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Ectopic Cdx2 Expression in Murine Esophagus Models an Intermediate Stage in the Emergence of Barrett's Esophagus

By Jianping Kong, Mary Ann Crissey, Shinsuke Funakoshi, James L. Kreindler and John P. Lynch


Barrett's esophagus (BE) is an intestinal metaplasia that occurs in the setting of chronic acid and bile reflux and is associated with a risk for adenocarcinoma. Expression of intestine-specific transcription factors in the esophagus likely contributes to metaplasia development. Our objective was to explore the effects of an intestine-specific transcription factor when expressed in the mouse esophageal epithelium. Transgenic mice were derived in which the transcription factor Cdx2 is expressed in squamous epithelium using the murine Keratin-14 gene promoter. Effects of the transgene upon cell proliferation and differentiation, gene expression, and barrier integrity were explored. K14-Cdx2 mice express the Cdx2 transgene in esophageal squamous tissues. Cdx2 expression was associated with reduced basal epithelial cell proliferation and altered cell morphology. Ultrastructurally two changes were noted. Cdx2 expression was associated with dilated space between the basal cells and diminished cell-cell adhesion caused by reduced Desmocollin-3 mRNA and protein expression. This compromised epithelial barrier function, as the measured trans-epithelial electrical resistance (TEER) of the K14-Cdx2 epithelium was significantly reduced compared to controls (1189 Ohm*cm2 ±343.5 to 508 Ohm*cm2±92.48, p = 0.0532). Secondly, basal cells with features of a transitional cell type, intermediate between keratinocytes and columnar Barrett's epithelial cells, were observed. These cells had reduced keratin bundles and increased endoplasmic reticulum levels, suggesting the adoption of secretory-cell features. Moreover, at the ultrastructural level they resembled “Distinctive” cells associated with multilayered epithelium. Treatment of the K14-Cdx2 mice with 5′-Azacytidine elicited expression of BE-associated genes including Cdx1, Krt18, and Slc26a3/Dra, suggesting the phenotype could be advanced under certain conditions. We conclude that ectopic Cdx2 expression in keratinocytes alters cell proliferation, barrier function, and differentiation. These altered cells represent a transitional cell type between normal squamous and columnar BE cells. The K14-Cdx2 mice represent a useful model to study progression from squamous epithelium to BE

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  1. (1994). A homeodomain protein related to caudal regulates intestine-specific gene transcription.
  2. (2008). A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification.
  3. (2003). Aberrant expression of CDX2 in Barrett’s epithelium and inflammatory esophageal mucosa.
  4. (2005). Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett’s esophagus.
  5. (2002). Acid exposure activates the mitogen-activated protein kinase pathways in Barrett’s esophagus.
  6. (1997). Acid modulation of HT29 cell growth and differentiation. An in vitro model for Barrett’s esophagus.
  7. (2006). Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett’s epithelium.
  8. (2009). Cdx genes, inflammation and the pathogenesis of Barrett’s metaplasia.
  9. (2010). Cdx genes, inflammation, and the pathogenesis of intestinal metaplasia.
  10. (2004). Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice.
  11. (2004). Cdx1 inhibits human colon cancer cell proliferation by reducing b-catenin/TCF transcriptional activity.
  12. (2002). Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice.
  13. (2009). CDX2 hox gene product in a rat model of esophageal cancer.
  14. (2010). Cdx2 promotes E-cadherin function and cell-cell adhesion in colon cancer cells by enhancing E-cadherin trafficking to the cell membrane. Am J Physiol Gastrointest Liver Physiol In
  15. (2010). Cdx2 regulates endo-lysosomal function and epithelial cell polarity.
  16. (2007). Characterization of telomerase-immortalized, non-neoplastic, human Barrett’s cell line (BAR-T).
  17. (2008). Chromatin remodeling during mouse and human embryonic stem cell differentiation.
  18. (2003). Chronic acid exposure leads to activation of the cdx2 intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes.
  19. (2002). Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice.
  20. (2006). Desmocollin switching in colorectal cancer.
  21. (1993). Detection by scanning electron microscopy of a distinctive esophageal surface cell at the junction of squamous and Barrett’s epithelium.
  22. (2004). Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium.
  23. (1996). Dilated intercellular spaces: a morphological feature of acid reflux–damaged human esophageal epithelium.
  24. (1997). Distribution of cytokeratin markers in Barrett’s specialized columnar epithelium.
  25. (2007). Duodenalcontent reflux into the esophagus leads to expression of Cdx2 and Muc2 in areas of squamous epithelium in rats.
  26. (1994). Effect of gastroduodenal juice and dietary fat on the development of Barrett’s esophagus and esophageal neoplasia: an experimental rat model.
  27. (2001). Epigenetic patterns in the progression of esophageal adenocarcinoma.
  28. (2003). Extended lifespan of Barrett’s esophagus epithelium transduced with the human telomerase catalytic subunit: a useful in vitro model.
  29. (2000). Fields of aberrant CpG island hypermethylation in Barrett’s esophagus and associated adenocarcinoma.
  30. (2009). Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice.
  31. (2004). Giantin is the major Golgi autoantigen in human anti-Golgi complex sera.
  32. (2002). Hallmarks of cancer progression in Barrett’s oesophagus.
  33. (2010). History, molecular mechanisms, and endoscopic treatment of Barrett’s esophagus.
  34. (2005). How to make a Barrett esophagus: pathophysiology of columnar metaplasia of the esophagus.
  35. (2004). Impact of the biliary diversion procedure on carcinogenesis in Barrett’s esophagus surgically induced by duodenoesophageal reflux in rats.
  36. (2009). Induction of Intestinalization in Human Esophageal Keratinocytes is a Multistep Process.
  37. (2004). Meir A
  38. (2006). Methylation of APC, TIMP3, and TERT: a new predictive marker to distinguish Barrett’s oesophagus patients at risk for malignant transformation.
  39. (2006). Molecular basis of Barrett’s oesophagus and oesophageal adenocarcinoma.
  40. (1996). Morphological characterization of the squamocolumnar junction of the esophagus in patients with and without Barrett’s epithelium.
  41. Moskaluk CA (2003) Cdx2 as a marker of epithelial intestinal differentiation in the esophagus.
  42. (2008). Multilayered epithelium in a rat model and human Barrett’s esophagus: similar expression patterns of transcription factors and differentiation markers.
  43. (2006). Multilayered epithelium may be found in patients with Barrett’s epithelium and dysplasia or adenocarcinoma.
  44. (2007). Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm.
  45. (2007). p63 Is essential for the proliferative potential of stem cells in stratified epithelia.
  46. (2004). Phenotype of columnarlined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett’s esophagus.
  47. (2001). Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett’s esophagus.
  48. (2001). Prospective evaluation of multilayered epithelium in Barrett’s esophagus.
  49. (2007). Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells.
  50. (2009). Regulation of CDX2 expression in esophageal adenocarcinoma.
  51. (1997). Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homoeodomain protein Cdx-2.
  52. (2008). Repression of the Desmocollin 2 gene in colorectal cancer cells is relieved by the homeodomain transcription factors Cdx1 and Cdx2.
  53. (2010). Returning to the stem state: epigenetics of recapitulating pre-differentiation chromatin structure.
  54. (1995). Scanning electron microscopy of the human esophagus: application to Barrett’s esophagus, a precancerous lesion.
  55. (2008). Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces.
  56. (2007). Substrate recognition by the protein disulfide isomerases.
  57. (2000). The caudalrelated homeodomain protein Cdx1 inhibits proliferation of intestinal epithelial cells by down-regulation of D-type cyclins.
  58. (2004). The homeodomain protein CDX2 is an early marker of Barrett’s oesophagus.
  59. (2008). The homeodomain transcription factor Cdx1 does not behave as an oncogene in normal mouse intestine.
  60. (2010). The intestine-specific transcription factor Cdx2 inhibits beta-catenin/TCF transcriptional activity by disrupting the beta-catenin/TCF protein complex.
  61. (2005). The mutagenic potential of duodenoesophageal reflux.
  62. (1991). Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation.
  63. (1997). Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy.

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