Kallikrein-Related Peptidase 4 Inhibits Laryngeal Squamous Cell Carcinoma Potentially via Involvement of the Wnt/β-Catenin Signaling Pathway

Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck with an increasing incidence worldwide. As a secreted serine protease, Kallikrein-related peptidase 4 (KLK4) has been reported to exert divergent tumor-modulating roles across multiple malignancies: it acts as a tumor suppressor in some cancers while promoting progression in others. However, its role in LSCC remains unclear. The aberrant activation of Wnt/β-catenin signaling is closely linked to tumor progression in most malignancies, hence we focused on this pathway to explore the downstream mechanism of KLK4. The expression of KLK4 was analyzed in clinical samples and LSCC cell lines using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. AMC-HN-8 cells were transfected with KLK4 plasmids, and the effects on proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) were assessed using EDU assays, flow cytometry, and western blotting. The regulatory role of KLK4 on the Wnt/β-catenin signaling pathway was further investigated by treating cells with the Wnt/β-catenin agonist SKL2001. KLK4 expression was significantly downregulated in LSCC clinical samples and cell lines. KLK4 overexpression in LSCC cells inhibited cell proliferation, promoted apoptosis, and reversed the abnormal expression of EMT-related molecular markers. Moreover, KLK4 overexpression modulated the Wnt/β-catenin signaling by downregulating Wnt3a, β-catenin, and downstream targets. Treatment with SKL2001 reversed these effects by restoring cell proliferation, reducing apoptosis, and promoting EMT. KLK4 modulates LSCC cell proliferation, apoptosis and the expression of EMT-related markers, which are associated with the activity of the Wnt/β-catenin signaling pathway.