Modulation of Mismatch Repair and Genomic Stability by MiR-155

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Mar 31

PMID 20351277

Citations 164

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Ionizing Radiation May Induce Tumors Partly Through the Alteration or Regulation of Mismatch Repair Genes.

Sun M, Monahan K, Moquet J, Barnard S Cancers (Basel). 2025; 17(4).

PMID: 40002162 PMC: 11852753. DOI: 10.3390/cancers17040564.

Circadian genes and non-coding RNAs: interactions and implications in cancer.

Yoon G, Roh J, Jang W, Kim W Anim Cells Syst (Seoul). 2025; 29(1):135-148.

PMID: 39944901 PMC: 11816739. DOI: 10.1080/19768354.2025.2459622.

A cross-sectional study comparing the expression of DNA repair molecules in subjects with and without atherosclerotic plaques.

Arapi B, Unal S, Malikova N, Omeroglu S, Guven M Mol Biol Rep. 2024; 51(1):953.

PMID: 39230767 DOI: 10.1007/s11033-024-09886-8.

Overlooked poor-quality patient samples in sequencing data impair reproducibility of published clinically relevant datasets.

Sprang M, Mollmann J, Andrade-Navarro M, Fontaine J Genome Biol. 2024; 25(1):222.

PMID: 39152483 PMC: 11328481. DOI: 10.1186/s13059-024-03331-6.

Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions.

Yan L, Shi J, Zhu J Discov Oncol. 2024; 15(1):294.

PMID: 39031216 PMC: 11265098. DOI: 10.1007/s12672-024-01163-1.

References

de la Chapelle A . Genetic predisposition to human disease: allele-specific expression and low-penetrance regulatory loci. Oncogene. 2009; 28(38):3345-8. PMC: 4348697. DOI: 10.1038/onc.2009.194. View

Mueller J, Gazzoli I, Bandipalliam P, Garber J, Syngal S, Kolodner R . Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases. Cancer Res. 2009; 69(17):7053-61. PMC: 2761236. DOI: 10.1158/0008-5472.CAN-09-0358. View

Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J . Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 1997; 57(21):4749-56. View

Wheeler J, Beck N, Kim H, Tomlinson I, Mortensen N, Bodmer W . Mechanisms of inactivation of mismatch repair genes in human colorectal cancer cell lines: the predominant role of hMLH1. Proc Natl Acad Sci U S A. 1999; 96(18):10296-301. PMC: 17882. DOI: 10.1073/pnas.96.18.10296. View

Tay Y, Zhang J, Thomson A, Lim B, Rigoutsos I . MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature. 2008; 455(7216):1124-8. DOI: 10.1038/nature07299. View

Lanza G, Ferracin M, Gafa R, Veronese A, Spizzo R, Pichiorri F . mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer. Mol Cancer. 2007; 6:54. PMC: 2048978. DOI: 10.1186/1476-4598-6-54. View

Umar A, Boland C, Terdiman J, Syngal S, de la Chapelle A, Ruschoff J . Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004; 96(4):261-8. PMC: 2933058. DOI: 10.1093/jnci/djh034. View

Kane M, Loda M, Gaida G, Lipman J, Mishra R, Goldman H . Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997; 57(5):808-11. View

Hampel H, Frankel W, Martin E, Arnold M, Khanduja K, Kuebler P . Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005; 352(18):1851-60. DOI: 10.1056/NEJMoa043146. View

10.

Loeb L . Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 1991; 51(12):3075-9. View

11.

Raschle M, Marra G, Nystrom-Lahti M, Schar P, Jiricny J . Identification of hMutLbeta, a heterodimer of hMLH1 and hPMS1. J Biol Chem. 1999; 274(45):32368-75. DOI: 10.1074/jbc.274.45.32368. View

12.

Acharya S, Foster P, Brooks P, Fishel R . The coordinated functions of the E. coli MutS and MutL proteins in mismatch repair. Mol Cell. 2003; 12(1):233-46. DOI: 10.1016/s1097-2765(03)00219-3. View

13.

Mao G, Pan X, Gu L . Evidence that a mutation in the MLH1 3'-untranslated region confers a mutator phenotype and mismatch repair deficiency in patients with relapsed leukemia. J Biol Chem. 2007; 283(6):3211-3216. DOI: 10.1074/jbc.M709276200. View

14.

Boland C, Thibodeau S, Hamilton S, Sidransky D, Eshleman J, Burt R . A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998; 58(22):5248-57. View

15.

Rehmsmeier M, Steffen P, Hochsmann M, Giegerich R . Fast and effective prediction of microRNA/target duplexes. RNA. 2004; 10(10):1507-17. PMC: 1370637. DOI: 10.1261/rna.5248604. View

16.

Svrcek M, El-Bchiri J, Chalastanis A, Capel E, Dumont S, Buhard O . Specific clinical and biological features characterize inflammatory bowel disease associated colorectal cancers showing microsatellite instability. J Clin Oncol. 2007; 25(27):4231-8. DOI: 10.1200/JCO.2007.10.9744. View

17.

Aaltonen L, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P . Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998; 338(21):1481-7. DOI: 10.1056/NEJM199805213382101. View

18.

Lynch H, de la Chapelle A . Hereditary colorectal cancer. N Engl J Med. 2003; 348(10):919-32. DOI: 10.1056/NEJMra012242. View

19.

Herman J, Umar A, Polyak K, Graff J, Ahuja N, Issa J . Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998; 95(12):6870-5. PMC: 22665. DOI: 10.1073/pnas.95.12.6870. View

20.

Yan H, Dobbie Z, Gruber S, Markowitz S, Romans K, Giardiello F . Small changes in expression affect predisposition to tumorigenesis. Nat Genet. 2001; 30(1):25-6. DOI: 10.1038/ng799. View