Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases.
Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases.
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缺氧诱导鼻咽癌外泌体中基质金属蛋白酶 13 的表达增强转移
DOI：
10.1038/s41419-018-0425-0
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发表时间：
2018-03-07
影响因子：
9
通讯作者：
You Y
中科院分区：
文献类型：
--
作者：
Shan Y;You B;Shi S;Shi W;Zhang Z;Zhang Q;Gu M;Chen J;Bao L;Liu D;You Y
外来体是由肿瘤细胞分泌的纳米囊泡。外泌体可以传递复杂的生物信息，并在多种病理条件下（如缺氧）诱导多种信号传导反应。缺氧与鼻咽癌（NPC）患者的侵袭性表型和不良预后相关。在这里，我们分析了来自缺氧NPC细胞的外泌体在以缺氧诱导因子-1 α（HIF-1α）依赖性方式增强常氧细胞转移中的作用。HIF-1α迅速积累并反式激活数百个基因，如基质金属蛋白酶（MMPs）。我们发现MMP-13在低氧条件下在外泌体和细胞中过表达。缺氧CNE 2细胞中HIF-1α的缺失导致外泌体中MMP-13水平的降低，并显著降低细胞的迁移和侵袭。此外，外泌体MMP-13显着上调波形蛋白的表达，同时降低E-钙粘蛋白水平在CNE 2细胞在体外和体内。MMP-13水平与HIF-1α表达（r = 0.679，P < 0.001）、淋巴结转移、临床分期（均P < 0.05）及预后不良密切相关（P < 0.01）。总之，我们的研究结果表明，缺氧外泌体负载MMP-13，这可以增强迁移和侵袭能力，并诱导微环境的变化，以促进NPC的侵袭性。
Exosomes are nano-vesicles secreted by tumor cells. Exosomes can transfer complex biological information and induce a diverse signaling response in a wide array of pathological conditions, such as hypoxia. Hypoxia is associated with aggressive phenotypes and poor outcomes in nasopharyngeal carcinoma (NPC) patients. Here, we analyzed the role of exosomes from hypoxic NPC cells in enhancing the metastases of normoxic cells in a hypoxia-induced factor-1α (HIF-1α)-dependent manner. HIF-1α rapidly accumulates and trans-activates hundreds of genes, such as matrix metalloproteinases (MMPs). We found that MMP-13 was over-expressed in exosomes and cells under hypoxic conditions. HIF-1α depletion in hypoxic CNE2 cells led to decreased MMP-13 levels in exosomes and significantly reduced cell migration and invasion. Moreover, exosomal MMP-13 significantly up-regulated Vimentin expression while decreasing E-cadherin levels in CNE2 cells in vitro and in vivo. Furthermore, MMP-13 levels were closely associated with HIF-1α expression (r = 0.679, P < 0.001), lymph node metastasis, clinical stage (all P < 0.05) and poor prognosis in NPC patients (P < 0.01). In conclusion, our findings suggest that the hypoxic exosomes were loaded with MMP-13, which could enhance migration and invasiveness and induce microenvironment changes to promote NPC aggressiveness.
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影响因子：
14.8
作者：
Nicoli, Stefania;Presta, Marco
通讯作者：
Presta, Marco
影响因子：
20.3
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