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Int J Cancer. 2018 Dec 11. doi: 10.1002/ijc.32060. [Epub ahead of print]

Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2.

Liu YD1,2, Yu L1,2,3, Ying L3,4, Balic J2,3, Gao H2,3, Deng NT5, West A2,3, Yan F6, Ji CB1,2,3, Gough D3,4, Tan P7,8,9, Jenkins BJ2,3, Li JK1.

Author information

1
Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
3
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
4
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.
5
Tumour Progression Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
6
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
7
Genome Institute of Singapore, Singapore, Singapore.
8
Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
9
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Abstract

Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.

KEYWORDS:

gastric cancer; metabolism; superoxide dismutase 2; toll-like receptor 2

PMID:
30536754
DOI:
10.1002/ijc.32060

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