# Pilot Project 2: Nrf2 Activation in Esophageal Squamous Cell Carcinogenesis In Vivo

> **NIH NIH U54** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $46,650

## Abstract

Abstract: 
Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans rather than Caucasian 
Americans at a ratio of about 4:1. African American patients with ESCC have much worse prognosis than their 
Caucasian counterparts. Therefore it is important to better understand molecular mechanisms of ESCC and 
develop targeted therapy for this deadly disease in order to reduce racial disparity. Recent NextGen sequencing 
studies have identified multiple driver mutations in human ESCC among which Nrf2 and Keap1 mutations are 
known to activate Nrf2 signaling. However, the molecular mechanisms of Nrf2-associated carcinogenesis have 
not been clearly understood particularly in vivo. Based on our preliminary data, we hypothesize that Nrf2 
activation induces esophageal hyperproliferation and hyperkeratosis through the EGFR/PI3K/Akt pathway and 
metabolic reprogramming. Using the Keap1-/- mouse model of esophageal hyperproliferation and hyperkeratosis, 
we plan to test our hypothesis with two specific aims: (1) To examine whether Nrf2 activation in Keap1-/- 
esophagus activates the EGFR/PI3K/Akt pathway and metabolic reprogramming through transcriptional 
regulation of genes of the EGFR/PI3K/Akt pathway and energy metabolism. (2)To test whether genetic or 
chemical inhibition of the EGFR/PI3K/Akt pathway or metabolic reprogramming may suppress esophageal 
phenotype in Keap1-/- mice, and whether inhibition of both events may have synergistic effect. This Pilot Project 
is aimed to understand the carcinogenic mechanisms of Nrf2 activation in esophageal squamous cell 
carcinogenesis in vivo. If successful, it will lay down a solid foundation for translational studies on Nrf2-high 
ESCC and contribute to reduction of cancer health disparity in the African American population.

## Key facts

- **NIH application ID:** 10247138
- **Project number:** 3U54CA156733-10S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Michael Benjamin Major
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,650
- **Award type:** 3
- **Project period:** 2010-09-28 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247138

## Citation

> US National Institutes of Health, RePORTER application 10247138, Pilot Project 2: Nrf2 Activation in Esophageal Squamous Cell Carcinogenesis In Vivo (3U54CA156733-10S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10247138. Licensed CC0.

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