Gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE), which are exceptionally common disorders in adult Americans, are strong risk factors for esophageal adenocarcinoma. The frequency of BE- associated adenocarcinoma has increased more than six-fold in the past few decades, and the development of chemopreventive therapies for this lethal tumor has been hampered by limited understanding of the molecular events underlying the pathogenesis and neoplastic progression of BE. We have preliminary data showing that Barrett's epithelial cells are more resistant to apoptosis induced by deoxycholic acid (DCA), a hydrophobic bile acid found in refluxed gastric juice, than the squamous cells that normally line the esophagus. Such apoptotic resistance might underlie the pathogenesis and persistence of Barrett's metaplasia, as esophageal squamous cells that succumb to bile acid-induced apoptosis are replaced by apoptosis-resistant Barrett's cells. Hydrophobic bile acids like DCA also have been shown to cause DNA damage, and extensive DNA damage normally triggers apoptosis. However, we have preliminary data from in vitro and in vivo studies showing that Barrett's cells respond to bile acid-induced DNA damage by activating anti-apoptotic survival pathways. This could facilitate the neoplastic progression of Barrett's metaplasia by allowing the survival of cells that have sustained cancer-promoting mutations. Moreover, our preliminary studies suggest that esophageal squamous cells from patients with BE may be more susceptible to apoptosis induced by DNA damage than esophageal squamous cells from GERD patients without BE. This predisposition of esophageal squamous cells to succumb to apoptosis also may contribute to the development of BE. Our preliminary data suggest that the NF-kB pathway plays a key role in the apoptotic resistance of Barrett's metaplasia. We also have preliminary data showing that ursodeoxycholic acid (UDCA), a hydrophilic bile acid, does not induce genotoxic damage in Barrett's cells in vitro or in vivo, and even protects against the DNA damage caused by DCA exposure. These findings suggest a potential chemopreventive role for UDCA. Recently, we have used telomerase technology to generate immortal, but benign (non-transformed), Barrett's cell lines and esophageal squamous cell lines from GERD patients with and without BE. We propose to use these cell lines as well as tissue specimens to explore the molecular pathways activated by bile-acid reflux that regulate apoptosis, and the role of those pathways in the development and neoplastic progression of BE. We hypothesize that bile acids influence apoptosis in esophageal cells through effects on the NF-:B pathway.
The aims of this study are to delineate the effects of bile acids on DNA damage, on the NF-:B pathway, and on apoptosis in normal esophageal squamous and metaplastic Barrett's cells in vitro and in patients in vivo, to disrupt the key NF-:B proteins and determine the effects of those disruptions on bile-acid mediated apoptosis in vitro, and to determine whether UDCA can protect against the effects of the more toxic bile acids on DNA injury and apoptosis in vitro.
The relevance to public health is the identification of specific molecular markers that can be used to select a subset of our many patients with gastroesophageal reflux disease who might benefit from aggressive anti- reflux therapies to prevent the development of Barrett's esophagus as well as to select a subgroup of patients with Barrett's esophagus who would benefit most from interventions to prevent esophageal adenocarcinoma.
|Asanuma, Kiyotaka; Huo, Xiaofang; Agoston, Agoston et al. (2016) In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-box 2) expression. Gut 65:1416-26|
|Yu, Chunhua; Huo, Xiaofang; Agoston, Agoston T et al. (2015) Mitochondrial STAT3 contributes to transformation of Barrett's epithelial cells that express oncogenic Ras in a p53-independent fashion. Am J Physiol Gastrointest Liver Physiol 309:G146-61|
|Chakraborty, Sharmistha; Li, Li; Puliyappadamba, Vineshkumar Thidil et al. (2014) Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks. Nat Commun 5:5811|
|Zhang, Qiuyang; Yu, Chunhua; Peng, Sui et al. (2014) Autocrine VEGF signaling promotes proliferation of neoplastic Barrett's epithelial cells through a PLC-dependent pathway. Gastroenterology 146:461-72.e6|
|Park, Jason Y; Zhang, Xi; Nguyen, Nathalie et al. (2014) Proton pump inhibitors decrease eotaxin-3 expression in the proximal esophagus of children with esophageal eosinophilia. PLoS One 9:e101391|
|Cheng, Edaire; Souza, Rhonda F; Spechler, Stuart Jon (2014) Eosinophilic esophagitis: interactions with gastroesophageal reflux disease. Gastroenterol Clin North Am 43:243-56|
|Peng, Sui; Huo, Xiaofang; Rezaei, Davood et al. (2014) In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids. Am J Physiol Gastrointest Liver Physiol 307:G129-39|
|Wang, David H; Tiwari, Anjana; Kim, Monica E et al. (2014) Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia. J Clin Invest 124:3767-80|
|Huo, Xiaofang; Zhang, Xi; Yu, Chunhua et al. (2014) In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-ÎºB and activator protein-1. Gut 63:1042-52|
|Cheng, Edaire; Zhang, Xi; Huo, Xiaofang et al. (2013) Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD. Gut 62:824-32|
Showing the most recent 10 out of 35 publications