Repressive role of stabilized hypoxia inducible factor 1α expression on transforming growth factor β‐induced extracellular matrix production in lung cancer cells

摘要

Activation of transforming growth factor β (TGF‐β) combined with persistent hypoxia often affects the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of epithelial‐mesenchymal transition (EMT). Hypoxia‐inducible factors (HIF), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF‐1α expression by protein phosphatase activity on dissociation of the E‐cadherin/β‐catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGF‐β. By using lung cancer cells treated with HIF‐1α stabilizers or carrying doxycycline‐dependent HIF‐1α deletion or point mutants, we investigated the role of stabilized HIF‐1α expression on TGF‐β‐induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGF‐β and hypoxia induced EMT phenotypes in H358 cells in which stabilized HIF‐1α expression was inhibited. Stabilized HIF‐1α protein expression inhibited the style="fixed-case">TGF‐β‐stimulated appearance of style="fixed-case">EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A ( style="fixed-case">VEGFA) expression. Inhibition of protein phosphatase 2A activity abrogated the style="fixed-case">HIF‐1α‐induced repression of the style="fixed-case">TGF‐β‐stimulated appearance of style="fixed-case">EMT phenotypes. This is the first study to show a direct role of stabilized style="fixed-case">HIF‐1α expression on inhibition of style="fixed-case">TGF‐β‐induced style="fixed-case">EMT phenotypes in lung cancer cells, in part, through protein phosphatase activity.