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Functional SNP in microRNA‐491‐5p binding site of MMP9 3′‐UTR affects cancer susceptibility
Author(s) -
Pirooz Homeira Javadi,
Jafari Niloofar,
Rastegari Mozhdeh,
FathiRoudsari Mehrnoosh,
Tasharrofi Nooshin,
Shokri Gelareh,
Tamadon Mona,
Sazegar Hossein,
Kouhkan Fatemeh
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26471
Subject(s) - microrna , three prime untranslated region , untranslated region , biology , genotype , mmp9 , snp , genetics , binding site , cancer research , single nucleotide polymorphism , gene , microbiology and biotechnology , messenger rna , downregulation and upregulation
MicroRNAs (miRNA) are small RNA molecules that negatively regulate gene expression through base pairing interactions between 3′‐UTR of the target mRNAs and seed sequence of miRNA. Any changes in the recognition site could destroy binding sites or modify binding affinity, resulting in evasion from miRNA regulation. A putative binding site for miR‐491‐5p resides in 3′‐UTR of MMP9, and a genetic variant (rs1056628 A → C) is present in this region. The role of MMP9 over expression well marked in various cancers. However, whether rs1056628 SNP in miR‐491‐5p binding site of MMP9 3′‐UTR could abrogate its post‐transcriptional regulation and affect cancer susceptibility remains largely unknown. To test this, the rs1056628 SNP was genotyped in 300 cases of lung, gastric and breast cancers and 200 age‐ and sex‐matched healthy controls. The results showed that compared with the AA genotype, C was a risk genotype for all three cancers development and was also associated with gastric and breast cancers metastasis and invasion. Based on the base pairing analysis and secondary structure evaluation of MMP9 mRNA and miR‐491‐5p, we found that miR‐491‐5p had a higher binding affinity for A genotype than the C genotype. The Luciferase activity of MMP9 3′‐UTR indicates differential regulation of two genetic variations of MMP9 . Overexpression of miR‐491‐5p decreased MMP9 mRNA level in cell lines of gastric, breast and lung cancers and thus leads to decreasing of the invasion ability. Therefore, for the first time we imply that the C variant of MMP9 contributes to the likelihood of gastric, breast and lung cancers susceptibility via a novel mechanism of subtle gene regulation through miRNA binding capacity.