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

You Dong Liu, Liang Yu, Le Ying, Jesse Balic, Hugh Gao, Nian Tao Deng, Alison West, Feng Yan, Cheng Bo Ji, Daniel Gough, Patrick Tan, Brendan J. Jenkins, Ji Kun Li

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)3056-3069
Number of pages14
JournalInternational Journal of Cancer
Volume144
Issue number12
DOIs
Publication statusPublished - 15 Jun 2019

Keywords

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

Cite this

Liu, You Dong ; Yu, Liang ; Ying, Le ; Balic, Jesse ; Gao, Hugh ; Deng, Nian Tao ; West, Alison ; Yan, Feng ; Ji, Cheng Bo ; Gough, Daniel ; Tan, Patrick ; Jenkins, Brendan J. ; Li, Ji Kun. / Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2. In: International Journal of Cancer. 2019 ; Vol. 144, No. 12. pp. 3056-3069.
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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",
author = "Liu, {You Dong} and Liang Yu and Le Ying and Jesse Balic and Hugh Gao and Deng, {Nian Tao} and Alison West and Feng Yan and Ji, {Cheng Bo} and Daniel Gough and Patrick Tan and Jenkins, {Brendan J.} and Li, {Ji Kun}",
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Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2. / Liu, You Dong; Yu, Liang; Ying, Le; Balic, Jesse; Gao, Hugh; Deng, Nian Tao; West, Alison; Yan, Feng; Ji, Cheng Bo; Gough, Daniel; Tan, Patrick; Jenkins, Brendan J.; Li, Ji Kun.

In: International Journal of Cancer, Vol. 144, No. 12, 15.06.2019, p. 3056-3069.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Yu, Liang

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AU - Gao, Hugh

AU - Deng, Nian Tao

AU - West, Alison

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