Abstract
Background: Proinflammatory cytokines TNFα and IL1β drive esophageal squamous cell carcinoma (ESCC) cell proliferation. However, the underlying molecular mechanism and potential therapeutic interventions to target this inflammatory signaling remain unclear.Methods: Plasminogen activator urokinase (PLAU) expression was analyzed using the public database (GEO and iProX) and molecular experiments (qRT‐PCR and Western blotting). The DNA‐binding activity of nuclear factor κB (NFκB) at the promoter of PLAU was analyzed using several online servers (AnimalTFDB, JASPAR, PROMO, Cistrome, and UCSC) and confirmed through ChIP‐qPCR. The role of PLAU in ESCC proliferation was investigated through PLAU overexpression experiments, GO annotation, CCK8 assay, and 5‐ethynyl‐2′‐deoxyuridine (EdU) incorporation assay.Results: PLAU expression was significantly higher in ESCC tissues compared to normal tissues and in ESCC cells compared to immortalized esophageal epithelial cells. Treatment with TNFα and IL1β induced NFκB binding at the PLAU promoter in ESCC cells, leading to increased PLAU expression. Conversely, treatment with BAY11‐7082, an NFκB inhibitor, significantly blocked this upregulation. Overexpression of PLAU promoted ESCC cell proliferation. Thus, our findings demonstrate that the TNFα/IL1β‐NFκB‐PLAU axis promotes ESCC cell proliferation. Moreover, EGCG inhibited NFκB binding to the PLAU promoter, thereby preventing PLAU upregulation in TNFα/IL1β‐treated ESCC cells and inhibiting ESCC cell proliferation induced by PLAU overexpression.Conclusion: EGCG effectively blocks the inflammatory signaling TNFα/IL1β‐NFκB‐PLAU, thereby inhibiting ESCC cell proliferation. Our study provides new insights into blocking the pro‐proliferative role of inflammation in ESCC and highlights EGCG as a potential therapeutic agent.
Published Version
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