Researchers aim to develop molecules that prevent CagA from tagging Runx3 for degradation.

Scientists claim to have identified a protein-protein interaction that could explain how CagA-positive Helicobacter pylori leads to the development of stomach cancer. The team, led by University of Illinois medical biochemistry professor Lin-Feng Chen, Ph.D., aims to design small molecule drugs that block the newly identified interaction between the bacterial CagA protein and the tumor suppressor transcription factor Runx3, as a potential approach to preventing gastric diseases induced by H. pylori. The research is published in Oncogene, in a paper titled, Helicobacter pylori CagA Targets Gastric Tumor Suppressor Runx3 for Proteasome-Mediated Degradation.

H. pylori is the only bacterium known to be associated with cancer, and although about two-thirds of the world’s population is infected with the bacterium, only a minority of these individuals develop gastric inflammation, ulcers, or stomach cancer as a result of infection, Dr. Chen and colleagues explain. Previous studies have also found that CagA-positive strains of H. pylori are more likely to cause inflammation and promote cellular abnormalities that lead to stomach cancer.

Meanwhile, another group of research has identified Runx3 as a key gastric cancer tumor suppressor and confirmed that loss of expression of the protein is associated with development of gastric cancer, the researchers reported.

To investigate how H. pylori infection causes gastric cancer, Dr. Chen’s team investigated Runx3 transcription activity in gastric epithelial cells infected with the organism. They found that while CagA-positive strains inhibited Runx3 activity and led to reduced levels of the protein, CagA-negative strains of H. pylori had no effect on Runx3 levels or its activity.

Subsequent studies found that CagA and Runx3 interact with each other in the cells. The researchers identified a domain within CagA, designated WW, that recognizes the PY motif in Runx3. Interaction between CagA and Runx3 was shown to lead to the transcription factor being tagged for degradation via ubiquitination.

“This study has uncovered a new step in the initiation of H. pylori-induced gastric cancer,” Dr. Chen claims. “In fact, CagA alone is sufficient to downregulate the Runx3 transcription activity and reduce the expression of Runx3, further supporting the importance of this bacterial protein in the genesis of gastric disease. This is the first time anybody has identified a unique domain within the amino-terminal region of the CagA protein, and it will help us to better understand how this oncogenic protein functions. ”

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