| 摘要: | 軟骨肉瘤是一種惡性的腫瘤，具有高度侵入及遠端轉移的能力且偏愛轉移至肺部。趨化素配體2 (Chemokine ligand 2, CCL2) 又稱為單核球趨化蛋白 (Monocyte chemoattractant protein-1, MCP-1)，屬於CC趨化素中的一員與疾病及癌症的形成相關。然而，CCL2對於人類軟骨肉瘤細胞爬行的機制仍未明瞭。在這研究中，我們發現在人類軟骨肉瘤細胞中，CCL2會誘導人類軟骨肉瘤細胞爬行及基質金屬蛋白?-9 (Matrix metalloproteinase-9, MMP-9) 表現，加入趨化素配體接受器2 (Chemokine receptor 2, CCR2)、Ras、Raf-1及MEK的抑制劑，可以有效抑制CCL2所增加軟骨肉瘤細胞的爬行及MMP-9的表現。CCL2刺激可活化Ras、Raf-1、MEK、ERK及NF-κB訊息，而給予Ras、Raf-1、MEK、ERK及NF-κB的專一性抑制劑和mutant則可抑制CCL2所誘導的細胞爬行及MMP-9表現。由實驗結果我們發現CCL2會活化Ras、Raf-1、MEK、ERK及NF-κB促使MMP-9的表現進而誘導軟骨肉瘤細胞的爬行。
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of cancers. However, the effect of CCL2 on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that CCL2 increased the migration and expression of matrix metalloproteinase (MMP)-9 in human chondrosarcoma cells. CCL2-mediated migration and MMP-9 up-regulation were attenuated by CCR2, Ras, Raf-1, and MEK inhibitor. Activation of the Ras, Raf-1, MEK, ERK, and NF-κB signaling pathway after CCL2 treatment was demonstrated, and CCL2-induced expression of MMP-9 and migration activity were inhibited by the specific inhibitor, and mutant of Ras, Raf-1, MEK, ERK, and NF-κB cascades. Taken together, our results indicated that CCL2 enhances the migration of chondrosarcoma cells by increasing MMP-9 expression through the CCR2 receptor, Ras, Raf-1, MEK, ERK, and NF-κB signal transduction pathway. |
