文章：

microRNA网络的遗传变异：对癌症研究的影响

Genetic variation in microRNA networks: the implications for cancer research

原文发布日期：2010-06-01

DOI: 10.1038/nrc2867

类型: Review Article

开放获取: 否

要点：

1. Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes (miR-SNPs) can be predicted to affect function by modulating the transcription of the primary transcript, pri-miRNA and pre-miRNA processing and maturation, or miRNA–mRNA interactions. Functional support for each of these mechanisms has been found for several individual miR-SNPs.
2. SNPs in mature miRNAs and miRNA binding sites function analogously to modulate the miRNA–mRNA interaction and create or destroy miRNA binding sites.
3. Several elements have to converge for an miRNA binding site SNP to be considered functional: the SNP must have a proven association with cancer, both the miRNA and its predicted target must be expressed in the tissue, and the allelic changes must result in differential binding of the miRNA and affect expression of the target gene.
4. Computational prediction of miRNA binding sites and up-to-date coverage of SNPs is an essential part of these studies. Programs such as Patrocles and PolymiRTS intercalate and cross-reference these data with dbSNP information, and as such are invaluable in aiding the search for polymorphic miRNA binding sites.
5. Case–control studies have provided evidence for an association of miR-SNPs and SNPs in miRNA-binding sites and cancer risk. These studies differ in the degree of functional support for the predicted interaction and mechanistic insight, as well as validation status.
6. Although still lacking biological validation, SNPs in the miRNA processing machinery are likely to affect the miRNAome as a whole, perhaps leading to overall suppression of miRNA output. Despite several reported associations, none of the studies of SNPs in miRNA processing machinery has been independently validated, nor has the biological mechanisms of how they affect miRNA maturation and cancer been delineated.
7. IsomiRs are miRNA structural variants that may arise from variable cleavage sites for DROSHA and DICER1 in the hairpin. A few isomiRs have been implicated in cancer, but associations with cancer risk have not been established.
8. Both the regulatory and coding regions of genes can harbour miRNA binding sites, but research in this area remains scant. Sensitive alleles identified in epidemiological studies, but with obscure functional roles, should perhaps be tested under miRNA prediction algorithms that are not limited to the 3′ untranslated region of genes, particularly if evidence indicates that altered expression of that gene can be associated with the phenotypes.

要点翻译：

1. 微小核糖核酸（miRNA）基因中的单核苷酸多态性（miR-SNPs）可预测通过调控初级转录本pri-miRNA的转录、pre-miRNA的加工与成熟过程或miRNA-mRNA相互作用来影响功能。目前已在多个独立的miR-SNPs中发现了支持这些机制的功能性证据。
2. 成熟miRNA及其结合位点中的SNPs通过类似方式调节miRNA-mRNA相互作用，从而创建或破坏miRNA结合位点。
3. 要确认某个miRNA结合位点SNP具有功能性需满足多个要素：该SNP必须被证实与癌症存在关联；miRNA及其预测靶标均需在组织中表达；等位基因变化必须导致miRNA差异性结合并影响靶基因表达。
4. miRNA结合位点的计算预测及SNPs的最新覆盖信息是这些研究的重要组成部分。Patrocles和PolymiRTS等程序通过整合dbSNP数据库进行交叉引用，为寻找多态性miRNA结合位点提供了宝贵工具。
5. 病例对照研究已证实miR-SNPs及miRNA结合位点SNPs与癌症风险存在关联。这些研究在功能性支持程度、机制性见解及验证状态方面存在差异。
6. 尽管尚缺乏生物学验证，miRNA加工机制中的SNPs很可能从整体上影响miRNA组，可能导致miRNA输出的整体抑制。虽然已有若干相关性报道，但miRNA加工机制中SNPs的研究既未获得独立验证，其影响miRNA成熟与癌症的生物学机制也尚未阐明。
7. IsomiRs（异构miRNAs）是源于DROSHA和DICER1在发夹结构中可变切割位点产生的miRNA结构变体。部分isomiRs已被证实与癌症相关，但其与癌症风险的关联尚未确立。
8. 基因的调控区和编码区均可存在miRNA结合位点，但该领域研究仍显不足。在流行病学研究中发现的功能机制不明的敏感等位基因，或需采用不限于基因3'非翻译区的miRNA预测算法进行验证——特别是在有证据表明该基因表达改变与表型相关时。

英文摘要：

Many studies have highlighted the role that microRNAs have in physiological processes and how their deregulation can lead to cancer. More recently, it has been proposed that the presence of single nucleotide polymorphisms in microRNA genes, their processing machinery and target binding sites affects cancer risk, treatment efficacy and patient prognosis. In reviewing this new field of cancer biology, we describe the methodological approaches of these studies and make recommendations for which strategies will be most informative in the future.

摘要翻译： 

许多研究强调了 microRNA 在生理过程中的作用，以及其失调如何导致癌症。最近有研究提出，microRNA 基因、其加工机制及靶结合位点中的单核苷酸多态性会影响癌症风险、治疗效果和患者预后。在回顾这一癌症生物学新领域时，我们描述了这些研究的方法学，并就未来最具信息价值的策略提出建议。

原文链接：

Genetic variation in microRNA networks: the implications for cancer research