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A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma

Oncogene volume 27, pages 2951–2960 (2008)Cite this article

Abstract

Vitamin A deficiency is associated with carcinogenesis, and upregulation of CYP26A1, a major retinoic acid (RA)-catabolizing enzyme, has recently been shown in cancer. We have previously demonstrated alterations of RA biosynthesis in Barrett's oesophagus, the precursor lesion to oesophageal adenocarcinoma. The aims of this study were to determine CYP26A1 expression levels and functional effects in Barrett's associated carcinogenesis. Retinoic acid response element reporter cells were used to determine RA levels in non-dysplastic and dysplastic Barrett's cell lines and endoscopic biopsies. CYP26A1 expression levels, with or without induction by RA and lithocholic acid, were determined by quantitative reverse transcriptase-PCR (RT–PCR) and immunohistochemistry. CYP26A1 promoter activity was determined by a luciferase reporter construct. CYP26A1 was stably overexpressed in GihTERT cells, which were evaluated for gene-expression changes (pathway array and quantitative RT–PCR), cellular proliferation (cytometric DNA profile and colorimetric assay) and invasion (in vitro matrigel assay) with or without the CYP inhibitor ketaconazole. RA levels decreased progressively with the degree of dysplasia (P<0.05) and were inversely correlated with CYP26A1 gene levels and activity (P<0.01). CYP26A1 expression was increased synergistically by RA and lithocholic acid (P<0.05). Overexpression of CYP26A1 led to induction of c-Myc, epidermal growth factor receptor and matrix metalloproteinase 3 as well as downregulation of tissue inhibitor metalloproteinase 1 and 3. Functional effects of CYP26A1 overexpression were increased proliferation (P<0.01) and invasion in vitro (P<0.01), which were inhibited by ketaconazole. Overexpression of CYP26A1 causes intracellular RA depletion and drives the cell into a highly proliferative and invasive state with induction of other known oncogenes.

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Acknowledgements

We thank Guillermo De La Cueva Mendez for his help and advice and Madhumita Das for her help with the invasion assays.

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  1. MRC-Cancer Cell Unit, MRC/Hutchison Research Centre, Cambridge, UK

    C-L Chang, E Hong, P Lao-Sirieix & R C Fitzgerald

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  1. C-L Chang
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  2. E Hong
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  3. P Lao-Sirieix
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Correspondence to R C Fitzgerald.

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Chang, CL., Hong, E., Lao-Sirieix, P. et al. A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma. Oncogene 27, 2951–2960 (2008). https://doi.org/10.1038/sj.onc.1210969

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