title: Increased sensitivity to chemotherapy induced by CpG-ODN treatment is mediated by microRNA modulation.
abstract: We recently reported that peritumoral CpG-ODN treatment, activating TLR-9 expressing cells in tumor microenvironment, induces modulation of genes involved in DNA repair and sensitizes cancer cells to DNA-damaging cisplatin treatment. Here, we investigated whether this treatment induces modulation of miRNAs in tumor cells and their relevance to chemotherapy response. Array analysis identified 20 differentially expressed miRNAs in human IGROV-1 ovarian tumor cells from CpG-ODN-treated mice versus controls (16 down- and 4 up-regulated). Evaluation of the role of the 3 most differentially expressed miRNAs on sensitivity to cisplatin of IGROV-1 cells revealed significantly increased cisplatin cytotoxicity upon ectopic expression of hsa-miR-302b (up-modulated in our array), but no increased effect upon reduced expression of hsa-miR-424 or hsa-miR-340 (down-modulated in our array). Accordingly, hsa-miR-302b expression was significantly associated with time to relapse or overall survival in two data sets of platinum-treated ovarian cancer patients. Use of bio-informatics tools identified 19 mRNAs potentially targeted by hsa-miR-302b, including HDAC4 gene, which has been reported to mediate cisplatin sensitivity in ovarian cancer. Both HDAC4 mRNA and protein levels were significantly reduced in IGROV-1 cells overexpressing hsa-miR-302b. Altogether, these findings indicate that hsa-miR-302b acts as a "chemosensitizer" in human ovarian carcinoma cells and may represent a biomarker able to predict response to cisplatin treatment. Moreover, the identification of miRNAs that improve sensitivity to chemotherapy provides the experimental underpinning for their possible future clinical use.
authors.affiliation: Functional Genomics Core Facility, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.forename: Martina
authors.initials: M
authors.lastname: Berardi
authors.forename: Michele
authors.initials: M
authors.lastname: Sommariva
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cataldo
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Marilena V
authors.initials: MV
authors.lastname: Iorio
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.forename: Andrea
authors.initials: A
authors.lastname: Balsari
mesh_terms: D000818:Animals; D002945:Cisplatin; D019295:Computational Biology; D004358:Drug Therapy / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D010984:Platinum / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: C408982:CPG-oligonucleotide; C532169:MIRN302A microRNA, human; D035683:MicroRNAs; D009838:Oligodeoxyribonucleotides; D010984:Platinum; D008156:Luciferases; D002945:Cisplatin