ADAMTS1, CRABP1, and NR3C1 identified as epigenetically deregulated genes in colorectal tumorigenesis

• Type: Article in International Scientific Journal
• Date: 2006

Authors

Lind, GE (Author) Other; Kleivi, K (Author) Other; Meling, GI (Author) Other; Manuel R Teixeira (Author) ICBAS; Thiis Evensen, E (Author) Other; Rognum, TO (Author) Other; Lothe, RA (Author) Other

Journal

The Journal is awaiting validation by the Administrative Services.

Title: CELLULAR ONCOLOGY

Vol. 28

Pages: 259-272

ISSN: 1570-5870

Indexing

ISI Web of Knowledge - 105 Citations

Scopus - 106 Citations

Other information

Authenticus ID: P-004-P9P

DOI: 10.1155/2006/949506

Abstract (EN): Background: Gene silencing through CpG island hypermethylation is a major mechanism in cancer development. In the present study, we aimed to identify and validate novel target genes inactivated through promoter hypermethylation in colorectal tumor development. Methods: With the use of microarrays, the gene expression profiles of colon cancer cell lines before and after treatment with the demethylating agent 5-aza-2'-deoxycytidine were identified and compared. The expression of the responding genes was compared with microarray expression data of primary colorectal carcinomas. Four of these downregulated genes were subjected to methylation-specific PCR, bisulphite sequencing, and quantitative gene expression analysis using tumors (n = 198), normal tissues (n = 44), and cell lines (n = 30). Results: Twenty-one genes with a CpG island in their promoter responded to treatment in cell lines, and were simultaneously down-regulated in primary colorectal carcinomas. Among 20 colon cancer cell lines, hypermethylation was subsequently identified for three of four analyzed genes, ADAMTS1 (85%), CRABP1 (90%), and NR3C1 (35%). For the latter two genes, hypermethylation was significantly associated with absence or reduced gene expression. The methylation status of ADAMTS1, CRABP1, and NR3C1 was further investigated in 11 6 colorectal carcinomas and adenomas. Twenty-three of 63 (37%), 7/60 (12%), and 2/63 (3%) adenomas, as well as 37/52 (71%), 25/51 (49%), and 13/51 (25%) carcinomas were hypermethylated for the respective genes. These genes were unmethylated in tumors (n = 82) from three other organs, prostate, testis, and kidney. Finally, analysis of normal colorectal mucosa demonstrated that the observed promoter hypermethylation was cancer-specific. Conclusion: By using a refined microarray screening approach we present three genes with cancer-specific hypermethylation in colorectal tumors, ADAMTS1, CRABP1, and NR3C1.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14