Development of the human cancer microRNA network.
Development of the human cancer microRNA network.
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DOI：
10.1186/1758-907x-1-6
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发表时间：
2010-02-02
期刊：
影响因子：
--
通讯作者：
Zhang MQ
中科院分区：
文献类型：
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作者：
Bandyopadhyay S;Mitra R;Maulik U;Zhang MQ
MicroRNA是一类在不同癌细胞中异常表达的小的非编码RNA。不同恶性肿瘤中miRNA的分子特征表明，这些miRNA不仅积极参与人类癌症的发病机制，而且在患者的生存中具有重要作用。在特定的癌症组织类型中特定的miRNA的差异表达模式已经在数百篇研究文章中报道。然而，已经进行了有限的尝试来整理这些大量的信息，并获得多个癌症类型中miRNA失调的全球视角。在这篇文章中，通过挖掘实验验证的癌症-miRNA关系的文献，开发了癌症-miRNA网络。这个网络提出了一些新的和有趣的生物学见解，这些见解在个别实验中并不明显，但在全球范围内研究时变得明显。从该网络中，已经基于挖掘癌症类型和miRNA之间关联的计算方法识别了许多癌症-miRNA模块。发现基于这些关联产生的模块具有许多共同的预测靶肿瘤/肿瘤抑制基因。这表明在选择性癌症组织或细胞系中，模块相关的miRNA对靶基因调控的组合效应。此外，这些模块的相邻miRNA（位于基因组位置50 kb内的miRNA组）显示出类似的失调模式，表明共同的调控途径。除此之外，邻近的miRNA也可能在癌组织中显示出类似的失调模式（差异共表达）。在这项研究中，我们发现在67%的癌症类型中，至少有两个相邻的miRNA显示下调，这是统计学显著的（P < 10-7，随机化检验）。对于邻近的miRNA获得了类似的结果，其在特定癌症类型中显示上调。这些结果阐明了这样一个事实，即相邻的miRNA可能在癌组织中与正常组织类型的差异共表达。此外，cancer-miRNA网络有效地检测许多癌症类型中失调的中心miRNA并鉴定癌症特异性miRNA。根据表达模式，有可能鉴定出具有强致癌或肿瘤抑制特征的枢纽。有限的工作已经做了揭示的事实，即一些miRNA可以控制通常改变的调控途径。然而，通过在所提出的网络模型中分析癌症-miRNA关系，这一点立即变得显而易见。这些在miRNA研究中提出了许多以前从未报道过的未解决的问题。这些观察结果有望对癌症产生强烈的影响，并可能对进一步的研究有用。
MicroRNAs are a class of small noncoding RNAs that are abnormally expressed in different cancer cells. Molecular signature of miRNAs in different malignancies suggests that these are not only actively involved in the pathogenesis of human cancer but also have a significant role in patients survival. The differential expression patterns of specific miRNAs in a specific cancer tissue type have been reported in hundreds of research articles. However limited attempt has been made to collate this multitude of information and obtain a global perspective of miRNA dysregulation in multiple cancer types. In this article a cancer-miRNA network is developed by mining the literature of experimentally verified cancer-miRNA relationships. This network throws up several new and interesting biological insights which were not evident in individual experiments, but become evident when studied in the global perspective. From the network a number of cancer-miRNA modules have been identified based on a computational approach to mine associations between cancer types and miRNAs. The modules that are generated based on these association are found to have a number of common predicted target onco/tumor suppressor genes. This suggests a combinatorial effect of the module associated miRNAs on target gene regulation in selective cancer tissues or cell lines. Moreover, neighboring miRNAs (group of miRNAs that are located within 50 kb of genomic location) of these modules show similar dysregulation patterns suggesting common regulatory pathway. Besides this, neighboring miRNAs may also show a similar dysregulation patterns (differentially coexpressed) in the cancer tissues. In this study, we found that in 67% of the cancer types have at least two neighboring miRNAs showing downregulation which is statistically significant (P < 10-7, Randomization test). A similar result is obtained for the neighboring miRNAs showing upregulation in specific cancer type. These results elucidate the fact that the neighboring miRNAs might be differentially coexpressed in cancer tissues as that of the normal tissue types. Additionally, cancer-miRNA network efficiently detect hub miRNAs dysregulated in many cancer types and identify cancer specific miRNAs. Depending on the expression patterns, it is possible to identify those hubs that have strong oncogenic or tumor suppressor characteristics. Limited work has been done towards revealing the fact that a number of miRNAs can control commonly altered regulatory pathways. However, this becomes immediately evident by accompanying the analysis of cancer-miRNA relationships in the proposed network model. These raise many unaddressed issues in miRNA research that have never been reported previously. These observations are expected to have an intense implication in cancer and may be useful for further research.