The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function
The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function
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DOI：
10.1158/0008-5472.can-06-4074
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发表时间：
2007-02-15
期刊：
影响因子：
11.2
通讯作者：
Lyko, Frank
中科院分区：
文献类型：
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作者：
Brueckner, Bodo;Stresemann, Carlo;Lyko, Frank
微小RNA（microRNAs，miRNAs）是一类小的非编码RNA，通过互补碱基配对和诱导RNA干扰途径抑制其靶mRNA。研究表明，miRNA的表达受DNA甲基化的调控，miRNA基因甲基化的改变可能与人类肿瘤的发生有关。在这项研究中，我们发现，人类let-7a-3基因的染色体22q13.31与CpG岛。Let-7a-3属于原型let-7 miRNA基因家族，被发现被DNA甲基转移酶DNMT 1和DNMT 3B甲基化。该基因在正常人组织中高度甲基化，但在一些肺腺癌中低甲基化。Let-7a-3低甲基化促进了基因的表观遗传再激活，并且let-7a-3在人肺癌细胞系中的表达升高导致了增强的肿瘤表型和转录谱的致癌变化。因此，我们的研究结果确定let-7a-3作为具有致癌功能的表观遗传调控的miRNA基因，并表明异常的miRNA基因甲基化可能有助于人类癌症表观基因组。
MicroRNAs (miRNAs) are small noncoding RNAs that repress their target mRNAs by complementary base pairing and induction of the RNA interference pathway. It has been shown that miRNA expression can be regulated by DNA methylation and it has been suggested that altered miRNA gene methylation might contribute to human tumorigenesis. In this study, we show that the human let-7a-3 gene on chromosome 22q13.31 is associated with a CpG island. Let-7a-3 belongs to the archetypal let-7 miRNA gene family and was found to be methylated by the DNA methyltransferases DNMT1 and DNMT3B. The gene was heavily methylated in normal human tissues but hypomethylated in some lung adenocarcinomas. Let-7a-3 hypomethylation facilitated epigenetic reactivation of the gene and elevated expression of let-7a-3 in a human lung cancer cell line resulted in enhanced tumor phenotypes and oncogenic changes in transcription profiles. Our results thus identify let-7a-3 as an epigenetically regulated miRNA gene with oncogenic function and suggest that aberrant miRNA gene methylation might contribute to the human cancer epigenome.