Chang Yu-Hsiang, Huang Yuan-Li, Tsai Hsiao-Chi, Chang An-Chen, Ko Chih-Yuan, Fong Yi-Chin, Tang Chih-Hsin
Program for Cancer Biology and Drug Discovery, China Medical University, Taichung 404328, Taiwan.
Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan.
Biomedicines. 2023 Oct 12;11(10):2768. doi: 10.3390/biomedicines11102768.
Osteosarcoma is a common malignant tumor in children and adolescents, known for its aggressive invasion and distant metastasis, leading to a poor prognosis. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basement membranes through their proteolytic activity, thereby promoting osteosarcoma metastasis. Chemokine ligand 2 (CCL2) is a well-studied chemokine that plays a significant role in the cell motility of many cancers. However, its specific involvement in osteosarcoma metastasis is not fully understood. The aim of this study is to examine the role of miRNAs in CCL2-mediated MMP expression and cell motility in human osteosarcoma. The analysis of immunohistochemistry data and databases associated a positive correlation between CCL2 or MMP-3 levels with the metastasis of osteosarcoma patients. The in vivo lung metastatic osteosarcoma model also demonstrated similar effects, showing higher levels of CCL2 and MMP-3 in lung metastatic osteosarcoma tissues. The stimulation of osteosarcoma cells with CCL2 enhanced migration and invasion abilities through the upregulation of MMP-3 synthesis. Our results also indicate that CCL2 enhances MMP-3-dependent cell motility by inhibiting miR-3659 synthesis. Therefore, CCL2 represents a promising therapeutic target for treating metastasis in osteosarcoma.
骨肉瘤是儿童和青少年常见的恶性肿瘤，以其侵袭性浸润和远处转移而闻名，导致预后不良。基质金属蛋白酶（MMPs）可通过其蛋白水解活性降解细胞外基质和基底膜，从而促进骨肉瘤转移。趋化因子配体2（CCL2）是一种研究充分的趋化因子，在许多癌症的细胞运动中起重要作用。然而，其在骨肉瘤转移中的具体作用尚未完全明确。本研究旨在探讨微小RNA（miRNAs）在CCL2介导的人骨肉瘤基质金属蛋白酶表达及细胞运动中的作用。免疫组化数据分析及相关数据库显示，CCL2或基质金属蛋白酶-3（MMP-3）水平与骨肉瘤患者转移呈正相关。体内肺转移骨肉瘤模型也显示出类似结果，肺转移骨肉瘤组织中CCL2和MMP-3水平更高。用CCL2刺激骨肉瘤细胞可通过上调MMP-3合成增强其迁移和侵袭能力。我们的结果还表明，CCL2通过抑制miR-3659合成增强MMP-3依赖性细胞运动。因此，CCL2是治疗骨肉瘤转移的一个有前景的治疗靶点。
