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Genome-wide Screen for miRNA Targets Using the MISSION Target ID Library
08:40

Genome-wide Screen for miRNA Targets Using the MISSION Target ID Library

Published on: April 6, 2012

Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility

Milena S Nicoloso1, Hao Sun, Riccardo Spizzo

  • 1Department of Experimental Therapeutics and the Center for RNA Interference and Non-coding RNAs, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Cancer Research
|March 25, 2010
PubMed

Insights

Single-nucleotide polymorphisms (SNPs) can alter microRNA (miRNA) binding sites, potentially influencing gene regulation and cancer susceptibility. This study identifies specific SNPs affecting miRNA interactions, suggesting a novel mechanism in cancer development.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Single-nucleotide polymorphisms (SNPs) are known to associate with polygenetic disorders like breast cancer (BC).
  • The impact of SNPs on microRNA (miRNA) gene regulation and their role in cancer susceptibility are not fully understood.
  • SNPs can potentially alter miRNA binding sites, affecting gene expression.

Purpose of the Study:

  • To investigate the extent to which SNPs interfere with miRNA gene regulation.
  • To test the hypothesis that disruption of miRNA target binding by SNPs is a widespread mechanism relevant to cancer susceptibility.
  • To identify specific SNPs that modify miRNA binding sites and gene regulation.

Main Methods:

  • In silico and in vitro analysis of SNPs associated with BC risk.
  • Bioinformatics analysis to predict the impact of SNPs on miRNA::mRNA duplex binding energy.
  • Case-control population study to assess the association of target SNPs with BC susceptibility.
  • Luciferase activity assays and protein level analysis in cancer cell lines with different genotypes.

Main Results:

  • Identified rs1982073-TGFB1 and rs1799782-XRCC1 as target SNPs modulating gene expression via differential miRNA interaction.
  • Genome-wide analysis predicted ~64% of transcribed SNPs as target SNPs capable of significantly altering miRNA::mRNA binding energy.
  • Germline occurrence of rs799917-BRCA1 and rs334348-TGFR1 varied significantly among populations with different BC risks.
  • Demonstrated differential regulation of target genes by specific miRNAs (miR-638, miR-628-5p) in cancer cell lines with different target SNP genotypes.

Conclusions:

  • Transcribed target SNPs alter miRNA gene regulation and protein expression.
  • This alteration contributes to cancer susceptibility through a novel mechanism of subtle gene regulation.
  • The findings highlight the importance of considering SNP-mediated miRNA regulation in understanding cancer risk.

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