The Role of Bile Acids in the Progression of Squamous Epithelium to Barrett's Esophagus and Esophageal Adenocarcinoma

Persistent Link:
http://hdl.handle.net/10150/195890
Title:
The Role of Bile Acids in the Progression of Squamous Epithelium to Barrett's Esophagus and Esophageal Adenocarcinoma
Author:
Goldman, Aaron
Issue Date:
2010
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Barrett's esophagus (BE) is a premalignant disease associated with esophageal adenocarcinoma (EAC). This condition is highly associated with gastroesophageal reflux disease (GERD) which is characterized as chronic exposure of the esophagus to acid and bile acids. An understanding of the cytotoxic and tumorigenic capacity of bile acids and acid during a reflux episode will lead to the identification of markers for therapeutic intervention. The major goal of the following studies was to determine the mechanisms responsible for bile acid-induced alteration in intracellular pH (pHi) the effect on DNA damage, apoptosis and the adaptive resistance to reflux episodes in cells derived from normal esophagus (HET1A) or BE (CP-A) and EAC (JH-EsoAd1). In addition, I explored the therapeutic potential of UDCA oral therapy in BE cells.Here we show a novel mechanism of bile acid-induced, nitric oxide-mediated inhibition of the sodium-hydrogen exchanger (NHE) is a pathway bile acids utilize to induce acid-mediated DNA damage. This same mechanism can elicit apoptosis-resistance which we demonstrate by the complete inhibition of NHE with pharmacological inhibitor of NHE, EIPA. In addition, chronic exposure of bile acids and acid, in-vitro, confers resistance to cytotoxicity and makes cells derived from the squamous epithelium of the esophagus resemble BE and EAC. Finally, modifying the bile acid composition with glycol-Ursodeoxycholic acid (GUDCA) prevents many of the malignant effects of bile acids and acid and suggests a possible therapeutic strategy for those that suffer from GERD. The conclusion from this study suggest that bile acid reflux should be controlled in patients who suffer from GERD
Type:
text; Electronic Dissertation
Keywords:
biochemistry; Carcinogenesis; DNA damage; Ion dynamics; Nitric oxide; physiology
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Cancer Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Dvorak, Katerina
Committee Chair:
Dvorak, Katerina

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleThe Role of Bile Acids in the Progression of Squamous Epithelium to Barrett's Esophagus and Esophageal Adenocarcinomaen_US
dc.creatorGoldman, Aaronen_US
dc.contributor.authorGoldman, Aaronen_US
dc.date.issued2010en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractBarrett's esophagus (BE) is a premalignant disease associated with esophageal adenocarcinoma (EAC). This condition is highly associated with gastroesophageal reflux disease (GERD) which is characterized as chronic exposure of the esophagus to acid and bile acids. An understanding of the cytotoxic and tumorigenic capacity of bile acids and acid during a reflux episode will lead to the identification of markers for therapeutic intervention. The major goal of the following studies was to determine the mechanisms responsible for bile acid-induced alteration in intracellular pH (pHi) the effect on DNA damage, apoptosis and the adaptive resistance to reflux episodes in cells derived from normal esophagus (HET1A) or BE (CP-A) and EAC (JH-EsoAd1). In addition, I explored the therapeutic potential of UDCA oral therapy in BE cells.Here we show a novel mechanism of bile acid-induced, nitric oxide-mediated inhibition of the sodium-hydrogen exchanger (NHE) is a pathway bile acids utilize to induce acid-mediated DNA damage. This same mechanism can elicit apoptosis-resistance which we demonstrate by the complete inhibition of NHE with pharmacological inhibitor of NHE, EIPA. In addition, chronic exposure of bile acids and acid, in-vitro, confers resistance to cytotoxicity and makes cells derived from the squamous epithelium of the esophagus resemble BE and EAC. Finally, modifying the bile acid composition with glycol-Ursodeoxycholic acid (GUDCA) prevents many of the malignant effects of bile acids and acid and suggests a possible therapeutic strategy for those that suffer from GERD. The conclusion from this study suggest that bile acid reflux should be controlled in patients who suffer from GERDen_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectbiochemistryen_US
dc.subjectCarcinogenesisen_US
dc.subjectDNA damageen_US
dc.subjectIon dynamicsen_US
dc.subjectNitric oxideen_US
dc.subjectphysiologyen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorDvorak, Katerinaen_US
dc.contributor.chairDvorak, Katerinaen_US
dc.contributor.committeememberGerner, Eugeneen_US
dc.contributor.committeememberDelamere, Nicholasen_US
dc.contributor.committeememberZhang, Donnaen_US
dc.contributor.committeememberWondrak, Georgen_US
dc.contributor.committeememberBernstein, Harrisen_US
dc.identifier.proquest11390en_US
dc.identifier.oclc752261257en_US
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