Publications
Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2
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-kappaB. 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.
Type | Journal |
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ISBN | 0020-7136 |
Authors | Liu, Y. D.; Yu, L.; Ying, L.; Balic, J.; Gao, H.; Deng, N. T.; West, A.; Yan, F.; Ji, C. B.; Gough, D.; Tan, P.; Jenkins, B. J.; Li, J. K. |
Responsible Garvan Author | Niantao Deng |
Publisher Name | INTERNATIONAL JOURNAL OF CANCER |
Published Date | 2019-06-15 |
Published Volume | 144 |
Published Issue | 12 |
Published Pages | 3056-3069 |
Status | Published in-print |
DOI | 10.1002/ijc.32060 |
URL link to publisher's version | https://www.ncbi.nlm.nih.gov/pubmed/30536754 |