RRM
2007 Rustbelt RNA Meeting
RRM
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Poster abstracts
Abstract:
PTC is the most common malignancy in thyroid tissue. A strong inherited genetic predisposition is suggested by case-control studies, however, no predisposing genetic factors have been convincingly identified. Several microRNAs are up-regulated in PTC tumors, the most striking being a 19-fold increase in the quantity of miR146b. Human miR146 occurs in two distinct forms; miR146a and miR146b, whose mature forms differ by only 2 nucleotides. Therefore, both miRs share many predicted target genes, while each also has its own unique predicted targets.
To elucidate the role of miR146 in PTC we sequenced pri-pre-miR146a and pri-pre-miR146b from genomic DNA of patient samples that had been analyzed for global miR expression (He at al. 2005). No previously undescribed sequence changes were detected. However, pre-miR146a contained a common G/C polymorphism in the passenger strand that causes mispairing within the predicted hairpin structure. Sequencing of genomic DNA from PTC patients and controls showed differences in the distribution of genotypes between cancer patients and controls, with G/C heterozygosity associated with an increased risk of acquiring PTC in comparison with either homozygosity. Strikingly somatic mutations leading to heterozygosity are found in tumor tissue, suggesting that the germline genotype at the SNP affects the predisposition to PTC, and second, that the genotype at the SNP is frequently mutated in PTC tumors. To determine the molecular basis for this we examined the impact of the G/C polymorphism on miR146a expression. Pre-miR146a and the mature miR accumulate in cells expressing the G-containing allele but not in cells expressing the C-containing allele. There is no difference in protein binding to either pre-miR when assayed by UV crosslinking of complexes formed with HeLa cell nuclear extract; however, RNA EMSA showed that higher order complexes assemble on on pre-miR146a-G but not pre-miR146a-C, indicating that the latter is inefficiently processed to the mature miR. Thus quantitative changes in miR146a resulting from G/C heterozygosity are a predisposing factor in the development and/or growth of PTC.
Kaarle Franssila, Helsinki University Central Hospital, Helsinki, Finland and Barbara Jarzab, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland provided tissue samples for genetic analyses.
References:
He et al. 2005. The role of microRNA genes in papillary thryroid carcinoma. PNAS 102(52)19075-19080.
Taganov et al. 2006. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. PNAS 103(33)12481-12486.
Keywords: microRNA, papillary thryoid carcinoma
