CST2 promotes melanoma malignant phenotypes through the IL-6-STAT3-NF-κB signaling axis

Background: This study aimed to investigate the expression and clinical significance of Cystatin SA (CST2) in melanoma as well as its biological functions and underlying molecular mechanisms in melanoma progression.

Methods: CST2 expression was analyzed in melanoma tissues using The Cancer Genome Atlas (TCGA) dataset. The prognostic value of CST2 was assessed using Kaplan–Meier analysis. In vitro gain- and loss-of-function experiments were performed to evaluate the effect of CST2 on melanoma cell proliferation, colony formation, and migration. Mechanistic studies included protein–protein docking and co-immunoprecipitation to detect the interaction between CST2 and IL-6. Western blotting was used to examine the activation status of IL-6 downstream signaling pathways.

Results: CST2 was significantly upregulated in melanoma tissues and was correlated with poor patient prognosis. Overexpression of CST2 promoted melanoma cell proliferation, clonogenicity, and migration, whereas CST2 knockdown suppressed these malignant behaviors. CST2 interacted with IL-6, and its knockdown reduced the expression of IL-6, phospho-STAT3, and phospho-NF-κB. These suppressive effects were reversed by IL-6 overexpression, indicating that CST2 exerted its oncogenic effects through the IL-6–STAT3–NF-κB axis.

Conclusions: CST2 promotes melanoma progression by activating the IL-6–STAT3–NF-κB signaling pathway, and may serve as a potential prognostic biomarker and therapeutic target in melanoma.