Abstract
Chromosomal rearrangements of band 19q13.4 are frequent cytogenetic alterations in benign thyroid adenomas. Apparently, these alterations lead to the upregulation of genes encoding microRNAs of two clusters mapping to the breakpoint region, i.e. miR-371-3 and C19MC. Since members of both clusters have been associated with neoplastic growth in other tumor entities the question arises whether or not their upregulation predisposes to malignant transformation of follicular cells of the thyroid. To address this question we have quantified the expression of miR-372 and miR-520c-3p in samples of 114 thyroid cancers including eight anaplastic thyroid carcinomas, 25 follicular thyroid carcinomas, 78 papillary thyroid carcinomas (including 13 follicular variants thereof), two medullary thyroid carcinomas and one oncocytic thyroid carcinoma. Additionally, we quantified miR-371a-3p and miR-519a-3p in selected samples. While in neither of the cases miR-520c-3p and miR-519a-3p were found to be upregulated, one papillary and one anaplastic thyroid carcinoma, respectively, showed upregulation of miR-372 and miR-371a-3p. However, in these cases fluorescence in situ hybridization did not reveal rearrangements of the common breakpoint region as affected in adenomas. Thus, these rearrangements do apparently not play a major role as first steps in malignant transformation of the thyroid epithelium. Moreover, there is no evidence that 19q13.4 rearrangements characterize a subgroup of thyroid adenomas associated with a higher risk to undergo malignant transformation. Vice versa, the mechanisms by which 19q13.4 rearrangements contribute to benign tumorigenesis in the thyroid remain to be elucidated.
Highlights
MicroRNAs are short non protein-coding RNA molecules that negatively regulate gene expression by binding to the 3' UTR of mRNA thereby inhibiting its transcription or promoting nucleolytic cleavage
We have demonstrated that these aberrations target the two miRNA gene clusters Chromosome 19 microRNA cluster (C19MC) and miR371-3 resulting in their transcriptional activation likely due to juxtaposing them to transcriptional activators [5] or by removal of CpG rich regions [6] upstream of the clusters
The expression of miRNAs of both clusters is abundant in embryonic stem cells (ESC) [7,8,9,10,11,12] and later becomes repressed in the embryo whereas expression of both clusters persists in the placenta until birth
Summary
MicroRNAs (miRNAs) are short non protein-coding RNA molecules that negatively regulate gene expression by binding to the 3' UTR of mRNA thereby inhibiting its transcription or promoting nucleolytic cleavage. We have demonstrated that these aberrations target the two miRNA gene clusters C19MC (chromosome 19 microRNA cluster) and miR371-3 resulting in their transcriptional activation likely due to juxtaposing them to transcriptional activators [5] or by removal of CpG rich regions [6] upstream of the clusters. In a recent set of interesting papers on miRNAs from the miR-371-3 cluster in tumors, their overexpression has been correlated with an invasive cellular behavior [16,17,18,19]. MiRNAs of C19MC have been described to have oncogenic as well as tumorsuppressive characteristics [for summary see [20]]
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