miR-503 represses human cell proliferation and directly targets the oncogene DDHD2 by non-canonical target pairing.
miR-503 represses human cell proliferation and directly targets the oncogene DDHD2 by non-canonical target pairing.
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DOI：
10.1186/s12864-015-1279-9
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发表时间：
2015-02-05
期刊：
影响因子：
4.4
通讯作者：
Iyer VR
中科院分区：
文献类型：
--
作者：
Polioudakis D;Abell NS;Iyer VR
调节哺乳动物细胞从静止到增殖转变的途径由多种miRNA介导。尽管我们对miRNA靶向的理解有了很大的提高，但大多数miRNA调控网络在很大程度上仍然是未知的，需要实验验证。在这里，我们鉴定了miR-503、miR-103和miR-494作为原代人类细胞增殖的负调节因子。我们通过RNA诱导沉默复合物（RISC）免疫沉淀和基因表达谱实验确定了它们的全基因组靶谱。全基因组靶谱的分析揭示了通过miR-503的非典型靶配对广泛调节基因表达的证据。我们鉴定了原癌基因DDHD 2作为miR-503的靶点，其需要在miR-503的典型5′种子区之外配对，代表了一种新的miRNA-靶点配对模式。进一步的生物信息学分析表明miR-503和DDHD 2参与了乳腺癌的发生。我们的研究结果提供了广泛的miR-503、miR-103和miR-494的全基因组靶点，并表明miR-503可能通过其直接非经典靶向DDHD 2而在乳腺癌中充当肿瘤抑制因子。本文的在线版本（doi：10.1186/s12864-015-1279-9）包含补充材料，可供授权用户使用。
The pathways regulating the transition of mammalian cells from quiescence to proliferation are mediated by multiple miRNAs. Despite significant improvements in our understanding of miRNA targeting, the majority of miRNA regulatory networks are still largely unknown and require experimental validation. Here we identified miR-503, miR-103, and miR-494 as negative regulators of proliferation in primary human cells. We experimentally determined their genome wide target profiles using RNA-induced silencing complex (RISC) immunoprecipitations and gene expression profiling. Analysis of the genome wide target profiles revealed evidence of extensive regulation of gene expression through non-canonical target pairing by miR-503. We identified the proto-oncogene DDHD2 as a target of miR-503 that requires pairing outside of the canonical 5′ seed region of miR-503, representing a novel mode of miRNA-target pairing. Further bioinformatics analysis implicated miR-503 and DDHD2 in breast cancer tumorigenesis. Our results provide an extensive genome wide set of targets for miR-503, miR-103, and miR-494, and suggest that miR-503 may act as a tumor suppressor in breast cancer by its direct non-canonical targeting of DDHD2. The online version of this article (doi:10.1186/s12864-015-1279-9) contains supplementary material, which is available to authorized users.
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