Modulation of mismatch repair and genomic stability by miR-155.
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.
Valeri
Nicola
N
Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210, USA.
Gasparini
Pierluigi
P
Fabbri
Muller
M
Braconi
Chiara
C
Veronese
Angelo
A
Lovat
Francesca
F
Adair
Brett
B
Vannini
Ivan
I
Fanini
Francesca
F
Bottoni
Arianna
A
Costinean
Stefan
S
Sandhu
Sukhinder K
SK
Nuovo
Gerard J
GJ
Alder
Hansjuerg
H
Gafa
Roberta
R
Calore
Federica
F
Ferracin
Manuela
M
Lanza
Giovanni
G
Volinia
Stefano
S
Negrini
Massimo
M
McIlhatton
Michael A
MA
Amadori
Dino
D
Fishel
Richard
R
Croce
Carlo M
CM
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
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