Credit: Neil Smith/NPG

Researchers have uncovered a novel pathway underlying the oncogenic effects of Helicobacter pylori infection in gastric cancer. The new findings show that H. pylori infection activates the pro-inflammatory transcription factor NF-κB, which in turn activates the oncogene DARPP-32 (also known as PPP1R1B), promoting cell survival.

Gastric cancer is the third most common cause of cancer-related death globally, and onset is frequently associated with H. pylori infection, which promotes gastric inflammation. H. pylori infection induces cell death and DNA damage in the gastric epithelium. However, the development of apoptosis-resistant cells with damaged DNA enhances the risk of tumorigenesis. The mechanisms underlying this process are unclear.

“We previously reported overexpression of DARPP-32 in about two-thirds of human gastric cancers,” explains author Wael El-Rifai. “Therefore, we became interested in investigating the possible relationship between DARPP-32, H. pylori infection and inflammation.”

...DARPP-32 is an important bridge between inflammation and cell survival

The team found that H. pylori infection resulted in increased DARPP-32 mRNA expression in a human gastric cancer cell line and in gastric tissue of infected mice, compared with non-infected controls. Using a luciferase reporter assay, the team also showed that H. pylori infection lead to upregulation of NF-κB-mediated transcriptional activity in cultured cells, which in turn increased expression of DARPP-32. Furthermore, human gastric mucosa samples showed increased NF-κB and DARPP-32 expression in cancerous tissue compared with normal tissue. Importantly, H. pylori-induced DARPP-32 expression was associated with increased cell survival and activation of the pro-survival AKT pathway in the gastric cancer cell line.

“These results suggest that DARPP-32 is an important bridge between inflammation and cell survival,” concludes El-Rifai. “The future development of potential inhibitors against DARPP-32 might be a novel strategy for treatment of gastric cancer.”