Downregulation of miR-375 in aldosterone-producing adenomas promotes tumour cell growth via MTDH
Downregulation of miR-375 in aldosterone-producing adenomas promotes tumour cell growth via MTDH
复制标题
醛固酮腺瘤中 miR-375 的下调通过 MTDH 促进肿瘤细胞生长
DOI：
10.1111/cen.12814
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发表时间：
2015-10-01
影响因子：
3.2
通讯作者：
Ning, Guang
中科院分区：
文献类型：
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作者：
He, Juan;Cao, Yanan;Ning, Guang
目的研究原发性醛固酮增多症（primary aldosteronism， PA）的遗传和分子基础是高血压的常见病因，但microRNAs （miRNAs）对肾上腺皮质细胞增殖和醛固酮产生的影响却知之甚少。在这里，我们对PA亚型中的miRNA表达模式进行了表征，以更好地了解其发病机制。方法采用微阵列分析方法检测醛固酮生成性腺瘤（APA）、单侧肾上腺增生（UAH）和正常肾上腺皮质组织中miRNA的表达。选择的差异表达mirna通过qRT-PCR在验证队列中进一步验证。我们使用功能获得法来探索特异性miRNA在体外的功能作用。结果发现miR-375、miR-7、miR-29b等31种mirna在三组间表达有显著差异。miR-375在PA患者肾上腺皮质组织中下调最多，其表达水平与APA肿瘤大小呈负相关。在人肾上腺皮质细胞系（H295R）中过表达miR-375可降低细胞增殖并抑制MTDH （metadherin，也称为星形胶质细胞升高基因-1）的表达。此外，通过荧光素酶报告基因检测证实MTDH是miR-375的直接靶标。H295R细胞中MTDH的敲除可减弱Akt-Ser473磷酸化，抑制细胞活力。结论miR-375通过靶向MTDH/Akt通路发挥其肿瘤抑制功能，可能是PA的潜在治疗靶点。
Objective Previous studies have investigated the genetic and molecular basis of primary aldosteronism (PA), a common cause of human hypertension, but the effects of microRNAs (miRNAs) on the adrenocortical cell proliferation and aldosterone production are largely obscure. Here, we characterized miRNA expression patterns in the subtypes of PA to gain a better understanding of its pathogenesis.Methods miRNA expression was assessed by microarray profiling analysis in aldosterone-producing adenoma (APA), unilateral adrenal hyperplasia (UAH) and normal adrenal cortex tissues. Selected differentially expressed miRNAs were further validated in a validation cohort by qRT-PCR. A gain-of-function approach was used to explore the functional role of the specific miRNA in vitro.Results Of 31 miRNAs including miR-375, miR-7 and miR-29b were found to be significantly differentially expressed among these three groups. miR-375 was the most downregulated one in adrenal cortex tissues from PA patients, and its expression level was inversely correlated with the tumour size in APA. Overexpression of miR-375 in a human adrenocortical cell line (H295R) reduced cell proliferation and suppressed the expression of MTDH (metadherin, also known as astrocyte elevated gene-1). Moreover, MTDH was verified as a direct target of miR-375 through luciferase reporter assays. Knock-down of MTDH in H295R cells attenuated Akt-Ser473 phosphorylation and inhibited cell viability.Conclusion Our findings suggest that miR-375 exerts its tumour-suppressive function via targeting MTDH/Akt pathway and implicate a potential therapeutic target in PA.