Melanoma poses a poor prognosis with high mortality rates upon metastasis. Exploring the molecular mechanisms governing melanoma progression paves the way for developing novel approaches to control melanoma metastasis and ultimately enhance patient survival rates. Extracellular galectin-3 (Gal-3) has emerged as a pleiotropic promoter of melanoma metastasis, exerting varying activities depending on its interacting partner. However, whether intracellular Gal-3 promotes melanoma aggressive behavior remains unknown. In this study, we explored Gal-3 expression in human melanoma tissues as well as in murine melanoma models to examine its causal role in metastatic behavior. We found that Gal-3 expression is downregulated in metastatic melanoma tissues compared with its levels in primary melanomas. Enforced silencing of Gal-3 in melanoma cells promoted migration, invasion, colony formation, in vivo xenograft growth, and metastasis and activated canonical oncogenic signaling pathways. Moreover, loss of Gal-3 in melanoma cells resulted in upregulated the expression of the prometastatic transcription factor NFAT1 and its downstream metastasis-associated proteins, matrix metalloproteinase 3, and IL-8. Overall, our findings implicate melanoma intracellular Gal-3 as a major determinant of its metastatic behavior and reveal a negative regulatory role for Gal-3 on the expression of NFAT1 in melanoma cells.

中文翻译：

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肿瘤内在半乳糖凝集素 3 抑制黑色素瘤转移

黑色素瘤预后不良，转移时死亡率高。探索控制黑色素瘤进展的分子机制为开发控制黑色素瘤转移的新方法并最终提高患者生存率铺平了道路。细胞外半乳糖凝集素 3 (Gal-3) 已成为黑色素瘤转移的多效性启动子，根据其相互作用的伙伴发挥不同的活性。然而，细胞内 Gal-3 是否促进黑色素瘤的侵袭行为仍不清楚。在这项研究中，我们探索了 Gal-3 在人类黑色素瘤组织以及小鼠黑色素瘤模型中的表达，以检查其在转移行为中的因果作用。我们发现，与原发性黑色素瘤中的水平相比，转移性黑色素瘤组织中 Gal-3 的表达下调。强制沉默黑色素瘤细胞中的 Gal-3 可促进迁移、侵袭、集落形成、体内异种移植物生长和转移，并激活经典致癌信号通路。此外，黑色素瘤细胞中 Gal-3 的缺失导致促转移转录因子 NFAT1 及其下游转移相关蛋白、基质金属蛋白酶 3 和 IL-8 的表达上调。总体而言，我们的研究结果表明黑色素瘤细胞内 Gal-3 是其转移行为的主要决定因素，并揭示了 Gal-3 对黑色素瘤细胞中 NFAT1 表达的负调节作用。