Cancer cell is generally characterized by enhanced glycolysis. Inflammasome activation is interaction with glycolysis. The concentration of lipopolysaccharide (LPS), a classic inflammasome activator, is significantly higher in colorectal cancer tissue than in normal intestinal mucosa. However, the mechanism of LPS on glycolysis and metastasis has not been fully elucidated. This study aimed to investigate the roles of LPS on inflammasome activation, glycolysis, and metastasis, and unravel metformin’s potential in treatment of CRC. We detected inflammasome activation and cell motility following LPS exposure in CRC cell lines. Glycolysis analysis was performed, and the key glycolytic rate-limiting enzymes were detected. Dual-luciferase reporter gene assay, co-immunoprecipitation, chromatin immunoprecipitation (ChIP) analysis, and ChIP-reChIP assay were performed to identify the specific mechanisms of LPS on glycolysis. Mouse metastasis models were used to determine the effects of LPS and metformin on metastasis. Correlation analysis of the expression of various molecules was performed in 635 CRC samples from The Cancer Genome Atlas and 83 CRC samples from our lab. LPS activates caspase-1 through NF-κB and upregulates the expression of Snail and HK3 depending on caspase-1 activation. LPS potentiates migration and invasion depending on accelerated glycolysis, which could be reversed by knockdown of glycolytic rate-limiting enzyme HK3. Nuclear Snail is upregulated by NF-κB under LPS treatment and then forms a complex with NF-κB, then directly binds to the HK3 promoter region to upregulate the expression of HK3. Metformin suppresses the NF-κB/Snail/HK3 signaling axis that is activated by LPS and then inhibits LPS-induced metastasis. In vivo, LPS-treated cells form more metastasis in the lungs of mice, and metformin completely reverses this effect of LPS. LPS activates inflammasomes in cancer cells through NF-κB and promotes metastasis through glycolysis enhanced by the NF-κB/Snail/HK3 signaling pathway in CRC. Metformin could prevent this effect of LPS.

中文翻译：

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脂多糖通过核因子-κB/ snail / hexokinase3信号转导轴促进糖酵解促进结直肠癌的转移。

癌细胞通常以糖酵解增强为特征。炎性体的激活是与糖酵解的相互作用。脂多糖（LPS）（一种典型的炎症小体激活剂）的浓度在大肠癌组织中明显高于正常肠粘膜。但是，LPS在糖酵解和转移中的机制尚未完全阐明。这项研究旨在调查LPS在炎症小体激活，糖酵解和转移中的作用，并揭示二甲双胍在CRC治疗中的潜力。在CRC细胞系中LPS暴露后，我们检测到了炎性体激活和细胞运动。进行糖酵解分析，并检测关键的糖酵解限速酶。双荧光素酶报告基因测定，免疫共沉淀，染色质免疫沉淀（ChIP）分析，进行了ChIP-reChIP分析，以鉴定LPS对糖酵解的具体机制。小鼠转移模型用于确定LPS和二甲双胍对转移的影响。在来自The Cancer Genome Atlas的635个CRC样本和来自我们实验室的83个CRC样本中，进行了各种分子表达的相关分析。LPS通过caspase-1激活，通过NF-κB激活caspase-1，并上调Snail和HK3的表达。LPS根据加速的糖酵解作用增强迁移和侵袭，可通过敲低糖酵解限速酶HK3来逆转。在LPS处理下，NF-κB上调了核蜗牛，然后与NF-κB形成复合物，然后直接与HK3启动子区域结合，从而上调HK3的表达。二甲双胍抑制被LPS激活的NF-κB/ Snail / HK3信号轴，然后抑制LPS诱导的转移。在体内，经LPS处理的细胞在小鼠肺部形成更多转移，而二甲双胍完全逆转了LPS的这种作用。LPS通过NF-κB激活癌细胞中的炎症小体，并通过CRC中NF-κB/ Snail / HK3信号通路增强的糖酵解促进转移。二甲双胍可以预防LPS的这种作用。