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Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis

Oncogene volume 33, pages 2540–2546 (2014)Cite this article

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Abstract

Signalling by the toll-like receptor (TLR) family of pathogen recognition receptors has emerged as a key molecular component in the pathogenesis of an increasing number of inflammatory-related cancers, among which gastric cancer rates as the second most lethal cancer world-wide. The myeloid differentiation factor 88 (MyD88) adapter molecule has a critical role in mediating innate immune signalling by members of the TLR and interleukin (IL)-1 families, and has been associated with either pro- or antitumourigenic responses in various cancer models. However, little is known about the in vivo role of MyD88 adapter-like (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to facilitating TLR4 and TLR2 signalling. To interrogate the role of these innate immune signalling components in gastric tumourigenesis, here we have employed the spontaneous gastric cancer gp130F/F mouse model, in which TLR2 promotes the growth of gastric tumours. Genetic ablation of Myd88 in gp130F/F mice suppressed tumourigenesis and was associated with increased apoptosis and reduced proliferation in the gastric tumour epithelium, comparable to that observed previously upon deletion of Tlr2 in gp130F/F mice. By contrast, the tumour burden in gp130F/F:Mal−/− mice was equivalent to their gp130F/F littermates. At the molecular level, suppressed tumourigenesis in gp130F/F:Myd88−/− mice correlated with reduced expression and activation of TLR2-regulated protumourigenic genes and signalling pathways, respectively. Consistent with the previously defined non-essential role for TLR2 in gastric tumour inflammation, the extent of inflammatory cell infiltrates in gastric tumours from gp130F/F:Mal−/− and gp130F/F:Myd88−/− mice remained unaltered compared with gp130F/F mice. Collectively, our data reveal a differential, but inflammation-independent, requirement for Mal and MyD88 during TLR2-promoted gastric tumourigenesis.

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Acknowledgements

This study was supported by research grants from the Association for International Cancer Research (UK), the Cancer Council of Victoria (Australia) and the National Health and Medical Research Council (Australia), as well as the Operational Infrastructure Support Program by the Victorian Government of Australia. BJ Jenkins is supported by a Senior Medical Research Fellowship awarded by the Sylvia and Charles Viertel Foundation.

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Author notes

  1. C L Kennedy

    Present address: 4Current address: Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia.,

  2. T Putoczki & M Ernst

    Present address: 5Current address: The Walter and Eliza Hall Institute for Medical Research, 1 G Royal Parade, Parkville, Victoria, Australia.,

Authors and Affiliations

  1. Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia

    C L Kennedy, M Najdovska, H Tye, L McLeod, L Yu & B J Jenkins

  2. Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia

    A Jarnicki, T Putoczki & M Ernst

  3. Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia

    P S Bhathal

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  1. C L Kennedy
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Correspondence to B J Jenkins.

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Kennedy, C., Najdovska, M., Tye, H. et al. Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. Oncogene 33, 2540–2546 (2014). https://doi.org/10.1038/onc.2013.205

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  • DOI: https://doi.org/10.1038/onc.2013.205

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