Statins Attenuate Helicobacter pylori CagA Translocation and Reduce Incidence of Gastric Cancer: In Vitro and Population-Based Case-Control Studies.

Chun-Jung Lin,Chia-Hung Kao,Yu-An Chen,Chih-Ho Lai,Min-Chuan Kao,Yuan-Man Hsu,Cheng-Li Lin,Hwai-Jeng Lin,Chun-Lung Feng,Wei-Chih Liao,Chih-Jung Chen,Saeid Ghavami

doi:10.1371/journal.pone.0146432

Abstract

Gastric cancer is the second leading cause of cancer-related death worldwide. The correlation of Helicobacter pylori and the etiology of gastric cancer was substantially certain. Cholesterol-rich microdomains (also called lipid rafts), which provide platforms for signaling, are associated with H. pylori-induced pathogenesis leading to gastric cancer. Patients who have been prescribed statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have exhibited a reduced risk of several types of cancer. However, no studies have addressed the effect of statins on H. pylori-associated gastric cancer from the antineoplastic perspective. In this study, we showed that treatment of gastric epithelial cells with simvastatin reduced the level of cellular cholesterol and led to attenuation of translocation and phosphorylation of H. pylori cytotoxin-associated gene A (CagA), which is recognized as a major determinant of gastric cancer development. Additionally, a nationwide case-control study based on data from the Taiwanese National Health Insurance Research Database (NHIRD) was conducted. A population-based case-control study revealed that patients who used simvastatin exhibited a significantly reduced risk of gastric cancer (adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.70–0.83). In patients exhibiting H. pylori infection who were prescribed simvastatin, the adjusted OR for gastric cancer was 0.25 (95% CI = 0.12–0.50). Our results combined an in vitro study with a nationwide population analysis reveal that statin use might be a feasible approach to prevent H. pylori-associated gastric cancer.

Highlights

Helicobacter pylori, a Gram-negative microaerophilic spiral bacterium, colonizes the human stomach and infects over 50% of the worldwide population [1,2]
These results indicated that the reduced levels of cellular cholesterol achieved by simvastatin attenuated Cytotoxin-associated gene A (CagA) translocation and phosphorylation in H. pylori-infected cells
The results indicated that in patients diagnosed with H. pylori infection, the adjusted odds ratios (ORs) for gastric cancer in patients prescribed simvastatin was 0.25, compared with those not prescribed simvastatin

Summary

Introduction

Helicobacter pylori, a Gram-negative microaerophilic spiral bacterium, colonizes the human stomach and infects over 50% of the worldwide population [1,2]. Persistent H. pylori infection is associated with several gastroenterological illnesses including gastritis, peptic ulcer, and gastric adenocarcinoma [3]. H. pylori can penetrate the mucosal layer and survive intracellularly in the gastric epithelial cells, thereby escaping host immune response or antimicrobial therapy [4,5]. Several virulence factors characterize H. pylori-induced pathogenesis [6]. Cytotoxin-associated gene A (CagA) is one of the most critical virulence factors of H. pylori [7,8]. Translocation of CagA by the cag-pathogenicity island (cag-PAI)-encoded type IV secretion system (TFSS) results in phosphorylation of the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs and induction of host cell pathogenesis, such as cell elongation (hummingbird phenotype) [9], induction of nuclear factor (NF)-κB activation, interleukin (IL)-8 secretion [10], and carcinogenesis [11]

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Results

Conclusion