Identification of integrins α6 and β7 as c-Jun- and transformation-relevant genes in highly invasive fibrosarcoma cells
Identification of integrins α6 and β7 as c-Jun- and transformation-relevant genes in highly invasive fibrosarcoma cells
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DOI：
10.1002/ijc.24391
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发表时间：
2009-09-01
影响因子：
6.4
通讯作者：
Hoelttae, Erkki
中科院分区：
文献类型：
--
作者：
Kielosto, Mari;Nummela, Pirjo;Hoelttae, Erkki
了解肿瘤细胞侵袭的机制对我们预防癌症死亡的尝试至关重要。我们通过DNA微阵列技术筛选了体内高度侵袭性的s -腺苷甲硫氨酸脱羧酶（AdoMetDC）过表达的小鼠成纤维细胞及其衍生物中c-Jun显性阴性突变体（TAM67）或c-Jun shRNA的表达变化。在检测到的一小部分靶基因中，整合素α 6和β 7、组织蛋白酶L和胸腺蛋白酶β 4在adometdc转化的细胞中均上调，在TAM67或c-Jun shRNA逆转转化后均下调。整合素α 6亚基的上调，与整合素PI配对，使转化细胞具有附着基膜层粘连蛋白和扩散的能力。此外，用中和抗体抑制整合素α 6或β 1功能可阻断adometdc -转化体和人HT-1080纤维肉瘤细胞在三维基质中的侵袭性。此外，免疫组织化学分析显示在高级别人纤维肉瘤中有很强的整合素- 6染色。我们的数据表明，c-Jun可以调节入侵的所有三个关键步骤：细胞粘附（整合素α 6），基底膜/细胞外基质降解（组织蛋白酶L）和细胞迁移（胸腺蛋白酶β 4）。此外，这是第一个将整合素β 7（一种与内皮/上皮细胞粘附分子结合的白细胞特异性整合素）与非白细胞来源细胞的转化表型联系起来的研究。由于肿瘤细胞侵袭是转移的先决条件，整合素- 6 β 1在纤维肉瘤细胞侵袭/扩散中的关键作用吸引了将整合素- 6 β 1拮抗剂单独或与组织蛋白酶1和胸腺蛋白酶- 4抑制剂联合作为化疗药物的试验。(c) 2009年
Understanding the mechanisms of tumor cell invasion is essential for our attempts to prevent cancer deaths. We screened by DNA microarrays the c-Jun- and transformation-related gene expression changes in S-adenosylmethionine decarboxylase (AdoMetDC)-overexpressing mouse fibroblasts that are highly invasive in vivo, and their derivatives expressing a tetracycline-inducible dominant-negative mutant of c-Jun (TAM67) or c-Jun shRNA. Among the small set of target genes detected were integrins alpha 6 and beta 7, cathepsin L and thymosin beta 4, all upregulated in the AdoMetDC-transformed cells and downregulated upon reversal of transformation by TAM67 or c-Jun shRNA. The upregulation of integrin alpha 6 subunit, pairing with integrin PI, endowed the transformed cells with the capability to attach to basement membrane laminin and to spread. Further, inhibition of integrin alpha 6 or beta 1 function with neutralizing antibodies blocked the invasiveness of AdoMetDC-transformants and human HT-1080 fibrosarcoma cells in three-dimensional Matrigel. Moreover, immunohistochemical analyses showed strong integrin alpha 6 staining in high-grade human fibrosarcomas. Our data show that c-Jun can regulate all three key steps of invasion: cell adhesion (integrin alpha 6), basement membrane/extracellular matrix degradation (cathepsin L) and cell migration (thymosin beta 4). In addition, this is the first study to associate integrin beta 7, known as a leukocyte-specific integrin binding to endothelial/epithelial cell adhesion molecules, with the transformed phenotype in cells of nonleukocyte origin. As tumor cell invasion is a prerequisite for metastasis, the observed critical role of integrin alpha 6 beta 1 in fibrosarcoma cell invasion/spreading allures testing antagonists to integrin alpha 6 beta 1, alone or combined with inhibitors of cathepsin 1, and thymosin beta 4, as chemotherapeutic agents. (C) 2009 UICC