microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis.
microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis.
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DOI：
10.1158/0008-5472.can-09-0236
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Hoffman AE;Zheng T;Yi C;Leaderer D;Weidhaas J;Slack F;Zhang Y;Paranjape T;Zhu Y
越来越多的证据表明 microRNA (miRNA) 在肿瘤发生中发挥重要作用。作为转录调节因子，改变的 miRNA 表达可能会影响许多与癌症相关的生物途径，表明 miRNA 可以充当肿瘤抑制因子和/或癌基因。我们首先通过筛选 15 个 microRNA 基因中的遗传变异进行遗传关联分析，发现 hsa-miR-196a-2 中的常见序列变异（rs11614913，C→T）与降低乳腺癌风险显着相关（纯合变异：OR=0.44，95% CI，0.28-0.70）。 miR-196a-2 前体上游 CpG 岛（-700 bp）的高甲基化也与乳腺癌风险降低相关（OR=0.35，95% CI，0.15-0.81）。通过将含有野生型或突变型 miR-196a-2 前体的表达载体递送到乳腺癌细胞中，我们证明这种变体导致 miRNA 前体加工成成熟形式的效率较低，并且调节靶基因的能力减弱。进行了全基因组表达微阵列，并基于通路的分析确定了由在 miR-196a-2 强制表达后显着改变的基因形成的癌症相关网络。诱变分析进一步表明，与野生型处理的细胞相比，用变体 miR-196a-2 处理的细胞对诱变剂攻击的细胞周期反应显着增强。综上所述，我们的研究结果表明，miR-196a-2可能在乳腺肿瘤发生中具有潜在的致癌作用，其成熟区域的功能遗传变异可以作为乳腺癌易感性的新型生物标志物。
Increasing evidence has suggested that microRNAs (miRNAs) play an important role in tumorigenesis. As transcriptional regulators, altered miRNA expression may affect many cancer-related biological pathways, indicating that miRNAs can function as tumor suppressors and/or oncogenes. We first performed a genetic association analysis by screening genetic variants in 15 microRNA genes and detected that a common sequence variant in hsa-miR-196a-2 (rs11614913, C→T) was significantly associated with decreased breast cancer risk (for homozygous variant: OR=0.44, 95% CI, 0.28-0.70). Hypermethylation of a CpG island upstream (-700 bp) of the miR-196a-2 precursor was also associated with reduced breast cancer risk (OR=0.35, 95% CI, 0.15-0.81). By delivering expression vectors containing either wild-type or mutant precursors of miR-196a-2 into breast cancer cells, we demonstrated that this variant led to less efficient processing of the miRNA precursor to its mature form, as well as diminished capacity to regulate target genes. A whole genome expression microarray was preformed and a pathway-based analysis identified a cancer-relevant network formed by genes significantly altered following enforced expression of miR-196a-2. Mutagenesis analysis further showed that cell cycle response to mutagen challenge was significantly enhanced in cells treated with variant miR-196a-2 compared to cells treated with the wild-type. Taken together, our findings suggest that miR-196a-2 might have a potentially oncogenic role in breast tumorigenesis, and the function genetic variant in its mature region could serve as a novel biomarker for breast cancer susceptibility.