Genetic variants of miRNA sequences and non–small cell lung cancer survival
Zhibin Hu, Jiaping Chen, Tian Tian, Xiaoyi Zhou, Haiyong Gu, Lin Xu, Yi Zeng, Ruifen Miao, Guangfu Jin, Hongxia Ma, Yijiang Chen, Hongbing Shen
Zhibin Hu, Jiaping Chen, Tian Tian, Xiaoyi Zhou, Haiyong Gu, Lin Xu, Yi Zeng, Ruifen Miao, Guangfu Jin, Hongxia Ma, Yijiang Chen, Hongbing Shen
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Research Article Oncology

Genetic variants of miRNA sequences and non–small cell lung cancer survival

Abstract

Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non–small cell lung cancer (NSCLC). When we assumed that disease susceptibility was inherited as a recessive phenotype, we found that the rs11614913 SNP in hsa-mir-196a2 was associated with survival in individuals with NSCLC. Specifically, survival was significantly decreased in individuals who were homozygous CC at SNP rs11614913. In the genotype-phenotype correlation analysis of 23 human lung cancer tissue samples, rs11614913 CC was associated with a statistically significant increase in mature hsa-mir-196a expression but not with changes in levels of the precursor, suggesting enhanced processing of the pre-miRNA to its mature form. Furthermore, binding assays revealed that the rs11614913 SNP can affect binding of mature hsa-mir-196a2-3p to its target mRNA. Therefore, the rs11614913 SNP in hsa-mir-196a2 may be a prognostic biomarker for NSCLC. Further characterization of miRNA SNPs may open new avenues for the study of cancer and therapeutic interventions.

Authors

Zhibin Hu, Jiaping Chen, Tian Tian, Xiaoyi Zhou, Haiyong Gu, Lin Xu, Yi Zeng, Ruifen Miao, Guangfu Jin, Hongxia Ma, Yijiang Chen, Hongbing Shen

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Figure 3

In vitro target binding assays for rs11614913 in CHO, 293T, and A549 cell lines.

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In vitro target binding assays for rs11614913 in CHO, 293T, and A549 cel...
Each transfection was performed with pRL-SV40 plasmids as normalizing controls. Data presented are the mean fold increase ± SD relative to LSP1 3′UTR luciferase reporter plasmids only (Blank) from 3 independent transfection experiments, and each was done in triplicate. (A) LSP1 3′UTR luciferase reporter plasmids with T allele hsa-mir-196a2 expression plasmid or C allele expression plasmid (P = 0.027, P = 0.028, and P = 0.028 for CHO, 293T, and A549 cell lines, respectively). (B) LSP1 3′UTR luciferase reporter plasmids with U allele chemically synthesized mature hsa-mir-196a2-3p miRNA or C allele mature miRNA (P = 0.035, P = 0.033, and P = 0.005 for CHO, 293T, and A549 cell lines, respectively).