ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor
ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor
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DOI：
10.1016/j.yexcr.2014.03.002
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发表时间：
2014-05-01
影响因子：
3.7
通讯作者：
Hirohata, Satoshi
中科院分区：
文献类型：
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作者：
Inagaki, Junko;Takahashi, Katsuyuki;Hirohata, Satoshi
血管生成和淋巴管生成在恶性肿瘤的进展、扩散和转移中起作用。ADAMTS 1是基质金属蛋白酶家族的成员，已知其抑制血管生成。重组ADAMTS 1显示出强烈抑制血管生成。在本研究中，我们研究了ADAMTSI是否抑制淋巴管生成。我们研究了正常人真皮淋巴微血管内皮细胞（HMVEC-dLy）转导或不转导腺病毒人ADAMTS 1基因治疗的细胞增殖和细胞迁移。然后，我们检查了ADAMTS 1转导的HMVEC-dLy中的VEGFC/VEGFR 3信号转导途径。与对照（未转导的HMVEC-dLy）相比，用转导的ADAMTS 1在Matrigel中的细胞增殖和管形成显著降低。在HMVEC-dLy中，ADAMTS 1基因治疗也减弱了VEGFR 3的磷酸化。免疫沉淀实验表明ADAMTS 1与VEGFC形成复合物。这些数据突出了ADAMTS 1在调节淋巴管生成中的新功能以及ADAMTS 1在癌症治疗中的治疗潜力。(c)2014 Elsevier Inc. All rights reserved.
Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTSI inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/ VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogeneSis and the therapeutic potential of ADAMTSI in cancer therapy. (c) 2014 Elsevier Inc. All rights reserved.