Introduction: Pancreatic cancer is characterized by its aggressive nature and poor prognosis, ranking among the most lethal malignancies. The tumor microenvironment, particularly the extracellular matrix (ECM), plays a crucial role in cancer progression. This study investigated the relationship between hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1) in regulating ECM protein expression in pancreatic cancer.
Methods: PANC-1 cells were cultured under both normoxic and hypoxic conditions. Pharmacological inhibition of HIF-1α and TGF-β1, as well as TGF-β1 stimulation, were employed to evaluate ECM protein expression. HIF-1α knockdown experiments and co-immunoprecipitation were performed to assess molecular interactions. Clinical specimens were analyzed for HIF-1α and TGF-β1 expression.
Results: HIF-1α was found to modulate ECM protein expression through the TGF-β1/Smad signaling pathway. Pharmacological inhibition of either HIF-1α or TGF-β1 significantly decreased the expression of ECM proteins, while TGF-β1 stimulation enhanced their production. HIF-1α knockdown abolished TGF-β1-induced ECM protein expression, indicating that HIF-1α is essential for TGF-β1-mediated ECM regulation. Co-immunoprecipitation experiments revealed a physical interaction between HIF-1α and TGF-β1. Clinical specimens showed significantly elevated expression of both HIF-1α and TGF-β1 in pancreatic cancer tissues compared to adjacent normal tissues, correlating with advanced disease stages.
Discussion: These findings elucidate a novel mechanism where HIF-1α and TGF-β1 cooperatively regulate ECM production in pancreatic cancer, providing potential therapeutic targets for intervention.
Keywords: Smad signaling pathway; extracellular matrix; hypoxia-inducible factor-1 alpha; pancreatic cancer; transforming growth factor beta 1.
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