Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus

Douglas Stairs, Hiroshi Nakagawa, Andres Klein-Szanto, Shukriyyah D. Mitchell, Debra G. Silberg, John W. Tobias, John P. Lynch, Anil K. Rustgi

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Background: Barrett's esophagus is a premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation program resulting in a simple columnar epithelium reminiscent of the small intestine. These changes are typically associated with the stratified squamous epithelium chronically exposed to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and Barrett's esophagus, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes have remained undefined. Methodology/Principal Findings: To begin to identify the genetic changes responsible for transdifferentiaiton in Barrett's esophagus, we performed a microarray analysis of normal esophageal, Barrett's esophagus and small intestinal biopsy specimens to identify candidate signaling pathways and transcription factors that may be involved. Through this screen we identified the Cdx1 homeodomain transcription factor and the c-myc pathway as possible candidates. Cdx1 and c-myc were then tested for their ability to induce transdifferentiation in immortalized human esophageal keratinocytes using organotypic culturing methods. Analyses of these cultures reveal that c-myc and cdx1 cooperate to induce mucin production and changes in keratin expression that are observed in the epithelium of Barrett's esophagus. Conclusions/Significance: These data demonstrate the ability of Cdx1 and c-myc to initiate the earliest stages of transdifferentiation of esophageal keratinocytes toward a cell fate characteristic of Barrett's esophagus.

Original languageEnglish (US)
Article numbere3534
JournalPLoS One
Volume3
Issue number10
DOIs
StatePublished - Oct 27 2008

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Barrett Esophagus
esophagus
epithelium
Epithelium
keratinocytes
Transcription Factors
Keratinocytes
Biopsy
Mucins
Microarrays
Keratins
Bile Acids and Salts
transcription factors
Association reactions
gastroesophageal reflux
Acids
bile salts
keratin
mucins
acids

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Stairs, Douglas ; Nakagawa, Hiroshi ; Klein-Szanto, Andres ; Mitchell, Shukriyyah D. ; Silberg, Debra G. ; Tobias, John W. ; Lynch, John P. ; Rustgi, Anil K. / Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus. In: PLoS One. 2008 ; Vol. 3, No. 10.
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Stairs, D, Nakagawa, H, Klein-Szanto, A, Mitchell, SD, Silberg, DG, Tobias, JW, Lynch, JP & Rustgi, AK 2008, 'Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus', PLoS One, vol. 3, no. 10, e3534. https://doi.org/10.1371/journal.pone.0003534

Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus. / Stairs, Douglas; Nakagawa, Hiroshi; Klein-Szanto, Andres; Mitchell, Shukriyyah D.; Silberg, Debra G.; Tobias, John W.; Lynch, John P.; Rustgi, Anil K.

In: PLoS One, Vol. 3, No. 10, e3534, 27.10.2008.

Research output: Contribution to journalArticle

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AU - Stairs, Douglas

AU - Nakagawa, Hiroshi

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AU - Silberg, Debra G.

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AU - Lynch, John P.

AU - Rustgi, Anil K.

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N2 - Background: Barrett's esophagus is a premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation program resulting in a simple columnar epithelium reminiscent of the small intestine. These changes are typically associated with the stratified squamous epithelium chronically exposed to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and Barrett's esophagus, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes have remained undefined. Methodology/Principal Findings: To begin to identify the genetic changes responsible for transdifferentiaiton in Barrett's esophagus, we performed a microarray analysis of normal esophageal, Barrett's esophagus and small intestinal biopsy specimens to identify candidate signaling pathways and transcription factors that may be involved. Through this screen we identified the Cdx1 homeodomain transcription factor and the c-myc pathway as possible candidates. Cdx1 and c-myc were then tested for their ability to induce transdifferentiation in immortalized human esophageal keratinocytes using organotypic culturing methods. Analyses of these cultures reveal that c-myc and cdx1 cooperate to induce mucin production and changes in keratin expression that are observed in the epithelium of Barrett's esophagus. Conclusions/Significance: These data demonstrate the ability of Cdx1 and c-myc to initiate the earliest stages of transdifferentiation of esophageal keratinocytes toward a cell fate characteristic of Barrett's esophagus.

AB - Background: Barrett's esophagus is a premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation program resulting in a simple columnar epithelium reminiscent of the small intestine. These changes are typically associated with the stratified squamous epithelium chronically exposed to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and Barrett's esophagus, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes have remained undefined. Methodology/Principal Findings: To begin to identify the genetic changes responsible for transdifferentiaiton in Barrett's esophagus, we performed a microarray analysis of normal esophageal, Barrett's esophagus and small intestinal biopsy specimens to identify candidate signaling pathways and transcription factors that may be involved. Through this screen we identified the Cdx1 homeodomain transcription factor and the c-myc pathway as possible candidates. Cdx1 and c-myc were then tested for their ability to induce transdifferentiation in immortalized human esophageal keratinocytes using organotypic culturing methods. Analyses of these cultures reveal that c-myc and cdx1 cooperate to induce mucin production and changes in keratin expression that are observed in the epithelium of Barrett's esophagus. Conclusions/Significance: These data demonstrate the ability of Cdx1 and c-myc to initiate the earliest stages of transdifferentiation of esophageal keratinocytes toward a cell fate characteristic of Barrett's esophagus.

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