趨化素3與骨肉瘤血管新生之關係

The Relationship Between Chemokine Ligand 3 And Angiogenesis of Osteosarcoma

廖芫雅(Yuan-Ya Liao)

指導教授 ： 周明智

中山醫學大學/醫學院/醫學研究所/博士(2016年)

摘要

骨肉瘤(Osteosarcoma)是骨骼系統之中最常見的原發性肉瘤(惡性腫瘤、癌症)，其特性是此腫瘤具有高度轉移能力，而趨化素3[(C-C motif) ligand 3] (CCL3)曾被報告具有促進腫瘤生長及轉移之作用，然而CCL3在骨肉瘤的作用並不清楚。Vascular endothelial growth factor-A (VEGF-A)為一個血管新生因子，可以促進血管內皮細胞產生新的血管，之前的研究也證實骨肉瘤會分泌VEGF。本論文發現CCL3及VEGF在骨肉瘤的病人含量較正常骨頭高，且與病人的惡性度有關，在骨肉瘤細胞株上外給CCL3可促進VEGF產生及human endothelial progenitor cells (EPCs) 移行及tube formation的作用，另外CCL3會抑制miR-374b表現，給予miR-374 mimic可以反轉由CCL3在細胞實驗中及動物實驗中所增加VEGF表現及血管新生作用。此論文研究發現CCL3可誘導VEGF 表現進而促進血管新生以及腫瘤生長，而CCL3是透過JNK, p38及ERK路徑而降低miR-374b來達到此作用。這些發現可能有助於去理解轉移的機制和發展骨肉瘤更有效的治療方式。

關鍵字

MAPK ； miR-374b ； VEGF ； Angiogenesis ； Osteosarcoma

並列摘要

Osteosarcoma is the most common sarcoma of bone, characterized by a high metastatic potential. However, the crosstalk between chemokine (C-C motif) ligand 3 (CCL3), which facilitates tumor progression and metastasis are largely unknown. Vascular endothelial growth factor-A (VEGF-A), an angiogenesis inducer and a highly specific mitogen for endothelial cells, has not been well explored in human osteosarcoma. Here we demonstrate the correlation of CCL3 and VEGF expressions, quantified by immunohistochemistry, with the tumor stage of human osteosarcoma tissues. Furthermore, CCL3 promotes VEGF expression in human osteosarcoma cells that subsequently induces human endothelial progenitor cells (EPCs) migration and tube formation. Phosphorylation of JNK, ERK, and p38 was found after CCL3 stimulation. In addition, JNK, ERK, and p38 inhibitor also abolished CCL3-induced VEGF expression and angiogenesis. We noted that CCL3 reduces the expression of miR-374b and miR-374b mimic by reversing CCL3-promoted VEGF expression and angiogenesis in vitro and in vivo. This study shows that CCL3 promotes VEGF expression and angiogenesis in human osteosarcoma cells by down-regulating miR-374b expression via JNK, ERK, and p38 signaling pathways. Thus, CCL3 may be a new molecular therapeutic target in osteosarcoma angiogenesis and metastasis.

並列關鍵字

血管新生 ； 骨肉瘤

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