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 | |
| Publication status | Published - Apr 13 2010 |
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Keywords
- Colorectal cancer
- DNA repair
- microRNA
ASJC Scopus subject areas
- General
Cite this
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
}
TY - JOUR
T1 - Modulation of mismatch repair and genomic stability by miR-155
AU - Valeri, Nicola
AU - Gasparini, Pierluigi
AU - Fabbri, Muller
AU - Braconi, Chiara
AU - Veronese, Angelo
AU - Lovat, Francesca
AU - Adair, Brett
AU - Vannini, Ivan
AU - Fanini, Francesca
AU - Bottoni, Arianna
AU - Costinean, Stefan
AU - Sandhu, Sukhinder K.
AU - Nuovo, Gerard J.
AU - Alder, Hansjuerg
AU - Gafa, Roberta
AU - Calore, Federica
AU - Ferracin, Manuela
AU - Lanza, Giovanni
AU - Volinia, Stefano
AU - Negrini, Massimo
AU - McIlhatton, Michael A.
AU - Amadori, Dino
AU - Fishel, Richard
AU - Croce, Carlo M.
PY - 2010/4/13
Y1 - 2010/4/13
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.
AB - 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.
KW - Colorectal cancer
KW - DNA repair
KW - microRNA
UR - http://www.scopus.com/inward/record.url?scp=77951030494&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951030494&partnerID=8YFLogxK
U2 - 10.1073/pnas.1002472107
DO - 10.1073/pnas.1002472107
M3 - Article
C2 - 20351277
AN - SCOPUS:77951030494
VL - 107
SP - 6982
EP - 6987
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 15
ER -