RNAi-mediated silencing of NOX4 inhibited the invasion of gastric cancer cells through JAK2/STAT3 signaling.

NADPH oxidase 4 (NOX4) is a member of the NADPH oxidase (NOX) family of enzymes and has been found abnormally expressed in human cancers. However, its role in gastric cancer (GC) is still unclear. In the current study, we reported that NOX4 expression levels were significantly up-regulated in GC tissues compared to normal tissues (P<0.0001). Higher NOX4 expression was significantly associated with poorer overall survival in GC patients. Silencing NOX4 in two NOX4 high expression GC cell lines, MGC-803 and BGC-823 cells, did not affect cell proliferation, while inhibited cell adhesion and cell invasion of GC cells. Furthermore, Gene set enrichment analysis (GSEA) results indicated that NOX4 expression was strongly associated with cell migration, epithelial-mesenchymal transition (EMT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. More interestingly, Interleukin-6 (IL-6) increased the invasion ability and activation of JAK2/STAT3 of MGC-803 and BGC-823 cells. Such effects were attenuated by NOX4 silencing. Overexpression of NOX4 in one NOX4 low expression GC cell line, SGC-7901 cells, significantly promoted cell invasion, which was impaired by treatment of JAK2 inhibitor, AG490. AG490 inhibited STAT3 activation in SW1990 cells. NOX4 may exert its function through JAK2/STAT3 pathway. In summary, the findings of this study indicate that NOX4 may promote the development of GC, potentially representing a novel prognostic marker for overall survival in GC.