Cmtm4 Deficiency Inhibits Helicobacter pylori-Induced Gastric Carcinogenesis.

Abstract

Helicobacter pylori is the main pathogenic factor in gastric cancer (GC), and the interleukin (IL)-17-mediated inflammatory response plays a crucial role in both H. pylori infection and gastric carcinogenesis. CMTM4, a subunit of the IL-17 receptor (IL-17R), has been implicated in immune responses, but its role in GC development remains unclear. In this study, we investigate the role of CMTM4 during H. pylori-induced gastric carcinogenesis using Cmtm4 knockout (KO) mice. Our findings indicated that Cmtm4 deficiency inhibited GC development and pseudopyloric metaplasia, while reducing DNA damage in the gastric mucosa. Mechanistically, Cmtm4 deletion downregulated the IL-17 signaling pathway in GC. Specifically, it suppressed the expression of IL-17 receptor RC (IL-17RC) and its downstream signaling molecules, resulting in the inhibition of nuclear factor-κ B (NF-κB) activation and a decrease in NADPH oxidase-1 (NOX1) levels. These results suggest that Cmtm4 deletion suppresses H. pylori-induced gastric carcinogenesis and precancerous lesion formation, potentially through the regulation of IL-17RC/NF-κB/NOX1 signaling, which may represent a new target for the early prevention of GC.