# The role of NRF2 in reflux-induced esophageal adenocarcinomas

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $351,131

## Abstract

ABSTRACT/SUMMARY: The incidence of esophageal adenocarcinoma (EAC) has increased more than six
fold over the past three decades. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts
abnormally refluxate into the esophagus affects almost 20% of adult US population. GERD leads to the
development of a glandular epithelium known as Barrett's esophagus (BE); the main risk factor for the
development of neoplastic lesions; high-grade dysplasia (HGD) and progression to EAC. We and others have
shown that chronic exposure of BE cells to acidic bile salts is associated with a dramatic increase in the burden
of reactive oxygen species (ROS) and oxidative stress. We have found that several members of the
glutathione family members that protect against oxidative stress in BE cells are silenced in neoplastic HGD and
EAC. EAC cells are exposed to high levels of ROS and oxidative stress due to chronic acidic bile reflux and
activation of oncogenes. Failure to control the cumulative levels of ROS and oxidative stress would be lethal to
cancer cells, if they remain uncorrected. We hypothesize that; with the silencing of several antioxidant genes
in progression from BE to HGD/EAC, cancer cells must develop an antioxidant network that prevents
uncontrolled accumulation of ROS. These adaptive mechanisms are crucial in promoting their survival in
response to high levels of ROS due to exposure to acidic bile salts, activation of oncogenes, and treatment
with chemotherapeutics. Our preliminary data demonstrated constitutive high levels of expression of NRF2 in
HGD/EAC, suggesting its role as an intrinsic adaptive molecular mechanism. We show for the first time that
accumulation of NRF2 protein and its activation in EAC is mainly dependent on redox factor 1 (REF1); not on
its physiological inhibitor KEAP1. In this proposal, we will investigate the biological relevance of NRF2
antioxidant functions in regulating ROS, oxidative stress, oxidative DNA damage, gene expression, and cell
survival in response to acidic bile salts and chemotherapeutics. The regulation of NRF2 by REF1 and its
transcription network will be investigated in Aim 1. In Aim 2, we will tackle previously unexplored roles of NRF2
in EAC tumorigenesis and identify the role of NRF2 in EAC cancer cell survival in response to acidic bile salts
and chemotherapeutics. The clinico-pathological significance of NRF2 expression and its significance as a
druggable target will be investigated alone and in combination with existing chemotherapeutics (Aim 3). In
summary, this project addresses gaps in our knowledge and tackles etiology-based biologically relevant
questions to uncover novel information regarding the role of NRF2 in regulating survival and chemotherapeutic
resistance in EAC. The findings are especially important as several NRF2 activators are available over
the counter and are also used to treat some clinical disorders such multiple sclerosis (MS). Treatments
with NRF2 activators may nee...

## Key facts

- **NIH application ID:** 9850088
- **Project number:** 5R01CA224366-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** WAEL EL-RIFAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,131
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850088

## Citation

> US National Institutes of Health, RePORTER application 9850088, The role of NRF2 in reflux-induced esophageal adenocarcinomas (5R01CA224366-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850088. Licensed CC0.

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