Bile acids are multifunctional modulators of the Barrett's carcinogenesis.
Bile salts play an important pathogenic role in the development of Barrett adenocarcinoma (BA). However, the precise role of different bile salts in this process is still unknown. The aim of the present study was to compare the effects of two different bile salts, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) on the expression of COX-2, CDX-2 and DNA repair enzymes (MUTYH, OGG-1) in the Barrett epithelial cancer cells (OE-19). OE-19 cells were incubated with DCAor UDCA(100 microM or 300 microM at pH=7.0) over 24 h. To investigate the involvement of NF kappaB, in separate experiments the cells were incubated with DCA in the presence of proteosome inhibitor (MG-132). Cells cycle and apoptosis were analyzed by FACS analysis. After incubation of OE-19 cells with bile salts, the expression of mRNA of COX-2, DNA repair enzymes (MUTYH, OGG-1) and caudal-related homebox transcription factor CDX-2 were measured by quantitative RT-PCR. OE-19 cell were also transfected with siRNA-RelA (p65) to asses effect of NF kappaB inactivation on COX-2 and CDX2 expression. DCA caused a stronger reduction in cell survival of OE-19 cells than UDCA. In addition, DCA stimulated directly the translocation of NF kappaB p65 (active form) in the nuclei of OE-19 cells. DCA caused stronger than UDCA stimulation of the COX-2 mRNA expression in these cells and this effect was significantly attenuated by the addition of inhibitor of NF kappaB activity (proteosome inhibitor MG-132). siRNA-RelA reduced expression not only of NF kappaB but also expression of COX-2 as well as CDX-2 mRNA. DCA caused stronger downregulation of mRNA for DNA repair enzymes MUTYH and OGG-1 than UDCA. In contrast, UDCA induced stronger CDX-2 mRNA expression than DCA in OE-19 cells. We conclude that bile salts are involved in the carcinogenesis of Barrett adenocarcinoma via inhibition of DNA repair enzymes and induction of COX-2 and this last effect is, at least partly, mediated by NF kappaB. DCA shows carcinogenic potential due to high upregulation of COX-2, CDX-2 and downregulation of DNA repair enzymes.
Burnat
G
G
Department of Medicine, Thuringia-Clinic Saalfeld, Teaching Hospital of the University of Jena, Germany.
Majka
J
J
Konturek
P C
PC
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics / Q000473:pathology; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism*; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism*
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D051546:Cyclooxygenase 2; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human