Elucidating the role of TLR2 in STAT3-mediated gastric tumourigenesis
thesisposted on 06.02.2017 by Tye, Yuet Mei
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
Gastric cancer (GC) is the second most lethal form of cancer world-wide, which represents a subset of inflammation-associated carcinogenesis. While it is accepted that deregulated interactions between gastric microbes (i.e. Helicobacter pylori) and the host innate immune system are likely to be involved in the pathogenesis of gastric inflammation (gastritis) and the development GC, the identity of oncogenic inflammatory regulators in the host gastric mucosa remains obscure. On this note, uncontrolled activation of cytokine signalling pathways, especially the pro-inflammatory and oncogenic transcription factor signal transducer and activator of transcription (STAT) 3, is implicated in various inflammation-associated cancers, including up to 50% of human GC cases. However, the downstream molecular consequences of aberrant STAT3 activation in promoting gastritis and subsequently gastric tumorigenesis are ill-defined. This thesis addresses the role of toll-like receptors (TLRs) which are key components of the innate immune system primarily known to trigger an inflammatory response upon pathogen detection during gastric tumourigenesis. Our mouse model for GC, was generated by a specific “knock-in” phenylalanine substitution at tyrosine 757 in the interleukin (IL)-6 cytokine family co-receptor gp130 (gp130F/F), which abolishes the negative feedback mechanism, thus leading to gp130-STAT3 hyper-activation. These mice spontaneously developed gastric hyperplasia and adenomatous lesions that resembled histopathological features similar to human intestinal-type GC. Notably, aberrant STAT3 activation in the gastric compartment of these mice directly caused a significant increase in the expression of TLR2, a receptor that is responsible for recognising a broad range of microbial products. In addition, genetic deletion of TLR2 in gp130F/F mice severely reduced the gastric tumour mass by approximately 50%. However, unexpectedly, the level of gastritis was comparable to gp130F/F mice. 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 gastric epithelial cell proliferation. Collectively, our data depicts an unexpected role for TLR2 in gastric tumourigenesis, whereby increased STAT3 activation resulted in over-expression of TLR2 to promote gastric tumour cell growth.