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
- Adair B
- Alder H
- Amadori D
- Bottoni A
- Braconi C
- Calore F
- Costinean S
- Croce CM
- Fabbri M
- Fanini F
- Ferracin M
- Fishel R
- Gafa R
- Gasparini P
- Lanza G
- Lovat F
- McIlhatton MA
- Negrini M
- Nuovo GJ
- Sandhu SK
- Valeri N
- Vannini I
- Veronese A
- Volinia S