Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1-mediated DNA methylation mechanism.

Rongrong Zhao,Yang Ou,Le Song,Siying Wang,Zhengxia Liu,Yakun Liu,Wenting Xu,Haifeng Ren

doi:10.1002/cam4.2892

Abstract

Krüppel‐like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5‐hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA‐TET1‐KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

Highlights

Gastric cancer (GC) originates from the gastric mucosal epithelium, is a common malignant tumor, and has a mortality rate that is ranked second for tumor-related diseases.[1,2] Surgery is currently the most effective treatment for GC, but targeted therapy is still the main treatment for patients who cannot tolerate surgery or for patients with recurrence after surgery.[3]
The results show that in GC patients without H pylori infection, Krüppel-like factor 4 (KLF4) expression has a strong positive rate of 51.9% in GC tissue, while in GC patients with H pylori infection, KLF4 expression has a positive rate of 27.9% in GC tissue; these results indicate that expression of KLF4 is apparently decreased in H pylori-infected patients compared to that in patients without H pylori infection (P = .042)
Lower KLF4 expression is related to patient prognosis and lymph node and distant metastases

Summary

| INTRODUCTION

Gastric cancer (GC) originates from the gastric mucosal epithelium, is a common malignant tumor, and has a mortality rate that is ranked second for tumor-related diseases.[1,2] Surgery is currently the most effective treatment for GC, but targeted therapy is still the main treatment for patients who cannot tolerate surgery or for patients with recurrence after surgery.[3]. Krüppel-like factor 4 (KLF4) is expressed in terminally differentiated epithelial cells of the gastrointestinal tract, lungs, and several other tissues.[5] The function of KLF4 is mainly to regulate cell differentiation and apoptosis.[6] It has been proposed that promoter methylation is required for KLF4 inactivation in GC6; clinical trials have demonstrated that targeting specific molecules to activate KLF4 is beneficial for therapeutic intervention of advanced solid tumors.[7] the molecular mechanisms of KLF4 need to be explored in GC. We sought to explore how KLF4 is inactivated in GC and aimed to analyze the relationships among CagA, KLF4, and TET1

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION