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Lipopolysaccharide-induced ?-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-?B signaling-dependent manner.

ABSTRACT: ?-Catenin is an important molecule involved in the maintenance of cell-cell adhesion and a prognostic marker in cancer since its expression is essential for preventing cancer metastasis. However, the mechanism that leads to the downregulation of ?-catenin in cancer progression remains unclear. The present study revealed that lipopolysaccharide (LPS)-induced NF-?B signaling activation suppressed ?-catenin expression and motility in SW620 colorectal cancer (CRC) cells, using real-time polymerase chain reaction, Western blotting, and transwell migration assays. LPS treatment reduced both the mRNA and protein expression of ?-catenin and thereby enhanced cell motility. Conversely, incubating cells with an NF-?B inhibitor disrupted these effects. Furthermore, the ectopic expression of p65 alone mimicked the effects of LPS stimulation. In CRC tissues, the presence of enteric bacterial LPS-related neutrophil-enriched foci was correlated with ?-catenin downregulation. Collectively, these findings suggest that LPS-induced NF-?B signaling is related to ?-catenin suppression and enhanced cell motility in CRC. Therefore, NF-?B is a novel potential therapeutic target for CRC metastasis.

SUBMITTER: Cheng G

PROVIDER: S-EPMC5167382 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Lipopolysaccharide-induced α-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-κB signaling-dependent manner.

Cheng Guoping G Yang Shifeng S Zhang Gu G Xu Yanxia Y Liu Xiaoling X Sun Wenyong W Zhu Liang L

OncoTargets and therapy 20161214

α-Catenin is an important molecule involved in the maintenance of cell-cell adhesion and a prognostic marker in cancer since its expression is essential for preventing cancer metastasis. However, the mechanism that leads to the downregulation of α-catenin in cancer progression remains unclear. The present study revealed that lipopolysaccharide (LPS)-induced NF-κB signaling activation suppressed α-catenin expression and motility in SW620 colorectal cancer (CRC) cells, using real-time polymerase c ...[more]

PMID: 28008274

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Project description:Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-κB)-mediated inflammatory pathway and pregnane X receptor (PXR)-regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression. We found that LPS induced significant activation of the NF-κB-mediated inflammatory pathway with concomitant impairment of intestinal nutrient absorption. AKG administration increased intracellular AKG and its metabolite concentrations and enhanced the mRNA expression of alpha-ketoglutarate dehydrogenase in vivo and in vitro. Thus dietary AKG supplementation reversed the adverse effects induced by LPS. We also found a strong inhibitory effects on the NF-κB-mediated inflammatory pathway, especially, in the AKG-treated intestinal tissues, LPS-induced NF-κB phosphorylation was inhibited and TNF-α was suppressed. Interestingly, AKG has potent effects in regulating the PXR and its downstream targets such as CYP3As and CYP2Bs in vivo and in vitro, although AKG is not a known PXR ligand. One potential mechanism for the up-regulation of the PXR pathway is through the down-regulation of NF-κB pathway which in turn de-represses the PXR-regulated target expression. Taken together, our results suggest that AKG improves intestinal immune system through modulating the interaction between PXR and NF-κB. Our findings have important implications for the prevention and treatment of intestinal inflammatory diseases in neonates.

Project description:Adenoma-adenocarcinoma transition is a key feature of colorectal cancer (CRC) occurrence and is closely regulated by tumor-associated macrophages (TAMs) and CD8+ T cells. Here, we investigated the effect of the NF-κB activator 1 (Act1) downregulation of macrophages in the adenoma-adenocarcinoma transition. This study used spontaneous adenoma-developing ApcMin/+, macrophage-specific Act1-knockdown (anti-Act1), and ApcMin/+; anti-Act1 (AA) mice. Histological analysis was performed on CRC tissues of patients and mice. CRC patients' data retrieved from the TCGA dataset were analyzed. Primary cell isolation, co-culture system, RNA-seq, and fluorescence-activated cell sorting (FACS) were used. By TCGA and TISIDB analysis, the downregulation of Act1 expression in tumor tissues of CRC patients negatively correlated with accumulated CD68+ macrophages in the tumor. Relative expression of EMT markers in the tumor enriched ACT1lowCD68+ macrophages of CRC patients. AA mice showed adenoma-adenocarcinoma transition, TAMs recruitment, and CD8+ T cell infiltration in the tumor. Macrophages depletion in AA mice reversed adenocarcinoma, reduced tumor amounts, and suppressed CD8+ T cell infiltration. Besides, macrophage depletion or anti-CD8a effectively inhibited metastatic nodules in the lung metastasis mouse model of anti-Act1 mice. CRC cells induced activation of IL-6/STAT3 and IFN-γ/NF-κB signaling and the expressions of CXCL9/10, IL-6, and PD-L1 in anti-Act1 macrophages. Anti-Act1 macrophages facilitated epithelial-mesenchymal-transition and CRC cells' migration via CXCL9/10-CXCR3-axis. Furthermore, anti-Act1 macrophages promoted exhaustive PD1+ Tim3+ CD8+ T cell formation. Anti-PD-L1 treatment repressed adenoma-adenocarcinoma transition in AA mice. Silencing STAT3 in anti-Act1 macrophages reduced CXCL9/10 and PD-L1 expression and correspondingly inhibited epithelial-mesenchymal-transition and CRC cells' migration. Act1 downregulation in macrophages activates STAT3 that promotes adenoma-adenocarcinoma transition via CXCL9/10-CXCR3-axis in CRC cells and PD-1/PD-L1-axis in CD8+ T cells.

Dataset Information

Lipopolysaccharide-induced ?-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-?B signaling-dependent manner.

Publications

Lipopolysaccharide-induced α-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-κB signaling-dependent manner.

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