Helicobacter pylori-induced DNA double-stranded break in the development of gastric cancer.

Abstract

Infection with cagA‐positive Helicobacter pylori strains plays an etiological role in the development of gastric cancer. The CagA protein is injected into gastric epithelial cells through a bacterial Type IV secretion system. Inside the host cells, CagA promiscuously associates with multiple host cell proteins including the prooncogenic phosphatase SHP2 that is required for full activation of the Ras–ERK pathway. CagA–SHP2 interaction aberrantly activates SHP2 and thereby deregulates Ras–ERK signaling. Cancer is regarded as a disease of the genome, indicating that H. pylori‐mediated gastric carcinogenesis is also associated with genomic alterations in the host cell. Indeed, accumulating evidence has indicated that H. pylori infection provokes DNA double‐stranded breaks (DSBs) by both CagA‐dependent and CagA‐independent mechanisms. DSBs are repaired by either error‐free homologous recombination (HR) or error‐prone non‐homologous end joining (NHEJ) or microhomology‐mediated end joining (MMEJ). Infection with cagA‐positive H. pylori inhibits RAD51 expression while dampening cytoplasmic‐to‐nuclear translocalization of BRCA1, causing replication fork instability and HR defects (known as “BRCAness”), which collectively provoke genomic hypermutation via non‐HR‐mediated DSB repair. H. pylori also subverts multiple DNA damage responses including DNA repair systems. Infection with H. pylori additionally inhibits the function of the p53 tumor suppressor, thereby dampening DNA damage‐induced apoptosis, while promoting proliferation of CagA‐delivered cells. Therefore, H. pylori cagA‐positive strains promote abnormal expansion of cells with BRCAness, which dramatically increases the chance of generating driver gene mutations in the host cells. Once such driver mutations are acquired, H. pylori CagA is no longer required for subsequent gastric carcinogenesis (Hit‐and‐Run carcinogenesis).