Molecular Mechanism of Helicobacter pylori-Induced Gastric Cancer

Abstract

Introduction: Various types of cancers threaten human life. The role of bacteria in causing cancer is controversial, but it has been determined that the Helicobacter pylori infection is one of the identified risk factors for gastric cancer. Helicobacter pylori infection is highly prevalent, and about half of the world^,s population is infected with it.

Objective: The aim of this study was the role of Helicobacter pylori in the development of gastric cancer.

Method: We obtained information from previously published articles.

Results and conclusion: The bacterium has various virulence factors, including cytotoxin- associated gene A, vacuolating cytotoxin A, and the different outer membrane proteins that cause cancer by different mechanisms. These virulence factors activate cell signaling pathways such as PI3-kinase/Akt, JAK/STAT and Ras, Raf, and ERK signaling that control cell proliferation. Uncontrolled proliferation can lead to cancer.

Keywords: Cytotoxin-associated gene A; Gastric cancer; Helicobacter pylori; Vacuolating cytotoxin A.

Fig. 1

Activation of Ras, Raf, and ERK by phosphorylated CagA. Binding of growth factor to a tyrosine kinase receptor leads to autophosphorylation and formation of binding sites for the SH2 domain of SHP2. Activated SHP2 activates the Ras. The activated Ras-GTP complex then activates the Raf protein kinase. Raf phosphorylates and activates the protein kinase MEK that in turn activates ERK. Activated ERK is translocated to the nucleus, where it phosphorylates the transcription factor ELk1. Activated ELK1 along with SRF binds to SRE and induce the expression of c-Fos and c-Jun genes. The ELK1-SRF complex transcription factor activates the transcription of cyclin D. Increased cyclin D causes cell proliferation. Src activates CagA that activates SHP2. Activated SHP2 causes uncontrolled cell proliferation

Fig. 2.

Activation of β-catenin by the non-phosphorylated CagA. Non-phosphorylated CagA binds to E-cadherin and separates E-cadherin and β-catenin. β-catenin enters the nucleus and complexes with Tcf. β-catenin/Tcf complex activates expression the genes encoding cyclin D1 and c-Myc that leads to abnormal cell proliferation.

Fig. 3.

Activation of the PI3-kinase/Akt pathway by VacA. PI 3 kinase is associated through its SH2 domain in the activated receptor tyrosine kinase. PI 3kinase phosphorylates the 3 position of inositol, converting phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5- triphosphate. Akt binds to plasma membranes by binding to phosphatidylinositol 3,4,5-triphosphate. It is then activated as a result of phosphorylation by two other protein kinases (PDK1 and mTORC2) that also bind PIP3. The GSK-3 is inhibited by Akt phosphorylation. Inactivated GSK3β is inactivated and leads to the accumulation of β-catenin in the cytoplasm. In the presence of VacA, GSK3β is inactivated and conducts to the accumulation of β-catenin in the cytoplasm. The β-catenin enters the nucleus where it acts as a coactivator TCF and LEF transcription factor for activating transcription of β-catenin-dependent genes such as cyclin D1. High expression of cyclin D1 is associated with cancer.