Altered expression and methylation pattern of tumor suppressor and DNA repair genes, in particular involved in mismatch repair (MMR) pathway, frequently occur in primary colorectal (CRC) tumors. However, little is known about (epi)genetic changes of these genes in precancerous and early stages of CRC. The aim of this pilot study was to analyze expression profile and promoter methylation status of important tumor suppressor and DNA repair genes in the early stages of experimentally induced colorectal carcinogenesis. Rats were treated with azoxymethane (AOM), dextran sodium sulphate (DSS) or with their combination, and sacrificed 1 or 4 months post-treatment period. The down-regulation of Apc expression in left colon, detectable in animals treated with DSS-AOM and sacrificed 1 month after the end of treatment, represents most early marker of the experimental colorectal carcinogenesis. Significantly reduced gene expressions were also found in 5 out of 7 studied MMR genes (Mlh1, Mlh3, Msh3 Pms1, Pms2), regarding the sequential administration of DSS-AOM at 4 months since the treatment. Strong down-regulation was also discovered for Apc, Apex1, Mgmt and TP53. Tumors developed in rectum-sigmoid region displayed significantly lower Apc and Pms2 expressions. The decreased expression of studied genes was not in any case associated with aberrant methylation of promoter region. Present data suggest that down-regulation of Apc and MMR genes are prerequisite for the development of CRC. In this study we addressed for the first time early functional alterations of tumor suppressor genes with underlying epigenetic mechanisms in experimentally induced CRC in rats.

Institute of Experimental Medicine Academy of Sciences of the Czech Republic Videnska 1083 14200 Prague 4 Czech Republic

Zobrazit více v PubMed

Cancer Res. 1985 Jan;45(1):76-9 PubMed

Cell Cycle. 2012 Apr 1;11(7):1261-2 PubMed

J Gastroenterol. 2006 Mar;41(3):185-92 PubMed

Cancer Genet Cytogenet. 2005 Oct 1;162(1):68-73 PubMed

Int J Oncol. 2004 Oct;25(4):973-81 PubMed

Clin Cancer Res. 2005 Feb 1;11(3):1203-9 PubMed

N Engl J Med. 2009 Dec 17;361(25):2449-60 PubMed

Oncol Rep. 2011 Nov;26(5):1091-7 PubMed

Mutagenesis. 2012 Mar;27(2):239-45 PubMed

Clin Genet. 2011 Jul;80(1):59-67 PubMed

Am J Pathol. 2001 Sep;159(3):1129-35 PubMed

Int J Oncol. 2013 Jan;42(1):127-33 PubMed

Fam Cancer. 2011 Dec;10(4):641-7 PubMed

J Clin Oncol. 2007 Sep 20;25(27):4231-8 PubMed

Inflamm Bowel Dis. 2011 Sep;17(9):1966-70 PubMed

Mol Carcinog. 2010 Jan;49(1):94-103 PubMed

Curr Colorectal Cancer Rep. 2012 Mar;8(1):66-81 PubMed

Cancer Res. 2000 Aug 15;60(16):4366-71 PubMed

Int J Oncol. 2008 Mar;32(3):609-17 PubMed

Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G7-17 PubMed

Cold Spring Harb Symp Quant Biol. 2005;70:335-41 PubMed

Transl Oncol. 2012 Apr;5(2):72-6 PubMed

Carcinogenesis. 2009 Feb;30(2):183-96 PubMed

Eur J Surg Oncol. 2010 May;36(5):431-8 PubMed

Endocr Regul. 2001 Mar;35(1):53-9 PubMed

Methods. 2010 Apr;50(4):217-26 PubMed

Gastroenterology. 2011 May;140(6):1807-16 PubMed

World J Gastroenterol. 2007 Jul 28;13(28):3784-91 PubMed

Dig Dis Sci. 2002 Jul;47(7):1447-57 PubMed

Genes Chromosomes Cancer. 2010 Aug;49(8):746-59 PubMed

Cancers (Basel). 2010;3(1):285-97 PubMed

Cancer Lett. 2009 Nov 28;285(2):182-9 PubMed

Eur J Pharmacol. 2009 Dec 25;625(1-3):131-42 PubMed

Appl Immunohistochem Mol Morphol. 2011 Dec;19(6):562-8 PubMed

Int J Cancer. 2010 Feb 15;126(4):830-40 PubMed