Retinoic acid-induced glandular differentiation of the oesophagus. Issue 7 (21st December 2006)

• Record Type: Journal Article
• Authors: Chang, Chih-Long; Lao-Sirieix, Pierre; Save, Vicki; De La Cueva Mendez, Guillermo; Laskey, Ron; Fitzgerald, Rebecca C
• Is Part Of: Gut. Volume 56:Issue 7(2007)
• Page Start: 906
• Page End: 917
• Publication Date: 2006-12-21
• Subjects: ATRA, all-trans retinoic acid -- BrdU, bromo-deoxyuridine -- CK, cytokeratin -- Ct, cycle threshold -- GAPDH, glyceraldehyde-3-phosphate dehydrogenase -- LCA, lithocholic acid -- RA, retinoic acid -- RARE, retinoic acid response elements -- RT-PCR, real-time PCR -- SE, squamous epithelium; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2006.097915
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Retinoic acid (RA) is a powerful differentiation agent. Barrett's oesophagus occurs when duodeno-gastro-oesophageal reflux causes squamous epithelium (SE) tissue to become columnar epithelium tissue by an unknown mechanism. The bile acid lithocholic acid (LCA) competes for the retinoid X receptor retinoid binding site. Hence, RA pathways may be implicated in Barrett's oesophagus. Methods: RA activity in tissues and cell lines treated with all -trans retinoic acid (ATRA) with or without LCA was assessed using a reporter. Expression of p21 was determined by real-time PCR in Barrett's oesophagus cell lines with or without LCA. SE and Barrett's oesophagus biopsy specimens were exposed to 100 μM of ATRA or 20 mM of a RA inhibitor, citral, in organ culture for >72 h. Characteristics of treated specimens, compared with untreated controls, were analysed by immunohistochemical analysis (cytokeratins (CKs), vimentin) and RT-PCR (CKs). Confocal microscopy assessed temporal changes in co-localisation of CK8/18 and vimentin. Cell proliferation was assessed by bromo-deoxyuridine incorporation and immunohistochemical analysis for Ki67 and p21. Results: RA biosynthesis was increased in Barrett's oesophagus compared with SE (p<0.001). LCA and ATRA caused a synergistic increase in RA signalling as shown by increased p21 (p<0.01). Morphological and molecular analysis of SE exposed to ATRA showed columnar differentiation independent of proliferation. Metaplasia could be induced from the stromal compartment alone and vimentin expression co-localised with CK8/18 at 24 h, which separated into CK8/18-positive glands and vimentin-positive stroma by 48 h. Citral-treated Barrett's oesophagus led to phenotypic and immunohistochemical characteristics of SE, which was independent of proliferation. Conclusion: RA activity is increased in Barrett's oesophagus and is induced by LCA. Under conditions of altered RA activity and an intact stroma, the oesophageal phenotype can be altered independent of proliferation.