Molecular network analysis and development of adverse outcome pathway (AOP) on chronic reactive oxygen species leading to human treatment-resistant gastric cancer

Abstract

Molecular signaling pathway networks are regulated in epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), which exhibit anti-cancer drug resistant features. To reveal the mechanism of human treatment-resistant gastric cancer (GC) and the relationship between oxidative stress response and GC, analysis on oxidative stress response and molecular networks in diffuse- and intestinal-type GC has been performed. The network pathways of GC were analyzed by Ingenuity Pathway Analysis (IPA). NRF2-mediated oxidative stress response network included molecules related to Regulation of EMT by growth factors pathway and Production of nitric oxide and reactive oxygen species in macrophages such as PI3K and AKT. We have developed the Adverse Outcome Pathway (AOP) on chronic reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer consists of Molecular Initiating Event (MIE) as chronic ROS, followed by Key Event (KE)1 as sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion, KE2 as proliferation / beta-catenin activation, KE3 as EMT, and AO as human treatment-resistant GC. Updates on the AOP development will be introduced.