Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer
Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer
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DOI：
10.1038/onc.2008.10
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发表时间：
2008-06-19
期刊：
影响因子：
8
通讯作者：
Tewari, M.
中科院分区：
文献类型：
--
作者：
Grady, W. M.;Parkin, R. K.;Tewari, M.
microrna是一种小的非编码RNA，通过对特定信使RNA靶点的转录后调控来影响基因调控网络。MicroRNA在人类恶性肿瘤中的表达失调，经常导致某些MicroRNA的表达缺失。我们报道了hsa-miR-342（一种编码于EVL基因内含子中的microRNA）的表达在人类结直肠癌中通常被抑制。hsa-miR- 342的表达与EVL的表达是协调的，我们的研究结果表明沉默的机制是EVL上游的CpG岛甲基化。我们发现EVL/hsa-miR-342位点在86%的结直肠癌和67%的腺瘤中存在甲基化，这表明它是结直肠癌发生的早期事件。此外，我们观察到，与未患结直肠癌的个体（12%）相比，同时患有癌症的个体在组织学上正常的结直肠粘膜中甲基化的频率（56%）更高，这表明存在涉及甲基化EVL/hsa-miR-342的“场缺陷”。此外，hsa-miR- 342在结直肠癌细胞系HT-29中的重组可诱导细胞凋亡，提示该microRNA可能具有促凋亡抑癌作用。总的来说，这些结果支持通过同源宿主基因的表观遗传改变来沉默癌症中内含子microrna的新机制。
MicroRNAs are small, non-coding RNAs that influence gene regulatory networks by post-transcriptional regulation of specific messenger RNA targets. MicroRNA expression is dysregulated in human malignancies, frequently leading to loss of expression of certain microRNAs. We report that expression of hsa-miR-342, a microRNA encoded in an intron of the gene EVL, is commonly suppressed in human colorectal cancer. The expression of hsa-miR- 342 is coordinated with that of EVL and our results indicate that the mechanism of silencing is CpG island methylation upstream of EVL. We found methylation at the EVL/hsa-miR-342 locus in 86% of colorectal adenocarcinomas and in 67% of adenomas, indicating that it is an early event in colorectal carcinogenesis. In addition, we observed a higher frequency of methylation ( 56%) in histologically normal colorectal mucosa from individuals with concurrent cancer compared to mucosa from individuals without colorectal cancer ( 12%), suggesting the existence of a 'field defect' involving methylated EVL/hsa-miR-342. Furthermore, reconstitution of hsa-miR- 342 in the colorectal cancer cell line HT-29 induced apoptosis, suggesting that this microRNA could function as a proapoptotic tumor suppressor. In aggregate, these results support a novel mechanism for silencing intronic microRNAs in cancer by epigenetic alterations of cognate host genes.