Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes
Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes
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DOI：
10.1038/onc.2014.300
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发表时间：
2015-07-01
期刊：
影响因子：
8
通讯作者：
Krueger, A.
中科院分区：
文献类型：
--
作者：
Cui, H.;Seubert, B.;Krueger, A.
金属蛋白酶组织抑制剂-1（TIMP-1）是近年来发现的一种促转移因子，与许多癌症的预后不良密切相关。这种相关性似乎是矛盾的，因为TIMP-1最好被描述为促肿瘤发生基质金属蛋白酶的抑制剂。直到最近，TIMP-1才被揭示为可以独立于其抑制特性调节癌症进展的信号分子。在本研究中，我们证明了外源性和内源性TIMP-1的增加导致肺腺癌细胞中CD 63/PI 3 K/AKT/HIF-1依赖性途径中miR-210的上调。TIMP-1诱导P110/P85 PI 3 K信号传导和AKT磷酸化。它还导致HIF-1 α蛋白水平的增加，与HIF-1调节的mRNA表达和microRNA miR-210的上调正相关。miR-210的下游靶点，即FGFRL 1、E2 F3、VMP-1、RAD 52和SDHD，在TIMP-1存在下降低。当TIMP-1在肿瘤细胞中过表达时，miR-210在体外和体内外泌体中积累。这些外来体促进人脐静脉内皮细胞（HUVEC）中的管形成活性，这反映在A549 L衍生的肿瘤异种移植物中血管生成增加。肿瘤中PI 3 K、AKT、HIF-1A和miR-210的活化和升高也证实了我们的体外数据。TIMP-1的这种新的促肿瘤发生信号功能可能解释了为什么肺癌患者中TIMP-1水平升高与预后不良高度相关。
Tissue inhibitor of metalloproteinases-1 (TIMP-1) recently emerged as a pro-metastatic factor highly associated with poor prognosis in a number of cancers. This correlation seemed paradox as TIMP-1 is best described as an inhibitor of pro-tumourigenic matrix metalloproteinases. Only recently, TIMP-1 has been revealed as a signalling molecule that can regulate cancer progression independent of its inhibitory properties. In the present study, we demonstrate that an increase of both exogenous and endogenous TIMP-1 led to the upregulation of miR-210 in a CD63/PI3K/AKT/HIF-1-dependent pathway in lung adenocarcinoma cells. TIMP-1 induced P110/P85 PI3K-signalling and AKT phosphorylation. It also led to increase of HIF-1 alpha protein levels positively correlating with HIF-1-regulated mRNA expression and upregulation of the microRNA miR-210. Downstream targets of miR-210, namely FGFRL1, E2F3, VMP-1, RAD52 and SDHD, were decreased in the presence of TIMP-1. Upon the overexpression of TIMP-1 in tumour cells, miR-210 was accumulated in exosomes in vitro and in vivo. These exosomes promoted tube formation activity in human umbilical vein endothelial cell (HUVECs), which was reflected in increased angiogenesis in A549L-derived tumour xenografts. Activation and elevation of PI3K, AKT, HIF-1A and miR-210 in tumours additionally confirmed our in vitro data. This new pro-tumourigenic signalling function of TIMP-1 may explain why elevated TIMP-1 levels in lung cancer patients are highly correlated with poor prognosis.