Wisal Abdulrhman Salem
Helicobacter pylori infection is the most important etiological factor, but gastric cancer is a major cause of cancer related death all over the world. The continuous colonization of the gastric mucosa by H. pylori causes chronic inflammation which leads to gastric carcinogenesis in complex host-pathogen interactions. The prolonged activation of the nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3) signaling pathways that act as critical molecular hubs between inflammation and oncogenic transformation are central to the process. H. pylori virulence factors, such as CagA, VacA, and urease, activate innate immune receptors and downstream adaptor molecules that cause NF-κB nuclear translocation and transcription of proinflammatory cytokines, including IL-1b, IL-6, and IL-8 and TNF-alpha. Such cytokines, in turn, amplify the action of inflammatory signaling and enhance the activation of STAT3 through the JAK/STAT axis through a self-perpetuating inflammatory circuit. NF-κB and STAT3 are activated in a coordinated and persistent manner that triggers an extensive repertoire of oncogenic programs such as epithelial-mesenchymal transition, anti-apoptotic response, immune evasion, stemness acquisition and metabolic re-programing. Interaction between these pathways also enhances tumor-promoting cues and lead to genomic instability and epigenetic disruption in the development of gastric cancer out of chronic gastritis. There is growing evidence that NF-κB/STAT3 signaling elements and their downstream targets may serve as effective diagnostic, prognostic, and predictive biomarkers. Besides, specific therapeutic approaches to interfere with such pathways individually or in combination-have shown promising preclinical and early clinical results. This review provides a summary of existing knowledge on H. pylori-induced NF-κB and STAT3 signaling pathways and addresses new therapeutic targets that can be used to implement precision medicine in gastric cancer.