A positive feedback loop between SERPINH1 and MMP-9/TGF-β1 promotes lung adenocarcinoma progression

Abstract

Lung adenocarcinoma (LUAD), the most predominant subtype of lung cancer, is a leading cause of cancer-related death worldwide. However, its underlying molecular mechanisms remain poorly understood. In this study, we identified that SERPINH1, a member of the serine protease inhibitor (serpin) superfamily, is upregulated in LUAD tissues and cells. Furthermore, high expression of SERPINH1 is associated with poor prognosis in patients. Functional experiments revealed that overexpression of SERPINH1 promotes the proliferation, invasion, and migration of LUAD cells. Further investigation showed that MMP-9 is a novel binding partner of SERPINH1. SERPINH1 enhances the protein levels of MMP-9 by inhibiting its ubiquitination, which in turn promotes the activation and secretion of extracellular TGF-β1, leading to the activation of cancer-associated fibroblasts (CAFs). Additionally, the sustained activation of TGF-β signaling further enhances the transcription of SERPINH1, establishing a positive feedback loop between SERPINH1 and TGF-β1. Taken together, our findings suggest that the SERPINH1/TGF-β1 positive feedback loop plays a crucial role in the onset and metastasis of LUAD. SERPINH1 may serve as a potential prognostic and therapeutic target in LUAD.