Osteosarcoma (OS) is one of the most prevalent primary bone tumors with a high degree of metastasis and poor prognosis. Epithelial-to-mesenchymal transition (EMT) is a cellular mechanism that contributes to the invasion and metastasis of cancer cells, and OS cells have been reported to exhibit EMT-like characteristics. Our previous studies have shown that the interaction between tumor necrosis factor superfamily member 11 (TNFRSF11A; also known as RANK) and its ligand TNFSF11 (also known as RANKL) promotes the EMT process in breast cancer cells. However, whether the interaction between RANK and RANKL enhances aggressive behavior by inducing EMT in OS cells has not yet been elucidated. In this study, we showed that the interaction between RANK and RANKL increased the migration, invasion, and metastasis of OS cells by promoting EMT. Importantly, we clarified that the RANK/RANKL axis induces EMT by activating the nuclear factor-kappa B (NF-κB) pathway. Furthermore, the NF-κB inhibitor dimethyl fumarate (DMF) suppressed migration, invasion, and EMT in OS cells. Our results suggest that the RANK/RANKL axis may serve as a potential tumor marker and promising therapeutic target for OS metastasis. Furthermore, DMF may have clinical applications in the treatment of lung metastasis in patients with OS.

中文翻译：

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RANK/RANKL轴通过激活NF-κB通路促进骨肉瘤的迁移、侵袭和转移


骨肉瘤（OS）是最常见的原发性骨肿瘤之一，转移程度高，预后差。上皮间质转化（EMT）是一种有助于癌细胞侵袭和转移的细胞机制，据报道OS细胞表现出类似EMT的特征。我们前期的研究表明，肿瘤坏死因子超家族成员11（TNFRSF11A；又称RANK）与其配体TNFSF11（又称为RANKL）之间的相互作用促进乳腺癌细胞的EMT过程。然而，RANK 和 RANKL 之间的相互作用是否通过诱导 OS 细胞 EMT 来增强攻击行为尚未阐明。在这项研究中，我们发现RANK和RANKL之间的相互作用通过促进EMT来增加OS细胞的迁移、侵袭和转移。重要的是，我们阐明了 RANK/RANKL 轴通过激活核因子-κB (NF-κB) 途径诱导 EMT。此外，NF-κB 抑制剂富马酸二甲酯 (DMF) 抑制 OS 细胞的迁移、侵袭和 EMT。我们的结果表明 RANK/RANKL 轴可能作为潜在的肿瘤标志物和有希望的 OS 转移治疗靶点。此外，DMF 可能在治疗 OS 患者肺转移方面具有临床应用价值。