title: Methylation-dependent activation of CDX1 through NF-κB: a link from inflammation to intestinal metaplasia in the human stomach.
abstract: The caudal homeobox factor 1 (CDX1) is an essential transcription factor for intestinal differentiation. Its aberrant expression in intestinal metaplasia of the upper gastrointestinal tract is a hallmark within the gastritis-metaplasia-carcinoma sequence. CDX1 expression is influenced by certain pathways, such as Wnt, Ras, or NF-κB signaling; however, these pathways alone cannot explain the transient expression of CDX1 in intestinal metaplasia or the molecular inactivation mechanism of its loss in cases of advanced gastric cancer. In this study, we investigated the epigenetic inactivation of CDX1 by promoter methylation, as well as the functional link of CDX1 promoter methylation to the inflammatory NF-κB signaling pathway. We identified methylation-dependent NF-κB binding to the CDX1 promoter and quantified it using competitive electrophoretic mobility shift assays and chromatin immunoprecipitation. A methylated CDX1 promoter was associated with closed chromatin structure, reduced NF-κB binding, and transcriptional silencing. Along the gastritis-metaplasia-carcinoma sequence, we observed a biphasic pattern of tumor necrosis factor-α (TNF-α) protein expression and an inverse biphasic pattern of CDX1 promoter methylation; both are highly consistent with CDX1 protein expression. The stages of hyper-, hypo-, and hyper-methylation patterns of the CDX1 promoter were inversely correlated with the NF-κB signaling activity along this sequence. In conclusion, these functionally interacting events drive CDX1 expression and contribute to intestinal metaplasia, epithelial dedifferentiation, and carcinogenesis in the human stomach.
authors: Institute of Pathology, University Hospital Erlangen, Erlangen, Germany. tilman.rau@uk-erlangen.de
authors: Tilman T
authors: TT
authors: Rau
authors: Anja
authors: A
authors: Rogler
authors: Myrjam
authors: M
authors: Frischauf
authors: Andreas
authors: A
authors: Jung
authors: Peter C
authors: PC
authors: Konturek
authors: Arno
authors: A
authors: Dimmler
authors: Gerhard
authors: G
authors: Faller
authors: Bettina
authors: B
authors: Sehnert
authors: Wael
authors: W
authors: El-Rifai
authors: Arndt
authors: A
authors: Hartmann
authors: Reinhard E
authors: RE
authors: Voll
authors: Regine
authors: R
authors: Schneider-Stock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D002843:Chromatin / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005756:Gastritis / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D008297:Male; D008679:Metaplasia; D008875:Middle Aged; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D055815:Young Adult
chemical_list: C491273:CDX1 protein, human; D002843:Chromatin; D018398:Homeodomain Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D001374:Azacitidine