Gastric cancer: genome damaged by bugs

Abstract

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The role of the microorganisms in gastric tumorigenesis attracts much attention in recent years. These microorganisms include bacteria, virus, and fungi. Among them, Helicobacter pylori (H. pylori) infection is by far the most important risk factor for GC development, with special reference to the early-onset cases. H. pylori targets multiple cellular components by utilizing various virulence factors to modulate the host proliferation, apoptosis, migration, and inflammatory response. Epstein-Barr virus (EBV) serves as another major risk factor in gastric carcinogenesis. The virus protein, EBER noncoding RNA, and EBV miRNAs contribute to the tumorigenesis by modulating host genome methylation and gene expression. In this review, we summarized the related reports about the colonized microorganism in the stomach and discussed their specific roles in gastric tumorigenesis. Meanwhile, we highlighted the therapeutic significance of eradicating the microorganisms in GC treatment.

Fig. 1. Molecular pathogenesis of H. pylori in gastric carcinogenesis.

The MEK–ERK and FAK signaling pathways are activated by phosphorylated CagA to mediate hummingbird phenotype of the epithelial cells and promote cell migration. The β-catenin is activated by nonphosphorylated intracellular CagA by disruption of the E-cadherin–β-catenin complexes or PI3K–AKT signaling. CagA activates JAK-STAT3 pathway by releasing IL-6/IL11 and activating gp130. Nuclear translocation of STAT3 initiates gene expression for cell proliferation. H. pylori peptidoglycan and VacA potentiate PI3K–AKT signaling to promote epithelial cell migration, increase proliferation, and reduce apoptosis. CagA, VacA, and peptidoglycan coordinate to activate NF-κB signaling cascade thus to transcriptionally upregulate proinflammatory cytokines such as IL-1 and IL-8, and promote inflammation.

Fig. 2. Different forms of EBV latency.

a Schematic illustration of the EBV genome and latent genes. b Latent gene expression spectrum in different forms of latency. EBVaGC belongs to latency I but LMP2A can be detected in approximately half of cases.

Fig. 3. EBV life cycle in stomach epithelial cells and the oncogenic properties in gastric carcinoma.

① Dissociative EBV from saliva or B cell enters stomach epithelial cells with the help of host receptor such as integrins, ephrin receptor A2, and NMHCIIA. Interaction of B cell and epithelial cell also facilitates the entry of EBV. ② Naked EBV-DNA is transported to nucleus, and then goes through ③ circulation, ④ chromatination, and CpG methylation. The latent infection is established followed by viral genome ⑤ transcription and ⑥ translation. The transcription products include ⑦ EBERs and ⑧ BART-miRNAs. The translational products are ⑨ LMP2A and ⑩ EBNA1. The oncogenic factors corporately promote gastric tumorigenesis. EBV can also induce ⑪ globally genomic methylation of the host cells.