Gastric cancer (GC) is the second most lethal form of cancer world-wide, which represents a subset of inflammation-associated carcinogenesis1. Deregulated interactions between gastric microbes (i.e. Helicobacter pylori) and the host innate-immune system are likely to promote the pathogenesis of this disease1, however the identity of the host oncogenic inflammatory regulators remain ill-defined. On this note, hyperactivation of the pro-inflammatory and oncogenic transcription factor signal transducer and activator of transcription (STAT) 3, is observed in 50% of human GC2, and yet the molecular basis by which STAT3 hyperactivation promotes gastritis and GC is still unknown
We report here that the innate immune pathogen sensor, Toll-like receptor 2 (TLR2), is a novel STAT3 target gene that is upregulated in our GC mouse model (gp130F/F), which is characterised by STAT3 hyperactivation. In addition, genetic ablation of TLR2 in gp130F/F mice significantly suppressed gastric tumourigenesis independent of gastritis. Interestingly, immunohistochemical analyses revealed that gp130F/F:Tlr2-/- mice had increased TUNEL-positive apoptotic cells and reduced PCNA-positive cells in the gastric mucosal epithelium, therefore implicating a role for TLR2 in gastric epithelial cell proliferation and survival. Consistent with our mouse data, we identified that activating TLR2, using synthetic lipopeptides, in human gastric epithelial cell lines promoted cell proliferation. Collectively, our data depicts an unexpected role for TLR2 in gastric tumourigenesis, whereby increased STAT3 activation results in over-expression of TLR2 to aid in the promotion of gastric epithelial cell growth.