A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis
A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis
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DOI：
10.1093/hmg/ddt426
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发表时间：
2014-01-15
影响因子：
3.5
通讯作者：
Yu, Jyh-Cherng
中科院分区：
文献类型：
--
作者：
Chu, Hou-Wei;Cheng, Chun-Wen;Yu, Jyh-Cherng
为了确定对调节乳腺癌进展重要的 microRNA，本研究使用了最近一项全基因组关联研究中对 837 名乳腺癌患者进行基因分型的 199 961 个单核苷酸多态性 (SNP) 数据，以确定与淋巴结转移 (LNM) 相关的位点。标记 15q22.2 位点的 SNP 显示与 LNM 显着相关，并且发现 miR-190a 是该区域唯一的 microRNA。 miR-190a 在 LNM 中的作用得到了以下发现的支持：miR-190a 表达增加抑制细胞迁移和侵袭，并且 miR-190a 的靶标是蛋白酶激活受体 1 (PAR-1)，它是多种癌症中的一种促进转移蛋白。此外，miR-190a的启动子区域被确定并发现含有一半雌激素反应元件，表明miR-190a受到雌激素受体（ER）信号传导的调节。 miR-190a 表达被 17 β-雌二醇激活并且 ER α 直接与该启动子结合，这一发现证实了这一点。以下研究结果表明了 ER α-miR190a-PAR-1 联系在乳腺肿瘤发生中的重要性：(i) 含 miR-190a 区域的遗传多态性与 LNM 之间的关联，该关联由 PAR-1 的 SNP 修饰，并且在 ER α 阳性患者中尤其显着；(ii) ER α 和 miR-190a 表达对肿瘤分级/癌症分期的综合影响。更重要的是，原发性乳腺癌中 miR-190a 的表达水平与总体生存率相关。这些发现表明，ER α 信号传导调节 miR-190a 表达，从而抑制 PAR-1 表达，与癌症转移的抑制相关。
To identify microRNAs that are important in regulating breast cancer progression, the present study used data for the 199 961 single-nucleotide polymorphisms (SNPs) in 837 breast cancer patients genotyped in a recent genome-wide association study to identify loci associated with lymph node metastasis (LNM). SNPs tagging the 15q22.2 locus showed a significant association with LNM and miR-190a was found to be the only microRNA in this region. The role of miR-190a in LNM was supported by the findings that increased miR-190a expression inhibited cell migration and invasiveness and that the target of miR-190a was protease-activated-receptor 1 (PAR-1), which is a metastasis promoting protein in several cancers. In addition, the promoter region of miR-190a was defined and found to contain half of an estrogen response element, suggesting that miR-190a is regulated by estrogen receptor (ER) signaling. This was confirmed by the findings that miR-190a expression was activated by 17 beta-estradiol and that ER alpha bound directly to this promoter. The importance of this ER alpha-miR190a-PAR-1 link in breast tumorigenesis is suggested by the findings of (i) an association between genetic polymorphism of the miR-190a-containing region and LNM that is modified by SNPs of PAR-1 and is particularly significant in ER alpha-positive patients and (ii) a combined effect of ER alpha and miR-190a expression on tumor grade/cancer stage. More importantly, the level of miR-190a expression in primary breast carcinomas correlated with overall survival. These findings suggest a novel pathway in which ER alpha signaling regulates miR-190a expression, causing inhibition of PAR-1 expression, correlated with inhibition of cancer metastasis.