MicroRNA binding site polymorphisms as biomarkers of cancer risk

Abstract

MicroRNAs (miRNAs) are well established as global gene regulators and thus, slight alterations in miRNA levels as well as their ability to regulate their targets may cause important cellular changes leading to cancer risk. 3´ untranslated region (UTR) miRNA binding site single nucleotide polymorphisms (SNPs) have added another layer of possible genetic variation involved in the complex process of oncogenesis. Identifying these key genetically inherited effectors of miRNA functioning has improved our understanding of the complexity of disease. Interest in the field has grown rapidly in only the last 5 years, with several studies reporting on the role of 3´UTR binding site SNPs as genetic markers of increased cancer susceptibility, as well as biomarkers of cancer type, outcome and response to therapy. Currently, there are numerous known miRNA binding site SNPs associated with multiple cancer subtypes.

Figure 1. miRNA biogenesis

miRNAs are transcribed by RNA polymerase II or III as long pri-miRNAs that are 5′ 7-methyl-guanosine-capped and polyadenylated. Pri-miRNAs are subsequently processed by the RNase III endonuclease Drosha in conjunction with the dsRNA binding protein DGCR8/Pasha, to form pre-miRNAs. Pre-miRNAs are exported from the nucleus to the cytoplasm in a Ran-GTP-dependent manner by exportin-5 and are subject to an additional processing step by another RNase III enzyme, Dicer, releasing a dsRNA duplex, which is then incorporated into the miRISC complex. At this point the mature miRNA is capable of regulating its target genes. pre-miRNA: Precursor miRNA; pri-miRNA: Primary miRNA

Figure 2. miRNA regulation of gene expression

miRNAs regulate gene expression through 3′ untranslated region complimentary binding to target mRNA. miRNAs downregulate mRNA protein translation or degrade the mRNAs.

Figure 3. MiRNA involvement in cancer pathogenesis

miRNAs are regulators of gene expression. Here we show miRNA role in cancer by regulation of tumor-suppressor genes and oncogenes. (A) Overexpression of miRNAs can decrease expression of tumor-suppressor genes. (B) Underexpression of miRNAs can increase expression of oncogenes.

Figure 4. Mutations in miRNA target sites: flawed target recognition

Mutations in the 3′ untranslated region (UTR) of mRNAs can lead to the obliteration or generation of a target recognition site for a specific miRNA. 3′UTR mutations can also lead to altered binding efficiency, creating looser binding or lower recognition frequency.