Plasminogen activator inhibitor-1 promotes the proliferation and blocks TGF-β1-dependent growth inhibition of cholesteatoma keratinocytes by ERK signaling.

OBJECTIVES: To examine the role of PAI-1 plays in the pathophysiology of cholesteatoma and to investigate how TGF-β1 and PAI-1 interact to regulate keratinocyte proliferation. METHODS: PAI-1 and TGF-β1 expression levels were assessed in pediatric and adult cholesteatoma specimens. Using an in vitro cholesteatoma keratinocyte model, the impacts of PAI-1 and TGF-β1 on cell proliferation were assessed. ERK signaling pathway involvement was examined to determine the underlying mechanisms. RESULTS: TGF-β1 and PAI-1 were significantly upregulated in all cholesteatoma tissues, with higher levels observed in pediatric cases. PAI-1 promoted the proliferation of cholesteatoma keratinocytes, whereas TGF-β1 exerted an inhibitory effect. Co-treatment with PAI-1 attenuated TGF-β1 induced growth inhibition. Mechanistically, PAI-1 promoted proliferative through activation of the ERK signaling pathway. CONCLUSION: PAI-1 counteracts the anti-proliferative effects of TGF-β1 via activation of ERK pathway, thereby facilitating the proliferation of cholesteatoma keratinocytes. These findings suggest that PAI-1 contributes to the dysregulated growth characteristic of cholesteatoma and may represent a potential thrapeutic target.