Evidence for acid-induced loss of Cdx2 expression in duodenal gastric metaplasia.
Gastric metaplasia in the duodenum (GMD) is characterized by transdifferentiation of intestinal epithelial cells into gastric foveolar cells within the duodenal mucosa. GMD is often associated with duodenal ulceration. Higher duodenal acidity due to increased gastric acid output into the duodenum has been implicated in the development of GMD. Intestinal development and homeostasis are controlled by the homeobox transcription factor Cdx2, which is considered to be the master regulator of intestinal differentiation. Using immunohistochemistry, the present study shows that GMD is associated with loss of expression of Cdx2 and its target gene product sucrase-isomaltase. Quantitative RT-PCR experiments using the intestinal cell line Caco2 revealed that Cdx2 and sucrase-isomaltase were down-regulated and gastric mucins MUC5AC and MUC6 were up-regulated under acidic culture conditions. Thus, it is suggested that increased acid exposure leads to GMD by impairing the transcription of Cdx2 and subsequently that of its intestine-specific target genes.
Faller
Gerhard
G
Institute of Pathology, University of Erlangen-Nuremberg, Krankenhausstrasse 8-10, 91054 Erlangen, Germany. gerhard.faller@patho.imed.uni-erlangen.de
Dimmler
Arno
A
Rau
Tilman
T
Spaderna
Simone
S
Hlubek
Falk
F
Jung
Andreas
A
Kirchner
Thomas
T
Brabletz
Thomas
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D030161:Avian Proteins; D018938:Caco-2 Cells; D002454:Cell Differentiation; D015536:Down-Regulation; D004386:Duodenum / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008679:Metaplasia / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013394:Sucrase-Isomaltase Complex / Q000235:genetics / Q000378:metabolism
D030161:Avian Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D013394:Sucrase-Isomaltase Complex