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. 2009 Feb 3;106(5):1502-5.
doi: 10.1073/pnas.0812591106. Epub 2009 Jan 21.

Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer

Krystian Jazdzewski  1 , Sandya Liyanarachchi, Michal Swierniak, Janusz Pachucki, Matthew D Ringel, Barbara Jarzab, Albert de la Chapelle
Affiliations

Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer

Krystian Jazdzewski et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Structure and target genes of the 3 mature microRNAs produced from premiR-146a. (A) The predicted structure of premiR-146a. The mature miR-146a is shown by red dots. The location of passenger strand miR-146a* is shown by blue dots. The location of the G/C SNP is shown by an arrow. (B) Target genes of the 3 mature products of premiR-146a (Target Rank score >0.35).
Fig. 2.
Fig. 2.
Quality control of custom designed stem loop real-time RT-PCR assay. Plots show the amplification of serial dilutions of synthesized mature miR-146a*G oligo. Similar results were obtained from the assay for miR-146a*C with serial dilutions of mature miR-146a*C oligo.
See this image and copyright information in PMC

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