title: MicroRNA-182-5p targets a network of genes involved in DNA repair.
abstract: MicroRNAs are noncoding regulators of gene expression, which act by repressing protein translation and/or degrading mRNA. Many have been shown to drive tumorigenesis in cancer, but functional studies to understand their mode of action are typically limited to single-target genes. In this study, we use synthetic biotinylated miRNA to pull down endogenous targets of miR-182-5p. We identified more than 1000 genes as potential targets of miR-182-5p, most of which have a known function in pathways underlying tumor biology. Specifically, functional enrichment analysis identified components of both the DNA damage response pathway and cell cycle to be highly represented in this target cohort. Experimental validation confirmed that miR-182-5p-mediated disruption of the homologous recombination (HR) pathway is a consequence of its ability to target multiple components in that pathway. Although there is a strong enrichment for the cell cycle ontology, we do not see primary proliferative defects as a consequence of miR-182-5p overexpression. We highlight targets that could be responsible for miR-182-5p-mediated disruption of other biological processes attributed in the literature so far. Finally, we show that miR-182-5p is highly expressed in a panel of human breast cancer samples, highlighting its role as a potential oncomir in breast cancer.
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.
authors.forename: Keerthana
authors.initials: K
authors.lastname: Krishnan
authors.forename: Anita L
authors.initials: AL
authors.lastname: Steptoe
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Martin
authors.forename: Shivangi
authors.initials: S
authors.lastname: Wani
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.forename: Mythily
authors.initials: M
authors.lastname: Mariasegaram
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
authors.forename: Alexander
authors.initials: A
authors.lastname: Vlassov
authors.forename: Nicole
authors.initials: N
authors.lastname: Cloonan
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D015331:Cohort Studies; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006367:HeLa Cells; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D015854:Up-Regulation
chemical_list: D019313:BRCA1 Protein; D035683:MicroRNAs; C538984:Mirn182 microRNA, human