Esophageal adenocarcinoma (EA) is a serious clinical problem due to its high and rapidly increasing incidence rate, and the limited treatment options currently available. This disease has now overtaken other histological types of esophageal tumors in the US. The major risk factor for EA is gastroesophageal reflux disease (GERD), which affects 10 to 20% of the US population. Under conditions of GERD, esophageal cells are ex- posed to acidic gastric juice frequently mixed with duodenal bile acids. The reflux exposure causes chronic inflammation, and excessive tissue and DNA damage, resulting in the accumulation of tumorigenic alterations and progression to EA through Barrett's metaplasia (BE). However, the majority of GERD and BE patients re- cover without malignant transformation, with only a fraction going on to develop an esophageal tumor. It is therefore important to uncover mechanisms that underlie tumor progression, to enable both the identification of targets for screening at risk patients and the development of new preventive therapies for esophageal tumors. We have developed an innovative hypothesis to investigate specific mechanisms of DNA damage repair in conditions of esophageal reflux injury and to apply this knowledge to design novel chemopreventive therapies. This hypothesis is supported by strong preliminary data from human tissues, animal models, and extensive in vitro studies. We have demonstrated that the p73 protein plays a critical role in esophageal tumorigenesis and regulation of DNA damage repair under conditions of esophageal reflux injury caused by GERD. We have also identified a new group of chemopreventive compounds that can specifically activate the protective function of p73 and decrease DNA damage caused by reflux. We will build on these findings to further investigate the role played by p73 and other members of the p53 protein family in the progression to esophageal adenocarcinoma.
In aim 1, we will dissect the mechanisms of DNA damage repair regulated by p73 under conditions of esophageal reflux.
In aim 2, we will investigate esophageal tumorigenesis in vivo. We will employ gastroesophageal reflux injury mouse models and esophageal organotypic cultures to recapitulate human GERD-associated pathology and dissect the mechanisms of DNA damage repair. These studies will be complemented with analyses of human esophageal precancerous and cancerous lesions.
In aim 3, we will explore the chemopreventive potential of compounds that induce the p73 protective activity under conditions of GERD. Our findings will have a strong impact on the understanding of multistep tumorigenesis associated with GERD and BE. Importantly, our results could help to reveal potential risk factors for esophageal tumor development and lay the groundwork for development of novel chemopreventive approaches in at risk patients with GERD and BE.

Public Health Relevance

The incidence of esophageal adenocarcinoma is steadily increasing during past thirty years in the US. The in- creasing incidence and limited treatment options make this tumor a serious health problem. The proposed re- search will provide new insights into esophageal tumorigenesis and lay the groundwork for development of novel chemopreventive applications.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002115-01A2
Application #
8732012
Study Section
Gastroenterology (GAST)
Project Start
2014-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Bhat, Ajaz A; Lu, Heng; Soutto, Mohammed et al. (2018) Exposure of Barrett's and esophageal adenocarcinoma cells to bile acids activates EGFR-STAT3 signaling axis via induction of APE1. Oncogene :
Bhardwaj, Vikas; Gokulan, Ravindran Caspa; Horvat, Andela et al. (2017) Activation of NADPH oxidases leads to DNA damage in esophageal cells. Sci Rep 7:9956
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Hong, Jun; Chen, Zheng; Peng, Dunfa et al. (2016) APE1-mediated DNA damage repair provides survival advantage for esophageal adenocarcinoma cells in response to acidic bile salts. Oncotarget 7:16688-702
Bhardwaj, Vikas; Horvat, Andela; Korolkova, Olga et al. (2016) Prevention of DNA damage in Barrett's esophageal cells exposed to acidic bile salts. Carcinogenesis 37:1161-1169
Bhardwaj, Vikas; Noto, Jennifer M; Wei, Jinxiong et al. (2015) Helicobacter pylori bacteria alter the p53 stress response via ERK-HDM2 pathway. Oncotarget 6:1531-43
Zaika, Alexander I (2015) Bacterial Pathogen Helicobacter pylori: A Bad AKTor Inhibits p53 Protein Activity [corrected]. Dig Dis Sci 60:822-3
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
Taylor, Chase; Loomans, Holli A; Le Bras, Gregoire F et al. (2015) Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma. Oncotarget 6:34228-44

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