title: Modulation of mismatch repair and genomic stability by miR-155.
abstract: Inactivation of mismatch repair (MMR) is the cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10-40% of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability [microsatellite instability (MSI)] are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer. Here we show that overexpression of miR-155 significantly down-regulates the core MMR proteins, hMSH2, hMSH6, and hMLH1, inducing a mutator phenotype and MSI. An inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer. Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Valeri
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: Chiara
authors.initials: C
authors.lastname: Braconi
authors.forename: Angelo
authors.initials: A
authors.lastname: Veronese
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Brett
authors.initials: B
authors.lastname: Adair
authors.forename: Ivan
authors.initials: I
authors.lastname: Vannini
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanini
authors.forename: Arianna
authors.initials: A
authors.lastname: Bottoni
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.forename: Sukhinder K
authors.initials: SK
authors.lastname: Sandhu
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Roberta
authors.initials: R
authors.lastname: Gafa
authors.forename: Federica
authors.initials: F
authors.lastname: Calore
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferracin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lanza
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Michael A
authors.initials: MA
authors.lastname: McIlhatton
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Richard
authors.initials: R
authors.lastname: Fishel
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology*; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C524942:MIRN155 microRNA, human; C501486:MLH1 protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein