# H. Pylori Relationship to Digestive Diseases and Cancer

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $453,641

## Abstract

Project Summary
Helicobacter pylori is the strongest identified risk factor for gastric cancer and contact between this microbial
pathogen and epithelial cells activates signaling pathways that drive oncogenesis. Our long-term objective is
to define targetable pathways induced by carcinogenic H. pylori strains that lead to oncogenic
epithelial responses. One H. pylori strain-specific determinant that augments cancer risk is the cag type IV
secretion system (TFSS), which translocates an oncoprotein (CagA) into epithelial cells following bacterial
attachment. A host molecule that influences gastric cancer in conjunction with H. pylori is the transcription co-
regulator ß-catenin. Expression of ß-catenin is increased in human gastric adenocarcinoma specimens and
nuclear accumulation of ß-catenin is enhanced within gastric adenomas and dysplasia; thus, aberrant
activation of ß-catenin precedes the development of gastric cancer. Importantly, we have demonstrated that
the H. pylori cag TFSS can activate ß-catenin in vitro and in vivo. A key regulator of ß-catenin is the nodal
kinase AKT, and genes within the AKT pathway are the most frequently altered in human cancers. Pertinent
to this application, human Akt polymorphisms are significantly associated with the development of gastric
pre-malignant and malignant lesions. In exciting new studies, we have demonstrated for the first time that H.
pylori activates AKT and ß-catenin in a novel model, human gastroids, via cag-dependent CagA translocation.
These results directly informed provocative new translational studies examining H. pylori isolates and gastric
samples harvested from a unique human population in Colombia in which individuals reside in either a high- or
low-risk region of gastric cancer. These data indicate that H. pylori-infected gastric tissues harbor increased
expression levels of ß-catenin target genes, which has focused our current studies on defining the role of ß-
catenin as a mediator of H. pylori-induced carcinogenesis. Our hypothesis is that selective activation of
AKT-mediated ß-catenin-dependent pathways contributes to the augmentation in carcinogenic risk
conferred by H. pylori cag+ strains. We will test this hypothesis via the following Aims:
1. Utilize gastroid systems derived from genetic mouse models and human samples to define the role of AKT
in regulating ß-catenin dependent oncogenic responses to H. pylori wild-type and isogenic mutant strains.
2. Define the effects of AKT deficiency and inhibition on gastric carcinogenesis using rodent models of H.
pylori-induced inflammation and cancer.
3. Validate findings in unique human populations that reside in high or low gastric cancer risk regions and use
these results to inform mechanistic studies focused on AKT and ß-catenin within the context of H. pylori.
These studies will help to identify people who are at greatest risk for H. pylori-induced stomach cancer, which
will greatly improve the diagnosis and therapy of this diseas...

## Key facts

- **NIH application ID:** 10379093
- **Project number:** 5R01CA077955-26
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RICHARD M. PEEK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,641
- **Award type:** 5
- **Project period:** 1997-09-30 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379093

## Citation

> US National Institutes of Health, RePORTER application 10379093, H. Pylori Relationship to Digestive Diseases and Cancer (5R01CA077955-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379093. Licensed CC0.

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