Regulation of the intestinal mucin MUC2 gene expression in vivo: evidence for the role of promoter methylation.
In the present work we investigated the in vivo regulation of the mucin gene MUC2, which is overexpressed in all mucinous colorectal carcinomas. The inhibition of methylation by 5-azadeoxycytidine induces de novo expression of MUC2 in the colon carcinoma cell line COLO 205. The expression is retained in xenograft tissue and the cells give rise to MUC2-expressing tumours in nude mice. The strong expression of MUC2 in the normal human goblet cells and in the tissue of human mucinous colorectal carcinomas is associated with the average methylation of about 50% at every investigated CpG site of the MUC2 promoter. In contrast, MUC2 promoter in the non-expressing normal columnar cells and in the non-mucinous carcinoma tissue is methylated to nearly 100%. These data show that (i) low methylation of MUC2 promoter is associated with MUC2 expression in vivo and (ii) the pattern of MUC2 promoter methylation in the normal goblet or columnar cells most closely resembles that in mucinous or non-mucinous colorectal carcinomas, respectively. They indicate that MUC2 expression in vivo is regulated by promoter methylation and support the hypothesis that cells with goblet-like differentiation give rise to mucinous colonic carcinomas.
Gratchev
A
A
Medizinische Klinik I, Gastroenterologie und Infektiologie, Universitätsklinikum Benjamin Franklin der Freien Universität Berlin, D-12200, Berlin, Germany.
Siedow
A
A
Bumke-Vogt
C
C
Hummel
M
M
Foss
H D
HD
Hanski
M L
ML
Kobalz
U
U
Mann
B
B
Lammert
H
H
Mansmann
U
U
Stein
H
H
Riecken
E O
EO
Hanski
C
C
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015152:Blotting, Northern; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D055262:Mucin-2; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C524625:MUC2 protein, human; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D012313:RNA; D000077209:Decitabine; D001374:Azacitidine