BACKGROUND: While most individuals infected with Helicobacter pylori (Hp) remain asymptomatic throughout their lifetime, in a small but significant proportion the resulting severe chronic inflammation (gastritis) drives development of gastric ulcers or stomach cancer. Stomach cancer is the third leading cause of cancer-related deaths globally. Progression to malignancy is preventable, provided Hp is eradicated early enough, thereby removing the inflammatory drive towards cancer. Antibiotics were effective in achieving this but an alarming rise in anti-microbial resistance has necessitated the identification of alternative treatments. Targeting factors that regulate the inflammation-causing gastritis provide an alternative approach.
RESULTS: We have identified a new therapeutic target, a host potassium channel regulatory subunit (SUR2) that has the potential to protect against Hp-associated diseases. Stomach cancer has poor prognosis; higher expression of the ABCC9 gene (encoding the potassium channel subunit, SUR2) in individuals with stomach cancer correlates with a significantly decreased overall survival compared to the lower expression cohort (N=876, P<0.0001). Analysing ABCC9 expression in the human gastric mucosa of normal, Hp infected and gastric cancer subjects revealed that gene expression was suppressed during Hp infection (P<0.01) but highly elevated in the presence of adenocarcinoma (P<0.05). Abcc9 expression was also significantly lowered in our mouse model of Helicobacter infection. Pharmaceuticals targeting SUR2 are already in clinical use for the treatment of several conditions. Treatment of Helicobacter-infected mice with two such drugs, Pinacidil and Nicorandil, was found to reduce gastritis. Since macrophages are a major mediator of Helicobacter-induced gastritis, we constructed an Abcc9 null mouse macrophage cell line with CRISPR technology. Stimulating Abcc9-/- macrophages with live Hp induced a more rapid and substantially greater secretion of pro-inflammatory cytokines as compared to wildtype cells, demonstrating that Abcc9 can regulate the response of immune cells to Hp infection.
Thus, we have discovered a novel role of ABCC9 as an important host factor in mediating Helicobacter-induced gastritis which makes it an attractive target for further drug development.