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表观遗传药物治疗诱导的微小RNA-492上调在体外抑制透明细胞肾细胞癌的恶性表型。

Upregulation of microRNA-492 induced by epigenetic drug treatment inhibits the malignant phenotype of clear cell renal cell carcinoma in vitro.

作者信息

Wu Aibing, Wu Kunpeng, Li Mingchun, Bao Lingli, Shen Xiang, Li Shunjun, Li Jinmei, Yang Zhixiong

机构信息

Oncology Center, The Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.

出版信息

Mol Med Rep. 2015 Jul;12(1):1413-20. doi: 10.3892/mmr.2015.3550. Epub 2015 Mar 26.

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer of the renal parenchyma. MicroRNAs (miRNAs) are non-coding RNAs of ~22 nucleotides in length, which function as post‑transcriptional regulators. Recently, the downregulation of miRNA (miR)-492 was observed to be associated with ccRCC; however, the molecular mechanism by which miR492 inhibited ccRCC remained to be elucidated. In the present study, it was demonstrated that miR-492 was markedly downregulated in ccRCC tissues when compared with adjacent normal tissues, as determined by reverse transcription-quantitative poymerase chain reaction (PCR). This downregulation was predominantly due to the hypermethylation of the CpG island of the miR-492 promoter, which was detected by methylation specific PCR and bisulfite genomic sequencing PCR, and was shown to inhibit miR-492 transcription. Through the use of a DNA demethylation agent, 5-aza-2'-deoxycytidine or the histone deacetylase inhibitor 4-phenylbutyric acid, the expression level of miR-492 was significantly upregulated in ccRCC cells, which further inhibited cell proliferation and invasion, while promoting cell apoptosis and adhesion. In conclusion, the present study provided novel insights into the potential mechanisms involved in ccRCC and it is hypothesized that miR-492 may become a promising therapeutic agent in the treatment of ccRCC.

摘要

透明细胞肾细胞癌(ccRCC)是肾实质中最常见的癌症类型。微小RNA(miRNA)是长度约为22个核苷酸的非编码RNA,其作为转录后调节因子发挥作用。最近,观察到miRNA(miR)-492的下调与ccRCC相关;然而,miR492抑制ccRCC的分子机制仍有待阐明。在本研究中,通过逆转录-定量聚合酶链反应(PCR)确定,与相邻正常组织相比,ccRCC组织中miR-492明显下调。这种下调主要是由于miR-492启动子的CpG岛发生高甲基化,通过甲基化特异性PCR和亚硫酸氢盐基因组测序PCR检测到,并且显示其抑制miR-492转录。通过使用DNA去甲基化剂5-氮杂-2'-脱氧胞苷或组蛋白脱乙酰酶抑制剂4-苯丁酸,ccRCC细胞中miR-492的表达水平显著上调,这进一步抑制了细胞增殖和侵袭,同时促进了细胞凋亡和黏附。总之,本研究为ccRCC潜在机制提供了新见解,并且推测miR-492可能成为治疗ccRCC的一种有前景的治疗药物。

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