SMYD3-MEK/ERK Axis Contributes to Intestinal Metaplasia and Helicobacter pylori-Associated Gastric Carcinogenesis

Chronic Helicobacter pylori infection induces gastric atrophy and intestinal metaplasia (IM), which are key precancerous lesions for gastric cancer. The purpose of this study was to determine the mechanisms by which mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling persists from active infection to the posteradication stage and contributes to gastric carcinogenic risk.

We investigated MEK/ERK signaling across different stages of H pylori-associated mucosal injury, from active infection to the posteradication state. Immunohistochemical analysis was performed using gastric biopsy specimens from H pylori-uninfected (n = 28), H pylori-infected (n = 42), and posteradicated (n = 120) patients, whereas gene expression profiling and organoid experiments were conducted on representative subsets of these samples.

MEK/ERK signaling was activated in H pylori-infected mucosa, particularly in the surface epithelium with severe atrophy and incomplete IM, and remained elevated after eradication. In the organoid model, MEK/ERK signaling was activated during differentiation and promoted expression of MUC2, an IM marker, whereas MEK inhibition suppressed it. Furthermore, SMYD3 enhanced MEK/ERK activity, implicating its role in this aberrant activation. In early gastric cancer specimens, co-upregulation of SMYD3 and p-ERK was observed in cancers with incomplete IM or mixed-type mucin phenotype.

These results suggest a mechanistic link between SMYD3-MEK/ERK activation and H pylori-associated gastric carcinogenesis, providing a potential therapeutic target.