Oncogenic Role of miR-15a-3p in 13q Amplicon-Driven Colorectal Adenoma-to-Carcinoma Progression.

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.

• Authors: Florence L M de Groen, Lisette M Timmer, Renee X Menezes, Begona Diosdado, Erik Hooijberg, Gerrit A Meijer, Renske D M Steenbergen, Beatriz Carvalho
• Journal: PloS one (PLoS One) Vol. 10 Issue 7 Pg. e0132495 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26148070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COPS2 protein, human
• Ion Channels
• MIRN15 microRNA, human
• MicroRNAs
• Mitochondrial Proteins
• Neoplasm Proteins
• RNA, Neoplasm
• Repressor Proteins
• UCP2 protein, human
• Uncoupling Protein 2
• COP9 Signalosome Complex

Topics

• Adenoma (genetics, metabolism, pathology)
• COP9 Signalosome Complex
• Cell Line, Tumor
• Chromosomes, Human, Pair 13 (genetics, metabolism)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Ion Channels (genetics, metabolism)
• Male
• MicroRNAs (biosynthesis, genetics)
• Mitochondrial Proteins (genetics, metabolism)
• Multigene Family
• Neoplasm Proteins (genetics, metabolism)
• RNA, Neoplasm (biosynthesis, genetics)
• Repressor Proteins (genetics, metabolism)
• Uncoupling Protein 2