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Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer

Oncogene volume 36, pages 5134–5144 (2017)Cite this article

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Abstract

Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50% of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130F/F and Gan) characterized by high tumor TLR2 expression. Notably, enrichment of this TLR2-regulated gene signature also positively correlated with augmented TLR2 expression in human GC tumors, and served as an indicator of poor patient survival. Furthermore, treatment of gp130F/F and cell line-derived xenograft (MKN1) GC mouse models with a humanized anti-TLR2 antibody suppressed gastric tumor growth, which was coincident with alterations to the TLR2-driven gene signature. Collectively, our study demonstrates that in the majority of GC patients, elevated TLR2 expression is associated with a growth-potentiating gene signature which predicts poor patient outcomes, thus supporting TLR2 as a promising therapeutic target in GC.

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Acknowledgements

This work was supported by research grants awarded by the National Health and Medical Research Council (NHMRC) of Australia and Cancer Council Victoria, as well as the Operational Infrastructure Support Program by the Victorian Government of Australia. AW is supported by an NHMRC Early Career Fellowship, KT is supported by Monash Graduate and Monash International Postgraduate Research Scholarships and BJJ is supported by an NHMRC Senior Medical Research Fellowship.

Author contributions

Conception and design: PT, BJJ. Development of methodology: AW, KT, PT, BJJ. Acquisition of data: AW, KT, HT, LY, MN, ND, SJL, JJB, EO-T. Analysis and interpretation of data: AW, KT, HT, LY, ND, SJL, EO-T, WM, PSB, TU, PT, BJJ. Writing, review and/or revision of the manuscript: AW, PM, BK, WM, MR, MO, TU, PT, BJJ. Study supervision: AW, BJJ.

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Author notes

  1. A C West and K Tang: These authors contributed equally to this work.

Authors and Affiliations

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

    A C West, K Tang, H Tye, L Yu, M Najdovska, J J Balic & B J Jenkins

  2. Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia

    A C West, K Tang, L Yu, J J Balic, P S Bhathal & B J Jenkins

  3. Genome Institute of Singapore, Singapore, Singapore

    N Deng, S J Lin & P Tan

  4. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan

    E Okochi-Takada & T Ushijima

  5. Opsona Therapeutics Ltd, Dublin, Ireland

    P McGuirk, B Keogh, W McCormack & M Reilly

  6. Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    M Oshima

  7. Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

    P Tan

  8. Cancer Sciences Institute of Singapore, National University of Singapore, Singapore, Singapore

    P Tan

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West, A., Tang, K., Tye, H. et al. Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer. Oncogene 36, 5134–5144 (2017). https://doi.org/10.1038/onc.2017.121

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