title: miR-223 is a coordinator of breast cancer progression as revealed by bioinformatics predictions.
abstract: MicroRNAs are single-stranded non-coding RNAs that simultaneously down-modulate the expression of multiple genes post-transcriptionally by binding to the 3'UTRs of target mRNAs. Here we used computational methods to predict microRNAs relevant in breast cancer progression. Specifically, we applied different microRNA target prediction algorithms to various groups of differentially expressed protein-coding genes obtained from four breast cancer datasets. Six potential candidates were identified, among them miR-223, previously described to be highly expressed in the tumor microenvironment and known to be actively transferred into breast cancer cells. To investigate the function of miR-223 in tumorigenesis and to define its molecular mechanism, we overexpressed miR-223 in breast cancer cells in a transient or stable manner. Alternatively we overexpressed miR-223 in mouse embryonic fibroblasts or HEK293 cells and used their conditioned medium to treat tumor cells. With both approaches, we obtained elevated levels of miR-223 in tumor cells and observed decreased migration, increased cell death in anoikis conditions and augmented sensitivity to chemotherapy but no effect on adhesion and proliferation. The analysis of miR-223 predicted targets revealed enrichment in cell death and survival-related genes and in pathways frequently altered in breast cancer. Among these genes, we showed that protein levels for STAT5A, ITGA3 and NRAS were modulated by miR-223. In addition, we proved that STAT5A is a direct miR-223 target and highlighted a possible correlation between miR-223 and STAT5A in migration and chemotherapy response. Our investigation revealed that a computational analysis of cancer gene expression datasets can be a relevant tool to identify microRNAs involved in cancer progression and that miR-223 has a prominent role in breast malignancy that could potentially be exploited therapeutically.
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy ; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Pinatel
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy ; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy ; Center for Molecular Systems Biology, University of Torino, Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Orso
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy ; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Penna
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy ; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy ; Center for Molecular Systems Biology, University of Torino, Torino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cimino
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy.
authors.forename: Angela Rita
authors.initials: AR
authors.lastname: Elia
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Circosta
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy ; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy ; Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy ; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy ; Center for Molecular Systems Biology, University of Torino, Torino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Taverna
mesh_terms: D020413:3' Untranslated Regions; D023102:Anoikis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D020029:Base Pairing; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019295:Computational Biology; D016208:Databases, Factual; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D035683:MicroRNAs; D050799:STAT5 Transcription Factor; C525067:MIR223, human