Esophageal adenocarcinoma (EAC) poses a serious clinical problem due to the increasing incidence and limited treatment options. One of the strongest known risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duode- nal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, gastroesophageal re- flux is characterized by continuous damage to esophageal cell DNA that increases the mutation rate and pro- motes genomic instability. GERD is common among veterans. However, only a percentage of affected individ- uals develop neoplasia, underscoring the importance of defining mechanisms that regulate tumorigenic interac- tions. We have developed an innovative hypothesis to explain how continued reflux induces tumorigenic altera- tions in the esophagus through inhibition of the DNA Damage Response (DDR), a critical tumor suppressor mechanism that is responsible for maintaining the integrity of the genome. This hypothesis is supported by strong preliminary data generated by animal and human studies. We will expand on these novel findings by detailing the impact of GERD on the DDR.
In aim 1, we will define previously unknown molecular mechanisms through which reflux inhibits the DDR.
In aim 2, we will investigate the DDR regulation in the esophageal niche using animal models of esophageal reflux injury. We will also ana- lyze human clinical specimens.
In aim 3, we will test various options to avert inhibition of the DDR induced by GERD in vivo. Combined, our studies will further elucidate the potential risk factors for tumorigenic alterations in the esophagus and lay the groundwork for novel therapeutic approaches that halt the development of malignant esophageal lesions.
Patients with esophageal adenocarcinoma have a poor survival rate and limited treatment options, making this tumor a serious health problem. The proposed research will provide new insights into esophageal tumorigenesis and lay the groundwork for development of novel chemopreventive and chemotherapeutic agents.
|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|
|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|
Showing the most recent 10 out of 16 publications