Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2
Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2
复制标题
Toll样受体2通过超氧化物歧化酶2调节胃癌代谢重编程
DOI：
10.1002/ijc.32060
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发表时间：
2019-06-15
影响因子：
6.4
通讯作者：
Li, Ji Kun
中科院分区：
文献类型：
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作者：
Liu, You Dong;Yu, Liang;Li, Ji Kun
Toll样受体（TLR）在识别保守的微生物和宿主衍生组分后在宿主防御中起关键作用，并且其失调是各种炎症相关癌症（包括胃癌（GC））的共同特征。尽管最近认识到代谢重编程是癌症的标志，但肿瘤发生过程中代谢改变的分子效应仍不清楚。在这里，使用生物能量学功能测定对人类GC细胞，我们发现，配体诱导的激活TLR 2，主要是通过TLR 1/2异二聚体，增强氧化磷酸化（OXPHOS）和糖酵解，偏向糖酵解活性。值得注意的是，用TLR 2配体刺激的人癌细胞的基于DNA微阵列的表达谱显示了先前参与代谢调节的致癌途径的基因集的显著富集，包括活性氧（ROS）、p53和Myc。此外，编码锰依赖性线粒体酶超氧化物歧化酶（SOD）2的氧化还原基因在mRNA和蛋白水平上被TLR 2下游的多种信号通路（即JAK-STAT 3、JNK MAPK和NF-κ B B）强烈诱导。此外，siRNA介导的SOD 2抑制改善了人GC癌细胞中TLR 2诱导的代谢转变。重要的是，患者来源的组织微阵列和临床数据集的生物信息学询问表明，TLR 2和SOD 2的上调表达在人GC中显著相关，并且TLR 2-SOD 2轴与晚期疾病的多个临床参数相关，包括远处转移、微血管浸润和分期，以及较差的生存率。总的来说，我们的研究结果揭示了一种新的TLR 2-SOD 2轴作为癌症治疗和预后的潜在生物标志物。
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-kappa B. 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.