CDX1 expression induced by CagA-expressing Helicobacter pylori promotes gastric tumorigenesis

Intestinal-type gastric cancer (GC) often results from Helicobacter pylori infection through intestinal metaplasia (IM), a transdifferentiated premalignant phenotype. Because H. pylori virulence factor CagA has been associated with aberrant expression of the transcription factor CDX1, which regulates intestinal differentiation, we explored its relationship with H. pylori infection and function during gastric carcinogenesis in normal gastric epithelial cells and GC cell lines. Infection of HFE 145 cells with CagA+ H. pylori increased expression of CDX1, as well as the epithelial-to-mesenchymal transition (EMT) markers Snail and Slug, increased invasion and migration, but those effect was not found in HFE 145 cells infected with CagA-deficient H. pylori. CDX1 overexpression increased expression of the intestinal markers Villin, sucrose isomaltase (SI) and MUC2, induced spheroid formation and enhanced expression of the stem cell markers CD44, SOX2, Oct4, and Nanog, while CDX1 knockdown inhibited proliferation and intestinal stemness. Treatment of CDX1-expressing cells with metformin, an anti-diabetic drug known to decrease risk of GC, decreased expression of EMT and stemness markers and reduced spheroid formation. In a murine xenograft model, combining metformin or shCDX1 with cisplatin reduced tumor growth, increased caspase-3 cleavage, and reduced expression of CD44 and MMP-9 to a greater degree than cisplatin alone. Patients with more advanced IM staging exhibited higher CDX1 expression than those with earlier IM staging (P=0.039), and those with H. pylori tended to have more CDX1 expression than non-infected patients (P=0.061). Finally, human tissue samples with higher CDX1 levels showed prominent CD44/SOX2 expression. Our findings indicate CagA+ H. pylori-induced CDX1 expression may enhance GC tumorigenesis and progression, and support therapeutic targeting of CDX1 in GC. Implications: This study shows that CDX1 contributes to the tumorigenesis and progression of gastric cancer and suggests the potential of targeting CDX1 to treat this malignancy.