Modulation of mismatch repair and genomic stability by miR-155

Nicola Valeri, Pierluigi Gasparini, Muller Fabbri, Chiara Braconi, Angelo Veronese, Francesca Lovat, Brett Adair, Ivan Vannini, Francesca Fanini, Arianna Bottoni, Stefan Costinean, Sukhinder K. Sandhu, Gerard J. Nuovo, Hansjuerg Alder, Roberta Gafa, Federica Calore, Manuela Ferracin, Giovanni Lanza, Stefano Volinia, Massimo NegriniMichael A. McIlhatton, Dino Amadori, Richard Fishel, Carlo M. Croce

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)6982-6987
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number15
DOIs
Publication statusPublished - Apr 13 2010

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Keywords

  • Colorectal cancer
  • DNA repair
  • microRNA

ASJC Scopus subject areas

  • General

Cite this

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., ... Croce, C. M. (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), 6982-6987. https://doi.org/10.1073/pnas.1002472107