Carcinogenesis Advance Access published online on December 4, 2003
Carcinogenesis, doi:10.1093/carcin/bgh032
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Swansea Clinical School, University of Wales Swansea
* Corresponding author. E-mail: mailto:g.j.jenkins{at}swansea.ac.uk.
Received 23 July 2003
; revised 12 November 2003
; accepted 15 November 2003
Barrett's oesophagus patients accumulate chromosomal defects during the histological progression to cancer, one of the most prominent of which is the amplification of the whole of chromosome 4. We aimed to study the role that the transcription factor NF-
The bile acid deoxycholic acid (DCA) at neutral pH, activates NF-
B and induces IL-8 expression in oesophageal cells in vitro
2 School of Biological Sciences, University of Wales Swansea; Department of Surgery, Morriston Hospital Swansea
3 School of Biological Sciences, University of Wales Swansea
4 Department of Pathology, Morriston Hospital Swansea
5 Department of Surgery, Morriston Hospital Swansea
B, a candidate cancer promoting gene, present on chromosome 4, plays in Barrett's oesophagus, using OE33 cells as a model. Specifically, we wanted to determine if NF-B was activated by exposure to bile acid (deoxycholic acid) in oesophageal cells. We employed pathway specific cDNA microarrays and real time PCR, to firstly identify bile acid induced genes and specifically to investigate the role of NF-B. An NF-B reporter system was used, as well as an inhibitor of NF-B (PDTC) to confirm the activation of NF-B by bile. We show that physiological levels of DCA (100-300µM) were capable of activating NF-B in OE33 cells and inducing NF-B target gene expression (particularly IB and IL-8). Other gene expression abnormalities were also shown to be induced by DCA. Importantly, preliminary experiments showed that NF-B activation by bile occurred at neutral pH, but not at acid pH. Acidic bile did however cause over-expression of the c-myc oncogene, as previously reported. Hence, we present data showing that NF-B may be a key mediator of carcinogenesis in bile exposed Barrett's tissues. In addition, neutral bile acids appear to play a significant part in reflux induced gene expression changes. We postulate that the activation of the survival factor NF-B by bile may be linked to the previous cytogenetic data from our laboratory showing the amplification of NF-B's chromosome (chromosome 4), during Barrett's cancer progression. Hence chromosome 4 amplification may provide a survival mechanism for bile exposed oesophageal tissues via NF-B.
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