Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer
Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer
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DOI：
10.1073/pnas.0812591106
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发表时间：
2009-02-03
影响因子：
11.1
通讯作者：
De la Chapelle, Albert
中科院分区：
文献类型：
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作者：
Jazdzewski, Krystian;Liyanarachchi, Sandya;De la Chapelle, Albert
先前的工作表明，microRNA-146a前体中单核苷酸多态(SNP Rs2910164)的杂合性G/C易患PTC(优势比=1.62，P=0.000007)，尽管其机制尚不清楚。在这里，我们表明GC杂合子不同于GG和CC纯合子，因为它们产生了3个成熟的microRNAs：1个来自前导链(miR-146a)，2个来自辅助链(miR-146A*G和miR-146A*C)，每个都有不同的目标基因集。对配对的肿瘤/正常样本的TaqMan分析显示，与同一腺体未受影响的部分相比，8个肿瘤中有7个肿瘤组织中miR-146a*基因的多态过度表达1.5-2.6倍。微阵列数据显示，GC和GG患者的肿瘤和未受影响的甲状腺部分出现了截然不同的转录本。这些被调控的基因主要参与细胞凋亡的调控，导致杂合子DNA损伤反应被夸大，这可能解释了癌症的易感性。我们认为，与以前的观点相反，来自miRs乘客链的转录产物可以深刻地影响下游效应。Premir序列中的多态杂合性可以通过产生额外的成熟MIR来引起上位性。我们认为，来自客体链的成熟miRs可能调节许多遗传过程。
Prior work has shown that heterozygosity G/C of single nucleotide polymorphism (SNP rs2910164) within the precursor of microRNA-146a predisposes to PTC (odds ratio = 1.62, P = 0.000007) although the mechanism was unclear. Here, we show that GC heterozygotes differ from both GG and CC homozygotes by producing 3 mature microRNAs: 1 from the leading strand (miR-146a), and 2 from the passenger strand (miR-146a*G and miR-146a*C), each with its distinct set of target genes. TaqMan analysis of paired tumor/normal samples revealed 1.5- to 2.6-fold overexpression of polymorphic miR-146a* in 7 of 8 tumors compared with the unaffected part of the same gland. The microarray data showed that widely different transcriptomes occurred in the tumors and in unaffected parts of the thyroid from GC and GG patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer. We propose that contrary to previously held views transcripts from the passenger strand of miRs can profoundly affect the downstream effects. Heterozygosity for polymorphisms within the premiR sequence can cause epistasis through the production of additional mature miRs. We propose that mature miRs from the passenger strand may regulate many genetic processes.