Abstract
Progression from colorectal adenoma to carcinoma is strongly associated with an accumulation of genomic alterations, including gain of chromosome 13. This gain affects the whole q arm and is present in 40%–60% of all colorectal cancers (CRCs). Several genes located at this amplicon are known to be overexpressed in carcinomas due to copy number dosage. A subset of these genes, including the mir-17~92 cluster, are functionally involved in CRC development. The present study set out to explore whether apart from mir-17~92, other miRNAs located at the 13q amplicon show a copy number dependent dosage effect that may contribute to 13q-driven colorectal adenoma-to-carcinoma progression. Integration of publically available miRNA expression, target mRNA expression and DNA copy number data from 125 CRCs yielded three miRNAs, miR-15a, -17, and -20a, of which high expression levels were significantly correlated with a 13q gain and which influenced target mRNA expression. These results could be confirmed by qRT-PCR in a series of 100 colon adenomas and carcinomas.Functional analysis of both mature miRNAs encoded by mir-15a, i.e. miR-15a-5p and miR-15a-3p, showed that silencing of miR-15a-3p significantly inhibited viability of CRC cells. Integration of miR-15a expression levels with mRNA expression data of predicted target genes identified mitochondrial uncoupling protein 2 (UCP2) and COP9 signalosome subunit 2 (COPS2) as candidates with significantly decreased expression in CRCs with 13q gain. Upon silencing of miR-15a-3p, mRNA expression of both genes increased in CRC cells, supporting miR-15a-3p mediated regulation of UPC2 and COPS2 expression. In conclusion, significant overexpression of miR-15a-3p due to gain of 13q is functionally relevant in CRC, with UCP2 and COPS2 as candidate target genes. Taken together our findings suggest that miR-15a-3p may contribute to adenoma-to-carcinoma progression.
Highlights
The development of colorectal cancer (CRC) is marked by the accumulation of several recurrent chromosomal alterations, including gains of 8q, 13q, and 20q and losses of 8p, 15q, 17p and 18q [1,2,3], which can lead to altered expression of oncogenes and tumour suppressor genes [4,5]
The same holds true for AURKA and TPX2 located at 20q, which were found to promote 20q amplicon-driven colorectal adenoma to carcinoma progression [9]
Publically available The Cancer Genome Atlas (TCGA) data from 125 CRC samples were used to analyse both miRNA expression levels and DNA copy number levels of the loci involved on chromosome 13 [17]
Summary
The development of colorectal cancer (CRC) is marked by the accumulation of several recurrent chromosomal alterations, including gains of 8q, 13q, and 20q and losses of 8p, 15q, 17p and 18q [1,2,3], which can lead to altered expression of oncogenes and tumour suppressor genes [4,5]. In addition to protein-encoding genes, DNA copy number changes may affect expression of microRNAs (miRNAs) [10,11]. MiRNAs are a family of small non-coding RNA molecules that play an important role in the regulation of many cellular processes by targeting the 3’ UTR of mRNA molecules, thereby leading to gene silencing [12]. Dysregulation of miRNA expression has been shown to play an important role in several human diseases, including cancer [13]
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