Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer.
Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer.
复制标题
G 蛋白偶联雌激素受体 (GPER) 的表观遗传下调在结直肠癌中发挥肿瘤抑制作用
DOI：
10.1186/s12943-017-0654-3
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发表时间：
2017-05-05
期刊：
影响因子：
37.3
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Liu Q;Chen Z;Jiang G;Zhou Y;Yang X;Huang H;Liu H;Du J;Wang H
背景雌激素信号在结直肠癌的发生发展中具有保护作用. G蛋白偶联雌激素受体（GPER）已被报道在激素相关癌症（CRC除外）中介导雌激素的非基因组效应。方法检测GPER在大肠癌组织中的表达及其与临床病理特征的关系。使用细胞，小鼠异种移植模型，和临床人类samples.ResultsGPER进一步研究的机制是显着（p< 0.01）下调CRC组织相比，他们匹配的相邻正常组织在我们的两个队列和三个独立的调查Oncomine数据库。与GPER水平较高的患者（n= 54）相比，GPER表达较低的患者（n= 36）的生存率显着（p< 0.01）较差。启动子甲基化和组蛋白H3去乙酰化参与了结直肠癌细胞系和临床组织中GPER的下调。GPER的特异性激动剂G-1激活GPER可抑制结直肠癌细胞的增殖、诱导细胞周期阻滞、细胞凋亡和内质网应激。活性氧（ROS）的上调诱导的持续ERK 1/2激活参与G-1诱导的细胞生长停滞。此外，G-1可通过经典IKKα/ IκBα途径和GSK-3β磷酸化抑制NF-κB的磷酸化、核定位和转录活性。基于HCT-116细胞的异种移植模型证实G-1可以抑制结直肠癌的体内进展。结论GPER的表观遗传学下调在结直肠癌中具有肿瘤抑制作用，其特异性激活可能是结直肠癌治疗的潜在方法。
BackgroundEstrogenic signals are suggested to have protection roles in the development of colorectal cancer (CRC). The G protein-coupled estrogen receptor (GPER) has been reported to mediate non-genomic effects of estrogen in hormone related cancers except CRC. Its expression and functions in CRC were investigated.MethodsThe expression of GPER and its associations with clinicopathological features were examined. The mechanisms were further investigated using cells, mouse xenograft models, and clinical human samples.ResultsGPER was significantly (p< 0.01) down regulated in CRC tissues compared with their matched adjacent normal tissues in our two cohorts and three independent investigations from Oncomine database. Patients whose tumors expressing less (n= 36) GPER showed significant (p< 0.01) poorer survival rate as compared with those with greater levels of GPER (n= 54). Promoter methylation and histone H3 deacetylation were involved in the down regulation of GPER in CRC cell lines and clinical tissues. Activation of GPER by its specific agonist G-1 inhibited proliferation, induced cell cycle arrest, mitochondrial-related apoptosis and endoplasmic reticulum (ER) stress of CRC cells. The upregulation of reactive oxygen species (ROS) induced sustained ERK1/2 activation participated in G-1 induced cell growth arrest. Further, G-1 can inhibit the phosphorylation, nuclear localization, and transcriptional activities of NF-κB via both canonical IKKα/ IκBα pathways and phosphorylation of GSK-3β. Xenograft model based on HCT-116 cells confirmed that G-1 can suppress the in vivo progression of CRC.ConclusionsEpigenetic down regulation of GPER acts as a tumor suppressor in colorectal cancer and its specific activation might be a potential approach for CRC treatment.