Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer <i>via</i> superoxide dismutase 2

Liu, You Dong; Yu, Liang; Ying, Le; Balic, Jesse J.; Gao, Hugh; Deng, Niantao; West, Adrian K.; Yan, Feng; Ji, Chenfeng; Gough, Daniel J.; Tan, Patrick; Jenkins, Brendan J.; Li, Ji Kun

doi:10.1002/ijc.32060

Cited by 47 publications

(41 citation statements)

References 48 publications

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“…In addition, the TLR signaling pathway are classical pattern recognition receptor pathway in the recognition of H. pylori and medicates the host immune responses against H. pylori [20]. Recent study indicated that up-regulated TLR2 was associated with advanced stage, distant metastasis, and poor clinical outcomes in gastric cancer [21]. Therefore, focusing on these biological function and pathways will help us elucidate the underlying mechanisms of STAD.…”

Section: Discussionmentioning

confidence: 99%

Identification of prognosis-related genes in the tumor microenvironment of stomach adenocarcinoma by TCGA and GEO datasets

Ren

Liang

2020

Bioscience Reports

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Accumulating evidence has demonstrated that tumor microenvironment (TME) plays a crucial role in stomach adenocarcinoma (STAD) development, progression, prognosis and immunotherapeutic responses. How the genes in TME interact and behave is extremely crucial for tumor investigation. In the present study, we used gene expression data of STAD available from TCGA and GEO datasets to infer tumor purity using ESTIMATE algorithms, and predicted the associations between tumor purity and clinical features and clinical outcomes. Next, we calculated the differentially expressed genes (DEGs) from the comparisons of immune and stromal scores, and postulated key biological processes and pathways that the DEGs mainly involved in. Then, we analyzed the prognostic values of DEGs in TCGA dataset, and validated the results by GEO dataset. Finally, we used CIBERSORT computational algorithm to estimate the 22 tumor infiltrating immune cells (TIICs) subsets in STAD tissues. We found that stromal and immune scores were significantly correlated with STAD subtypes, clinical stages, Helicobacter polyri infection, and stromal scores could predict the clinical outcomes in STAD patients. Moreover, we screened 307 common DEGs in TCGA and GSE51105 datasets. In the prognosis analyses, we only found OGN, JAM2, RERG, OLFML2B, and ADAMTS1 genes were significantly associated with overall survival in TCGA and GSE84437 datasets, and these genes were correlated with the fractions of T cells, B cells, macrophages, monocytes, NK cells and DC cells, respectively. Our comprehensive analyses for transcriptional data not only improved the understanding of characteristics of TME, but also provided the targets for individual therapy in STAD.

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Section: Discussionmentioning

confidence: 99%

Identification of prognosis-related genes in the tumor microenvironment of stomach adenocarcinoma by TCGA and GEO datasets

Ren

Liang

2020

Bioscience Reports

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“…This indicates that TLRs may differ in downstream modulators and thus express diverse biological characteristics. In addition, the involvement of JAK-STAT3, JNK MAPK and NF-kB cascades contribute to this metabolic change 11 , which can be consider as the cell-autonomous effects as well as the mutations of AGS and NUGC4 cell lines could cause the difference. In summary, we discovered that TLR2 activation mainly promote mitochondrial respiration and reduced ROS production in order to protect cells while CpG suppressed the function of OXPHOS and glycolysis, may provide insights in different roles of TLR2 and TLR9.…”

Section: Discussionmentioning

confidence: 99%

“…To explore the potential mechanism of TLRs activation in metabolic reprogramming 11 , we examined the expression of key genes involving in mitochondrial function, glycolysis and oxidative phosphorylation etc. As shown in Fig.…”

Section: Tlr2 Activation Promotes the Expression Of Key Genes In Contmentioning

confidence: 99%

“…Furthermore, we provided the evidence that synthetic ligand induced TLR2 activation in human GC epithelial cells with high TLR2 expression enhanced both OXPHOS and glycolysis along with a strong STAT3 dependent transcriptional induction of SOD2. The augment of this redox mitochondrial protein expression enforced a more glycolytic metabolic phenotype as well as suppressed ROS production from TLR2-induced oxidation activity 11 . In agreement with these ndings, TLR2-SOD2 axis is associated with multiple clinical parameters of high malignancy and poor survival in gastric cancer patients 11 .…”

Section: Introductionmentioning

confidence: 99%

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Activation of Toll-like receptor 2 via specific agonists promotes OXPHOS and glycolysis in gastric cancer cells rather than other Toll-like receptors

li¹,

Ji²,

liu³

et al. 2020

Preprint

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Background Toll-like receptor (TLR)2 activation via microbial and host stimuli plays important roles in the regulation of metabolic reprogramming in immune cells. We recently showed that ligand-induced TLR2 activation enhanced OXPHOS and glycolytic activity of gastric epithelial (cancer) cells, thus promoting tumour progression. Objective To investigate the full spectrum of TLR family members whose ligand-dependent activation can cause metabolic reprogramming in gastric cancer (GC) cells. Methods The expression of TLR family members was measured by RT-qPCR and Western blotting in a panel of human GC cells. Metabolic changes in human GC cells which were induced by agonists for different TLRs (TLR2, 4, 9) were identified by performing the Seahorse bioenergetic assay, as well as by measuring L-lactate and ROS production. The expression of genes involved in oxidative phosphorylation and glycolysis was also profiled in stimulated GC cells by RT-qPCR. Western blot further characterized the expression of SOD2, a key downstream target of TLR2 signaling in GC. Results TLR2 signaling activated by either synthetic molecules or whole pathogen antigen enhanced glycolytic activity and mitochondrial respiration in TLR2-high expressing cells, whereas ligand-induced TLR4 and TLR9 activation inhibited mitochondrial respiration or extracellular acidification rate. Furthermore, genes implicated in the regulation of glucose metabolism and the redox system, such as HIF1A, PFKFB3 and SOD2, were upregulated downstream of TLRs. Conclusion Our study reveals that ligand-induced activation of specific TLRs mediates diverse metabolic phenotype in human GC cells. TLR2 is the only family member that promotes both OXPHOS and glycolysis, which may result in tumor progression.

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“…6,7 Metabolic reprogramming has been identified as a hallmark of GC and is required for GC cell survival and metastases. 8,9 However, the underlying molecular mechanism associated with aerobic glycolysis and metabolic reprogramming during GC differentiation and metastasis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

<p>Monoamine Oxidase A is a Major Mediator of Mitochondrial Homeostasis and Glycolysis in Gastric Cancer Progression</p>

Chen¹,

Li²,

Sun³

et al. 2020

CMAR

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Objective: Monoamine oxidase A (MAO-A) is a mitochondrial protein involved in tumourigenesis in different types of cancer. However, the biological function of MAO-A in gastric cancer development remains unknown. Methods: We examined MAO-A expression in gastric cancer tissues and in gastric cancer cell lines by immunohistochemistry and Western blot analyses. CCK8, FACS and bromodeoxyuridine incorporation assays were performed to assess the effects of MAO-A on gastric cancer cell proliferation. The role of MAO-A in mitochondrial function was determined through MitoSOX Red staining, ATP generation and glycolysis assays. Results: In the present study, we observed that MAO-A was significantly upregulated in gastric cancer tissues and in AGS and MGC803 cells. The observed MAO-A inhibition indicated decreased cell cycle progression and proliferation. Silencing MAO-A expression was associated with suppressed migration and invasion of gastric cancer cells in vitro. Moreover, alleviated mitochondrial damage in these cells was demonstrated by decreased levels of mitochondrial reactive oxygen species and increased ATP generation. MAO-A knockdown also regulated the expression of the glycolysis rate-limiting enzymes hexokinase 2 and pyruvate dehydrogenase. Finally, we observed that the glycolysis-mediated effect was weakened in AGS and MGC803 cells when MAO-A was blocked. Conclusion: The findings of the present study indicate that MAO-A is responsible for mitochondrial dysfunction and aerobic glycolysis, which in turn leads to the proliferation and metastasis of human gastric tumour cells.

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

Cited by 47 publications

References 48 publications

Identification of prognosis-related genes in the tumor microenvironment of stomach adenocarcinoma by TCGA and GEO datasets

Identification of prognosis-related genes in the tumor microenvironment of stomach adenocarcinoma by TCGA and GEO datasets

Activation of Toll-like receptor 2 via specific agonists promotes OXPHOS and glycolysis in gastric cancer cells rather than other Toll-like receptors

<p>Monoamine Oxidase A is a Major Mediator of Mitochondrial Homeostasis and Glycolysis in Gastric Cancer Progression</p>

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