Matrix Metalloproteinase-9 Is Upregulated in Nucleophosmin-Anaplastic Lymphoma Kinase-Positive Anaplastic Lymphomas and Activated at the Cell Surface by the Chaperone Heat Shock Protein 90 to Promote Cell Invasion
Matrix Metalloproteinase-9 Is Upregulated in Nucleophosmin-Anaplastic Lymphoma Kinase-Positive Anaplastic Lymphomas and Activated at the Cell Surface by the Chaperone Heat Shock Protein 90 to Promote Cell Invasion
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DOI：
10.1158/0008-5472.can-10-0861
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发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Gaits-Iacovoni, Frederique
中科院分区：
文献类型：
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作者：
Lagarrigue, Frederic;Dupuis-Coronas, Sophie;Gaits-Iacovoni, Frederique
许多间变性大细胞淋巴瘤（ALCL）表达嵌合癌基因NPM-ALK，其驱动恶性转化和侵袭。在这项研究中，我们发现NPM-ALK表达增加了基质金属蛋白酶-9（MMP-9）的表达。因此，我们发现，100%的ALK（+）ALCL活检标本也是MMP-9（+），而ALK（-）肿瘤仅为36.3%。机制研究表明，Rac 1驱动MMP-9分泌。MMP抑制剂GM 6001和MMP-9阻断抗体可阻断NPM-ALK（+）细胞的侵袭能力。有趣的是，透明质酸受体CD 44作为MMP-9和细胞表面上的伴侣热休克蛋白90的对接表面，其中MMP-9被切割和激活。膜相关的MMP-9定位于侵袭伪足，其显示出强的明胶酶活性。综上所述，我们的观察结果强化了分子伴侣在调节蛋白活化状态中发挥主要细胞外作用的概念，并揭示了对ALK（+）ALCL扩散和侵袭至关重要的新因素。他们还指出了对ALK（+）ALCL至关重要的新因素。Cancer Res; 70（17）; 6978-87. (C)2010年AACR。
Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.3% of ALK(-) tumors. Mechanistic studies revealed that Rac1 drove MMP-9 secretion. The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells. Interestingly, the hyaluronan receptor CD44 acted as a docking surface for MMP-9 and the chaperone heat shock protein 90 on the cell surface, where MMP-9 was cleaved and activated. Membrane-associated MMP-9 was localized to invadopodia, which display a strong gelatinase activity. Taken together, our observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL. They also point out new factors crucial for ALK(+) ALCL. Cancer Res; 70(17); 6978-87. (C) 2010 AACR.