Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells
Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells
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Resistin 通过抑制人软骨肉瘤细胞中的 miR-186 促进 VEGF-C 相关淋巴管生成
DOI：
10.1016/j.bcp.2018.05.001
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发表时间：
2018-08-01
影响因子：
5.8
通讯作者：
Wang, Shih-Wei
中科院分区：
文献类型：
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作者：
Su, Chen-Ming;Tang, Chih-Hsin;Wang, Shih-Wei
软骨肉瘤是一种常见的原发性骨恶性肿瘤，可以通过血管系统转移到其他器官。转移过程中的关键步骤，淋巴管生成，涉及血管内皮生长因子-C（VEGF-C）。然而，淋巴管生成在软骨肉瘤转移中的作用仍有待阐明。越来越多的证据表明，脂肪细胞和单核细胞分泌的细胞因子β-胡萝卜素也促进肿瘤的发病。值得注意的是，软骨肉瘤很容易转移。在这项研究中，我们证明，在人软骨肉瘤细胞中，cadrin增强VEGF-C的表达和淋巴管内皮细胞（LECs）相关的淋巴管生成。我们还表明，c-Src信号通路和下调microRNA（miR）-186，通过c-Src触发VEGF-C依赖性淋巴管生成。在软骨肉瘤细胞中过表达的degrin显着增强VEGF-C的生产和LEC相关的淋巴管生成在体外和肿瘤相关的淋巴管生成在体内。抵抗素水平与VEGF-C依赖的淋巴管生成正相关，通过下调软骨肉瘤组织临床样本中的miR-186表达。这项研究是第一次评估抵抗素通过上调人软骨肉瘤中VEGF-C表达促进LEC相关淋巴管生成的机制。我们认为，在VEGF-C相关的软骨肉瘤转移的肿瘤淋巴管生成中，c-myc可能是一个分子靶点。
Chondrosarcoma is a common primary malignant tumor of the bone that can metastasize through the vascular system to other organs. A key step in the metastatic process, lymphangiogenesis, involves vascular endothelial growth factor-C (VEGF-C). However, the effects of lymphangiogenesis in chondrosarcoma metastasis remain to be clarified. Accumulating evidence shows that resistin, a cytokine secreted from adipocytes and monocytes, also promotes tumor pathogenesis. Notably, chondrosarcoma can easily metastasize. In this study, we demonstrate that resistin enhances VEGF-C expression and lymphatic endothelial cells (LECs)-associated lymphangiogenesis in human chondrosarcoma cells. We also show that resistin triggers VEGF-C-dependent lymphangiogenesis via the c-Src signaling pathway and down-regulating micro RNA (miR)-186. Overexpression of resistin in chondrosarcoma cells significantly enhanced VEGF-C production and LECs-associated lymphangiogenesis in vitro and tumor-related lymphangiogenesis in vivo. Resistin levels were positively correlated with VEGF-C-dependent lymphangiogenesis via the down-regulation of miR-186 expression in clinical samples from chondrosarcoma tissue. This study is the first to evaluate the mechanism underlying resistin-induced promotion of LECs-associated lymphangiogenesis via the upregulation of VEGF-C expression in human chondrosarcomas. We suggest that resistin may represent a molecular target in VEGF-C-associated tumor lymphangiogenesis in chondrosarcoma metastasis.