Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
PLoS One. 2012;7(4):e35101. doi: 10.1371/journal.pone.0035101. Epub 2012 Apr 10.
Osteosarcoma is characterized by a high malignant and metastatic potential. CCL5 (previously called RANTES) was originally recognized as a product of activated T cells, and plays a crucial role in the migration and metastasis of human cancer cells. It has been reported that the effect of CCL5 is mediated via CCR receptors. However, the effect of CCL5 on migration activity and integrin expression in human osteosarcoma cells is mostly unknown.
METHODOLOGY/PRINCIPAL FINDINGS: Here we found that CCL5 increased the migration and expression of αvβ3 integrin in human osteosarcoma cells. Stimulation of cells with CCL5 increased CCR5 but not CCR1 and CCR3 expression. CCR5 mAb, inhibitor, and siRNA reduced the CCL5-enhanced the migration and integrin up-regulation of osteosarcoma cells. Activations of MEK, ERK, and NF-κB pathways after CCL5 treatment were demonstrated, and CCL5-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of MEK, ERK, and NF-κB cascades. In addition, over-expression of CCL5 shRNA inhibited the migratory ability and integrin expression in osteosarcoma cells.
CONCLUSIONS/SIGNIFICANCE: CCL5 and CCR5 interaction acts through MEK, ERK, which in turn activates NF-κB, resulting in the activations of αvβ3 integrin and contributing the migration of human osteosarcoma cells.
骨肉瘤的特点是恶性程度高、转移性强。CCL5（以前称为RANTES）最初被认为是激活的 T 细胞的产物，在人类癌细胞的迁移和转移中发挥着关键作用。据报道，CCL5 的作用是通过 CCR 受体介导的。然而，CCL5 对人骨肉瘤细胞迁移活性和整合素表达的影响大多未知。
方法/主要发现：在这里，我们发现 CCL5 增加了人骨肉瘤细胞的迁移和αvβ3 整合素的表达。CCL5 刺激细胞增加了 CCR5 但不增加 CCR1 和 CCR3 的表达。CCR5 mAb、抑制剂和 siRNA 减少了 CCL5 增强的骨肉瘤细胞的迁移和整合素上调。证明了 CCL5 处理后 MEK、ERK 和 NF-κB 通路的激活，并且 CCL5 诱导的整合素表达和迁移活性被 MEK、ERK 和 NF-κB 级联的特异性抑制剂和突变体抑制。此外，CCL5 shRNA 的过表达抑制了骨肉瘤细胞的迁移能力和整合素表达。
结论/意义：CCL5 和 CCR5 的相互作用通过 MEK、ERK 起作用，进而激活 NF-κB，导致αvβ3 整合素的激活，并促进人骨肉瘤细胞的迁移。
