title: 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.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Florence L M
authors.initials: FL
authors.lastname: de Groen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Lisette M
authors.initials: LM
authors.lastname: Timmer
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Renee X
authors.initials: RX
authors.lastname: Menezes
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Begona
authors.initials: B
authors.lastname: Diosdado
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: C402762:COPS2 protein, human; D007473:Ion Channels; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D000075686:COP9 Signalosome Complex