Modulation of mismatch repair and genomic stability by miR-155.


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.

  • 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
PubMed ID
Appears In
Proc Natl Acad Sci U S A, 2010, 107 (15)