CDX1 Expression Induced by CagA-ExpressingHelicobacter pyloriPromotes Gastric Tumorigenesis

Abstract

Intestinal-type gastric cancer often results from Helicobacter pylori infection through intestinal metaplasia, 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 gastric cancer cell lines. Infection of HFE 145 cells with CagA þ 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 effects were 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 antidiabetic drug known to decrease the risk of gastric cancer, 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 intestinal metaplasia staging exhibited higher CDX1 expression than those with earlier intestinal metaplasia staging (P ¼ 0.039), and those with H. pylori tended to have more CDX1 expression than noninfected patients (P ¼ 0.061). Finally, human tissue samples with higher CDX1 levels showed prominent CD44/ SOX2 expression. Our findings indicate CagA þ H. pyloriinduced CDX1 expression may enhance gastric cancer tumorigenesis and progression, and support therapeutic targeting of CDX1 in gastric cancer.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.

Helicobacter pylori Virulence Factors Exploiting Gastric Colonization and its Pathogenicity

“…In addition to the type of EPIYA-motifs, strains with amino acid polymorphism within the Western-specific EPIYA-B motif like EPIYT-B may influence CagA activity, reducing the ability to induce hummingbird phenomena and IL-8 expression conferring lower risk for gastric cancer and a higher risk for duodenal ulcer development [159]. A recent study demonstrated that secreted H. pylori CagA can induce caudal type homeobox 1 (CDX1) expression, which is a homeobox transcription factor that plays an important role in human intestine development and maintenance [160,161]. CDX1 activation promotes cell proliferation, invasion/migration, intestinalization of gastric epithelial cells, and stem cell-like phenotype induction leading to cancer development and failure of common gastric cancer chemotherapies [160].…”

Caudal type homeoboxes as a driving force in Helicobacter pylori infection-induced gastric intestinal metaplasia

“…47 In vitro, the expression level of CDX2 increased in GC cell lines infected by H. pylori, and abnormal expression of CDX1 was induced by infection with CagA-positive H. pylori strains. 49,50 In addition, some studies indicated that the CDX2 expression level will decrease after H. pylori eradication prior to the development of GIM. 51,52 However, a prospective study showed that H. pylori eradication had no significant effect on GIM development.…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Accumulation of intracellular CagA was confirmed in CD44+ gastric CSCs [138]. H. pylori-infected (CagA-positive) gastric cancer cells exhibit CSC properties via increased expression of surface markers-CD44 and Lgr5 with Nanog, Oct4, and c-myc upregulation [139,140]. CagA impairs transcription factor CDX1 expression, promoting EMT, and CSC features in gastric epithelial cells [141].…”