Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Abstract

Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a "hit-and-run" process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the "hit-and-run" process of gastric carcinogenesis.

Pediatric gastritis and its impact on hematologic parameters

“…[ 36 ] It is important to note that in our research lymphocyte counts were significantly higher in patients with non- H pylori gastritis in comparison to healthy controls and H pylori gastritis. As it is well known that H pylori expresses a carcinogenic potential, [ 38 ] lack of relevant proliferation of lymphocytes in patients from group 1 might suggest a possible long-term malignant transformation. PLR and NLR were proven to be reliable inflammatory markers for the diagnosis and staging of gastric cancer, whether used individually or in combination.…”

Molecular Mechanisms Contributing Bacterial Infections to the Incidence of Various Types of Cancer

“…In order to study the association between H. pylori and gastric carcinoma, epidemiological studies were carried out since 1991. Numerous studies on a large number of individuals were conducted, and reports were published [ 31 – 33 ]. These studies provided valuable insights and strongly encouraged subsequent studies.…”

Pathways of Gastric Carcinogenesis, Helicobacter pylori Virulence and Interactions with Antioxidant Systems, Vitamin C and Phytochemicals

“…Cation transport regulator 1 (CHAC1) overexpression in human gastric epithelial (AGS) cells infected with CagA-positive H. pylori has been shown to degrade glutathione via glutamylcyclotransferase activity, leading to accumulation of ROS [110]. CagA also interferes with the tumour suppressor apoptosis-stimulating protein of p53 2 (ASPP2), also known as Bcl2-binding protein (Bbp)/tumor suppressor p53-binding protein 2 (p53 BP2), and CHAC1 causes loss of function somatic mutations in the TP53 tumour suppressor gene [101][102][103]110,111]. CagA can increase the degradation of TP53 by E3 ubiquitin ligases, ARF-BP1 (ARF-binding protein 1) and HDM2 (human double minute 2), leading to failure of apoptosis, resistance to anoikis, EMT and gastric stem cell generation [101].…”