YKL-40 inhibits melanoma progression and metastasis by inducing immune cell infiltration in a mouse model

Abstract

Abstract Background YKL-40, a glycoprotein implicated in the pathophysiology of various solid tumors, exhibits a paradoxical expression profile in melanoma, characterized by reduced levels in tumor tissues relative to normal cutaneous tissues. Interestingly, elevated YKL-40 expression in melanoma patients correlates with markedly enhanced survival outcomes, positing a putative tumor-suppressive role for YKL-40 in this malignancy. Methods This study entailed the ectopic induction of YKL-40 in human melanoma (A375) and murine melanoma (B16F10) cell lines to elucidate its impact on cellular proliferation, migration, and invasion processes. Additionally, in vivo analysis involving a subcutaneous melanoma mouse model was deployed to evaluate tumor progression, and a pulmonary metastasis model was employed to quantify tumor cell metastatic dissemination upon YKL-40 overexpression. RNA-Seq analysis was conducted to identify possible mechanisms and possible signaling pathways involved. Results Ectopic YKL-40 expression in melanoma cell lines led to significant attenuation in cell proliferation, migration, and invasion. Furthermore, YKL-40 overexpression was associated with suppressed tumor growth in the subcutaneous melanoma mouse model and reduced tumor cell metastasis in the pulmonary metastasis model. RNA-Seq analysis revealed that YKL-40 overexpression leads to the upregulation of immune cell infiltration-related signaling pathways, including cytokine receptor interactions, natural killer cell-mediated cytotoxicity, and T and B lymphocyte receptor signaling. Conclusion The findings suggest that YKL-40 may play a tumor-suppressive role in melanoma by regulating tumor-immune interactions, highlighting its potential utility in immunotherapy-based treatment strategies for melanoma. The upregulation of immune cell infiltration-related signaling pathways further accentuates the regulatory capacity of YKL-40 in melanoma immune response modulation, offering new insights into its biological function and therapeutic potential.