在常氧和缺氧条件下对这些细胞反应的影响是由GPER介导的。在566例CRC患者肿瘤样本的队列中，GPER表达与CRC 3-4期女性患者的低生存率显著相关，但与分期匹配的男性人群无关。我们的研究结果支持E2在缺氧条件下通过GPER介导的er β阴性结直肠癌中潜在的促肿瘤作用，并提出了一种通过GPER拮抗治疗干预的新途径。
The estrogen receptor ERβ is the predominant ER subtype expressed in normal well-differentiated colonic epithelium. However, ERβ expression is lost under the hypoxic microenvironment as colorectal cancer (CRC) malignancy progresses. This raises questions about the role of signalling through other estrogen receptors such as ERα or G-protein coupled estrogen receptor (GPER, GPR30) by the estrogen 17β-estradiol (E2) under hypoxic conditions after ERβ is lost in CRC progression. We tested the hypothesis that E2 or hypoxia can act via GPER to contribute to the altered phenotype of CRC cells. GPER expression was found to be up-regulated by hypoxia and E2 in a panel of CRC cell lines. The E2-modulated gene, Ataxia telangiectasia mutated (ATM), was repressed in hypoxia via GPER signalling. E2 treatment enhanced hypoxia-induced expression of HIF1-α and VEGFA, but repressed HIF1-α and VEGFA expression under normoxic conditions. The expression and repression of VEGFA by E2 were mediated by a GPER-dependent mechanism. E2 treatment potentiated hypoxia-induced CRC cell migration and proliferation, whereas in normoxia, cell migration and proliferation were suppressed by E2 treatment. The effects of E2 on these cellular responses in normoxia and hypoxia were mediated by GPER. In a cohort of 566 CRC patient tumor samples, GPER expression significantly associated with poor survival in CRC Stages 3-4 females but not in the stage-matched male population. Our findings support a potentially pro-tumorigenic role for E2 in ERβ-negative CRC under hypoxic conditions transduced via GPER and suggest a novel route of therapeutic intervention through GPER antagonism.