Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis.
E-cadherin belongs to the cadherin family of calcium-dependent cell-adhesion molecules. The cadherins play an essential role in biological processes such as ordering of cell sorting, migration, and differentiation, and their malfunctioning is connected with neoplasia. Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia. Transcriptional silencing of tumor-suppressor genes by promoter methylation has been observed in different types of human cancers and dysplasia. To explore the mode of E-cadherin regulation, 156 biopsy samples from 26 patients with long-standing ulcerative colitis were screened. To detect the methylation status of our samples, a methylation-specific PCR was applied. Methylation of the E-cadherin (CDH1) promoter was detected in 93% of the patients with dysplastic biopsy samples, in contrast to only 6% of the patients without dysplasia (P < 0.001). We also examined the level of synthesis of E-cadherin protein by immunohistochemical staining in different paraffin-embedded samples of dysplastic and non-dysplastic origin in a subset of our patients. Samples with dysplasia displayed reduced levels, whereas samples without dysplasia revealed normal E-cadherin protein synthesis. These results show that the E-cadherin promoter is subjected to epigenetic control in colorectal ulceration. Obviously, this event may play an important role in the progression from chronic inflammation to colorectal cancer. For this reason, methylation of the CDH1 promoter is an attractive new biomarker for detecting ulcerative colitis patients with a high risk for developing colorectal cancers.
Division of Molecular Genetics, Institute of Anthropology and Human Genetics, University of Tübingen, Tübingen, Germany. piaaza@yahoo.de
Pia
P
Azarschab
Rainer
R
Porschen
Michael
M
Gregor
Nikolaus
N
Blin
Karlheinz
K
Holzmann
D000782:Aneuploidy; D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D003082:Colectomy / Q000379:methods; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic
D014408:Biomarkers, Tumor; D015820:Cadherins