AUTHOR=Guo Houle , Zhao Zhanxue , Liu Linxun 

TITLE=HIF‐1α modulates pancreatic cancer ECM proteins via the TGF‐β1/Smad signaling pathway introduction

JOURNAL=Frontiers in Oncology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1564655

DOI=10.3389/fonc.2025.1564655

ISSN=2234-943X

ABSTRACT=IntroductionPancreatic 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.MethodsPANC-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.ResultsHIF-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.DiscussionThese findings elucidate a novel mechanism where HIF-1α and TGF-β1 cooperatively regulate ECM production in pancreatic cancer, providing potential therapeutic targets for intervention.