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 Negrini; Michael A. McIlhatton; Dino Amadori; Richard Fishel; Carlo M. Croce

doi:10.1073/pnas.1002472107

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

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Research output: Contribution to journal › Article

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 language	English
Pages (from-to)	6982-6987
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	15
DOIs	https://doi.org/10.1073/pnas.1002472107
Publication status	Published - 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

Modulation of mismatch repair and genomic stability by miR-155. / Valeri, Nicola; Gasparini, Pierluigi; Fabbri, Muller; Braconi, Chiara; Veronese, Angelo; Lovat, Francesca; Adair, Brett; Vannini, Ivan ; Fanini, Francesca; Bottoni, Arianna; Costinean, Stefan; Sandhu, Sukhinder K.; Nuovo, Gerard J.; Alder, Hansjuerg; Gafa, Roberta; Calore, Federica; Ferracin, Manuela; Lanza, Giovanni; Volinia, Stefano; Negrini, Massimo; McIlhatton, Michael A.; Amadori, Dino; Fishel, Richard; Croce, Carlo M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 15, 13.04.2010, p. 6982-6987.

Research output: Contribution to journal › Article

Valeri, N, Gasparini, P, Fabbri, M, Braconi, C, Veronese, A, Lovat, F, Adair, B, Vannini, I , Fanini, F, Bottoni, A, Costinean, S, Sandhu, SK, Nuovo, GJ, Alder, H, Gafa, R, Calore, F, Ferracin, M, Lanza, G, Volinia, S, Negrini, M, McIlhatton, MA, Amadori, D, Fishel, R & Croce, CM 2010, 'Modulation of mismatch repair and genomic stability by miR-155', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 15, pp. 6982-6987. https://doi.org/10.1073/pnas.1002472107

Valeri, Nicola ; Gasparini, Pierluigi ; Fabbri, Muller ; Braconi, Chiara ; Veronese, Angelo ; Lovat, Francesca ; Adair, Brett ; Vannini, Ivan ; Fanini, Francesca ; Bottoni, Arianna ; Costinean, Stefan ; Sandhu, Sukhinder K. ; Nuovo, Gerard J. ; Alder, Hansjuerg ; Gafa, Roberta ; Calore, Federica ; Ferracin, Manuela ; Lanza, Giovanni ; Volinia, Stefano ; Negrini, Massimo ; McIlhatton, Michael A. ; Amadori, Dino ; Fishel, Richard ; Croce, Carlo M. / Modulation of mismatch repair and genomic stability by miR-155. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 15. pp. 6982-6987.

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N2 - 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.

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10.1073/pnas.1002472107