# Molecular Pathobiology of Gastric Carcinogenesis

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2023 · —

## Abstract

Gastric cancer is the third leading cause of cancer-associated death worldwide. The global cancer statistics
report indicated an estimated 1,033,701 new gastric cancer cases and 782,685 deaths occurred in 2018.
Several studies have reported frequent association of gastric adenocarcinoma with Helicobacter pylori (H.
pylori) infection. The World Health Organization has classified H. pylori as a class I carcinogen and the main
risk factor for gastric cancer. Despite efforts to eradicate H. pylori, infection remains a global health problem
with almost half of the world’s population infected. According to a recent study of U.S soldiers deployed to the
Middle East and Far East, the incidence of H. pylori infection was 7.3 percent per year compared to 2.5
percent of U.S. military recruits living at home. This increase represents a major increase in risk. When
epithelial cells lose their protective capacity, they become prone to the carcinogenic effects of H. pylori, leading
to the development of intestinal metaplasia, gastric dysplasia and progression to cancer. Our recent
preliminary data in this proposal, demonstrates frequent overexpression of oncogenic FGFR4 signaling in
gastric cancer. Using in vitro and in vivo models as well as H. pylori infection, we demonstrated a novel link
between pro-inflammatory signaling (STAT3) and overexpression and activation of FGFR4. Functionally, we
found that FGFR4 plays a critical role in regulating the level and activity of NRF2, a major anti-oxidant
transcription factor, in response to cellular stress induced by H. pylori or chemotherapy. The FGFR4-NRF2
signaling promoted cell survival and resistance to chemotherapeutics. Based on our novel findings, we
hypothesize that the dynamic pro-inflammatory oncogenic cross-talk between STAT3, FGFR4 and cellular anti-
oxidant capacity plays a critical role in gastric tumorigenesis. Our goal is to understand the molecular and
functional consequences of FGFR4 in the multi-step gastric carcinogenesis cascade. In this proposal, we will
investigate mechanisms of activation of FGFR4 in gastric tumorigenesis (Aim 1). We will determine the
downstream molecular and biological functions of activation of FGFR4 and antioxidant response in gastric
tumorigenesis in Aim 2. The translational significance of activation FGFR4 and NRF2 across stages of human
gastric tumorigenesis will be investigated (Aim 3). In addition, Aim 3 will also determine the therapeutic
significance of inhibiting FGFR4 as a single agent or in combinations with standards of care in pre-clinical
models of gastric tumorigenesis. This proposal tackles etiology-based biologically-relevant questions to
uncover novel information regarding the role of H. pylori, inflammation, oxidative stress, and tumorigenic
signaling in the multi-step gastric tumorigenesis. A successful completion of this project will have a positive
impact on understanding the biology and identification of diagnostic, prognostic and possibly therapeutic...

## Key facts

- **NIH application ID:** 10695906
- **Project number:** 5I01BX001179-11
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** WAEL EL-RIFAI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695906

## Citation

> US National Institutes of Health, RePORTER application 10695906, Molecular Pathobiology of Gastric Carcinogenesis (5I01BX001179-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10695906. Licensed CC0.

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