Modulation of mismatch repair and genomic stability by miR-155

Valeri, N. et al. (2010) Modulation of mismatch repair and genomic stability by miR-155. Proceedings of the National Academy of Sciences of the United States of America, 107(15), pp. 6982-6987. (doi: 10.1073/pnas.1002472107) (PMID:20351277) (PMCID:PMC2872463)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Braconi, Professor Chiara and Valeri, Dr Nicola
• Authors: Valeri, N., Gasparini, P., Fabbri, M., Braconi, C., Veronese, A., Lovat, F., Adair, B., Vannini, I., Fanini, F., Bottoni, A., Costinean, S., Sandhu, S.K., Nuovo, G.J., Alder, H., Gafa, R., Calore, F., Ferracin, M., Lanza, G., Volinia, S., Negrini, M., McIlhatton, M.A., Amadori, D., Fishel, R., and Croce, C.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490