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Homophilic Interaction of CD147 Promotes IL-6-Mediated Cholangiocarcinoma Invasion via the NF-κB-Dependent Pathway.

ABSTRACT: Cholangiocarcinoma (CCA), an aggressive cancer of bile ducts, is a well-known chronic inflammation-related disease. The major impediment in CCA treatment is limited treatment options for advanced disease; hence, an alternative is urgently required. The role of CD147 on cytokine production has been observed in inflammation-related diseases, but not in CCA. Therefore, this study was focused on CD147-promoting proinflammatory cytokine production and functions. Proinflammatory cytokine profiles were compared between CD147 expressing CCA cells and CD147 knockout cells (CD147 KO). Three cytokines, namely interleukin (IL)-6, IL-8, and granulocyte-monocyte colony-stimulating factor (GM-CSF), were dramatically diminished in CD147 KO clones. The involvement of the CD147-related cytokines in CCA invasion was established. CD147-promoted IL-6, IL-8, and GM-CSF secretions were regulated by NF-κB nuclear translocation, Akt activation, and p38 phosphorylation. CD147-fostering IL-6 production was dependent on soluble CD147, CD147 homophilic interaction, and NF-κB function. The overexpression of specific genes in CCA tissues compared to normal counterparts emphasized the clinical importance of these molecules. Altogether, CD147-potentiated proinflammatory cytokine production leading to CCA cell invasion is shown for the first time in the current study. This suggests that modulation of CD147-related inflammation might be a promising choice for advanced CCA treatment.

SUBMITTER: Dana P

PROVIDER: S-EPMC8706168 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo analyze the association of Nur77 with overall survival of gastric cancer patients and investigate the role of Nur77 in invasion and migration of gastric cancer cells.MethodsOncomine database was used to analyze the expression of Nur77 in gastric cancer and gastric mucosa tissues, and the distribution characteristics of Nur77 protein between gastric cancer and normal tissues were compared using Human Protein Atlas. GEPIA2 was used to analyze the relationship of Nur77 expression and the patients' survival. The expression of Nur77 in gastric cancer cell lines GES-1, AGS and MKN-45 were detected by Western blotting. The regulatory interactions between IL-6 and Nur77 were verified by transfecting the cells with specific Nur-77 siRNA and Nur-77-overexpressing plasmid. The changes in migration ability of the cells following Nur-77 knockdown were assessed with scratch assay. The effect of Nur-77 overexpression or IL-6 knockdown, or their combination, on migration and invasion of the gastric cancer cells were examined using Transwell assay. The effect of Nur77 expression level on NF-κB/IL-6 pathway activation was analyzed using Western blotting.ResultsOncomine database showed that gastric cancer tissues expressed a significantly higher level of Nur77 mRNA than normal tissues (P < 0.05). Nur77 expression was detected mostly in the nucleus, and a high Nur77 expression was associated with a poor survival outcome of the patients (P < 0.05). In gastric cancer cells, the high expression of Nur77 participated in the regulation of IL-6. Nur77 silencing significantly lowered the migration ability of the cells (P < 0.05), and IL-6 silencing significantly attenuated the enhanced migration caused by Nur77 overexpression (P < 0.05). Nur77 participates in the activation of NF-κB/IL-6 signaling pathway by regulating the expression of p-p65, p65, p-Stat3 and Stat3.ConclusionA high Nur77 expression is strongly correlated with a poor prognosis of gastric cancer patients. Nur77 promotes the invasion and migration of gastric cancer cells possibly by regulating the NF-κB/IL-6 signaling pathway.

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Homophilic Interaction of CD147 Promotes IL-6-Mediated Cholangiocarcinoma Invasion via the NF-κB-Dependent Pathway.

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