Esophageal adenocarcinoma (EAC) is a serious clinical problem due to its 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 EAC 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 mixed with duodenal bile salts. The reflux exposure causes chronic inflammation, and excessive oxidative DNA damage, resulting in the accumulation of tumorigenic alterations and progression to EAC through Barrett's metaplasia (BE). However, the precise molecular events underlying the malignant transformation of esophageal cells remain poorly understood, thereby limiting the identification of targets for screening at risk patients and the development of new therapies for esophageal tumors. We have developed an innovative hypothesis to investigate tumorigenic transformation of esophageal cells in conditions of esophageal reflux injury. This hypothesis is supported by strong preliminary data from human tissues, animal models, and extensive in vitro studies. We have demonstrated that the 6Np73 protein plays a critical role in esophageal tumorigenesis by inhibiting key tumor suppressor proteins in Barrett's esophageal cells exposed to chronic gastroesophageal reflux. We have also identified pathological factors that lead to 6Np73 activation. We will build on these findings to further investigate the role played by 6Np73 and other members of the p53 protein family in the progression to esophageal adenocarcinoma.
In aim 1, we will dissect the mechanisms of 6Np73 upregulation during progression to EAC.
In aim 2, we will investigate esophageal tumorigenesis in vivo. We will employ novel mouse model of gastroesophageal reflux injury and esophageal organotypic cul- tures to recapitulate human GERD-associated pathology and dissect the function of 6Np73. These studies will be complemented with analyses of human esophageal precancerous and cancerous lesions.
In aim 3, we will explore the biological functions in the regulation of oxidative DNA damage induced by gastroesophageal reflux. 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 devel- opment and lay the groundwork for development of novel chemotherapeutic approaches in at risk patients with GERDand BE.

Public Health Relevance

Esophageal adenocarcinoma is the fastest rising of any tumors in the United States and Western World. The increasing incidence and limited treatment options make this tumor a serious health problem. The proposed research will provide novel information on the mechanisms of the development of this disease and may facili- tate the development of new diagnostics and therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Yassin, Rihab R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
United States
Zip Code
Horvat, Andela; Noto, Jennifer M; Ramatchandirin, Balamurugan et al. (2018) Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells. Oncogene 37:5054-5065
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
Horvat, Andela; Zaika, Alexander I (2017) How does bacterial pathogen Helicobacter pylori control responses to cellular stress? Future Microbiol 12:105-108
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
Zaika, Alexander I; Wei, Jinxiong; Noto, Jennifer M et al. (2015) Microbial Regulation of p53 Tumor Suppressor. PLoS Pathog 11:e1005099
Wei, Jinxiong; Noto, Jennifer M; Zaika, Elena et al. (2015) Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut 64:1040-8
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

Showing the most recent 10 out of 14 publications