Targeting Nox4 and Interleukin-6 crosstalk can be a potential strategy for Gastric Cancer prevention

Abstract

Over 950000 million people are being affected in Gastric Cancer (GC) in each year. And so many patients are dying for its lethality. That means prognosis and treatment strategies are not well enough for its treatment. So, in the present scenario research work on this disease is truly significant and necessary. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase or NOX) is a family of enzyme consists of seven NOX isoforms members, such as- NOX1, NOX2, NOX3, NOX4, NOX5 and dual oxidase (DUOX) 1 and 2, that possess similarities in terms of enzyme function and structure. All these seven isoforms are transmembrane proteins (having six transmembrane domains) with a NADPH binding site, a FAD-binding site and four heme-binding histidines. Among these enzymes (NOX family), NOX4 is highly expressed in Gastric Cancer (GC) cells. As well as it was observed that high expression of NOX4 is correlated with worse overall survival (OS) in all GC patients. Interestingly, high mRNA expression of NOX4 indicates a worse OS in stage III/IV GC patients, but not in stage I/II GC patients. That is suggesting, NOX4 may contribute to the GC progression and play a crucial role in its (GC) late-stage. And it is observed that NOX4 is related with the cell invasion by regulating the JAK2/STAT3 signaling pathway. Functionally this enzyme family is leading with production of Reactive Oxygen Species (ROS) by utilizing NADPH. Few common examples of ROS are hydrogen peroxide (H₂O₂), superoxide anion (O₂^-) and hydroxyl radicles (OH) etc. These NOX producing ROS are connected to carcinogenesis as it is involved with so many cellular processes like cell proliferation, DNA damage and angiogenesis etc. On the other hand, recent studies show that Interleukin-6 (IL-6) is significantly related with the cell invasion and JAK2/STAT3 activation. That means both compounds (NOX4 and IL-6) are related with JAK2/STAT3 signaling pathway. And this JAK2/STAT3 signaling actually activates those genes which are associated with cell proliferation and anti-apoptosis. So, it is suggested that, targeting both Nox4 and IL-6 may be a fruitful strategy in GC treatment