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Carcinogenesis Advance Access published online on October 8, 2008
Carcinogenesis, doi:10.1093/carcin/bgn227
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Induction of Intestinalization in Human Esophageal Keratinocytes is a Multi-step Process

Jianping Kong1, Hiroshi Nakagawa1, Brandon Isariyawongse1, Shinsuke Funakoshi1, Debra Silberg2,1, Anil K. Rustgi1 and John P. Lynch1

1 Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2 AstraZeneca LP, Wilmington, DE19850-5437, USA

Send reprints and correspondence to: John P. Lynch, MD. Ph.D., Division of Gastroenterology /650 CRB, 415 Curie Blvd., Philadelphia, PA. 19104, Telephone: 215-898-0161, Fax: 215-573-2024, Email: lynchj{at}mail.med.upenn.edu

Barrett's esophagus (BE) is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. The molecular mechanisms underlying its development are not understood. Cdx2 is an intestine-specific transcription factor that is ectopically expressed in BE, but its role in this process is unclear. Herein we describe a novel cell-culture model for BE. Retroviral-mediated Cdx2 expression in immortalized human esophageal keratinocytes (EPC-hTERT) could transiently be established but not maintained and was associated with a reduction in cell proliferation. Co-expression of cyclin D1, but not a dominant-negative p53, rescued proliferation in the Cdx2-expressing cells. Cdx2 expression in the EPC-hTERT.D1 cells decreased cell proliferation but did not induce intestinalization. We investigated for other treatments to enhance intestinalization and found that acidic culture conditions uniformly killed EPC-hTERT.D1.Cdx2 cells. However, treatment with 5-aza-2-deoxycytidine (5-AzaC) to demethylate epigenetically silenced genes did appear to be tolerated. Multiple Cdx2 target genes, markers of intestinal differentiation, and markers of Barrett's esophagus, were induced by this 5-AzaC treatment. More interestingly, the expression level of several of these genes was enhanced only in the EPC-hTERT.D1-Cdx2 cells treated with 5-AzaC. Two of these, SLC26a3/DRA (down-regulated in adenoma) and NHE2 (Na+/H+ exchanger 2), were not previously known to be elevated in BE, however we confirmed their elevation in BE tissue samples. 5-AzaC treatment also induced cell senescence, even at low doses. We conclude that ectopic proliferation signals, alterations in epigenetic gene regulation, and the inhibition of tumor suppressor mechanisms are required for Cdx2-mediated intestinalization of human esophageal keratinocytes in BE.

Received May 9, 2008; revised August 28, 2008; accepted September 24, 2008.


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