Targetome profiling, pathway analysis and genetic association study implicate miR-202 in lymphomagenesis.
Targetome profiling, pathway analysis and genetic association study implicate miR-202 in lymphomagenesis.
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DOI：
10.1158/1055-9965.epi-12-1131-t
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Zhu Y
中科院分区：
文献类型：
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作者：
Hoffman AE;Liu R;Fu A;Zheng T;Slack F;Zhu Y
MiRNAs与许多肿瘤发生途径有关，以前的研究发现miR-202基因异常与多种癌症类型有关，包括滤泡性淋巴瘤。用核糖核蛋白免疫沉淀微阵列(RIP-Chip)鉴定miR-202靶标，并用Invenity Path分析工具研究鉴定靶标之间的功能相互作用。我们还进行了一项基于人群的遗传关联研究，研究miR-202茎环序列中的多态与非霍奇金淋巴瘤的风险。体外功能获得实验进一步阐明了该变异体的功能意义。通过转录组范围的RIP-Chip分析鉴定了141个miR-202靶点组的潜在成员。已识别靶点之间的功能相互作用表明miR-202调控基因参与了与血液功能和癌症相关的生物学途径。与此一致，一项使用人类血液样本的遗传关联分析显示，miR-202前体序列中的胚系突变(Rs12355840)与滤泡性淋巴瘤(FL)风险之间存在显著关联。体外功能分析进一步证明，变异等位基因导致miR-202水平降低，可能是通过改变前体加工效率。综上所述，我们的发现表明miR-202参与了滤泡淋巴肿大的发生。这些发现表明miR-202在FL中是一个潜在的肿瘤抑制因子，并值得研究miR-202作为FL风险的一个新的生物标志物。
miRNAs have been implicated in numerous tumorigenic pathways, and previous studies have associated miR-202 dysregulation with various cancer types, including follicular lymphoma. The miR-202 targetome was identified by ribonucleoprotein immunoprecipitation-microarray (RIP-Chip), and functional interactions among identified targets were investigated using the Ingenuity Pathway Analysis tool. We also performed a population-based genetic association study of a polymorphism within the miR-202 stem-loop sequence and risk of non-Hodgkin lymphoma. In vitro gain-of-function experiments were further conducted to elucidate the functional significance of the variant. 141 potential members of the miR-202 targetome were identified by a transcriptome-wide RIP-Chip assay. Functional interactions among identified targets suggested that miR-202 regulated genes are involved in biological pathways relevant for hematological function and cancer. Consistent with this, a genetic association analysis using human blood samples revealed a significant association between a germline mutation (rs12355840) in the miR-202 precursor sequence and follicular lymphoma (FL) risk. An in vitro functional assay further demonstrated that the variant allele resulted in diminished miR-202 levels, possibly by altering precursor processing efficiency. Taken together, our findings suggest that miR-202 is involved in follicular lymphomagenesis. These findings implicate miR-202 as a potential tumor suppressor in FL and warrant the investigation of miR-202 as a novel biomarker of FL risk.