β1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment
β1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment
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DOI：
10.1158/0008-5472.can-05-2588
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Languino, LR
中科院分区：
文献类型：
--
作者：
Goel, HL;Moro, L;Languino, LR
癌细胞和细胞外基质（ECM）之间的相互作用调节癌症进展。β（1C）和β（1A）整联蛋白是β（1）整联蛋白亚家族的两种胞质变体，在前列腺癌中差异表达。使用基因表达分析，我们在这里表明，β（1C）变体，细胞增殖的抑制剂，这是在前列腺癌下调，上调胰岛素样生长因子-II（IGF-II）的mRNA和蛋白质水平。相反，PIA不影响IGF-II水平。我们提供的证据表明，β（1C）介导的IGF-II水平上调增加粘附层粘连蛋白-1，基底膜蛋白下调前列腺癌，β（1C）胞质域包含的结构基序足以增加细胞粘附层粘连蛋白-1。这种通过IGF-II局部支持细胞粘附于层粘连蛋白-1的自分泌机制通过活化生长因子受体结合蛋白2相关的结合物-1/SH2-含有蛋白酪氨酸磷酸酶2/磷脂酰肌醇3-激酶途径由O 1胞质结构域选择性调节。因此，肿瘤微环境中β（1C）整联蛋白、其配体层粘连蛋白-1和IGF-II的同时局部缺失可能通过降低癌细胞粘附特性促进前列腺癌细胞侵袭和转移。因此，可以想象，β（1C）的再表达将足以将肿瘤表型逆转为非增殖性和高度粘附的正常表型。
The interactions between cancer cells and the extracellular matrix (ECM) regulate cancer progression. The beta(1C) and beta(1A) integrins, two cytoplasmic variants of the beta(1) integrin subfamily, are differentially expressed in prostate cancer. Using gene expression analysis, we show here that the beta(1C) variant, an inhibitor of cell proliferation, which is down-regulated in prostate cancer, up-regulates insulin-like growth factor-II (IGF-II) mRNA and protein levels. In contrast, PIA does not affect IGF-II levels. We provide evidence that beta(1C)-mediated upregulation of IGF-II levels increases adhesion to Laminin-1, a basement membrane protein down-regulated in prostate cancer, and that the beta(1C) cytoplasmic domain contains the structural motif sufficient to increase cell adhesion to Laminin-1. This autocrine mechanism that locally supports cell adhesion to Laminin-1 via IGF-II is selectively regulated by the 01 cytoplasmic domain via activation of the growth factor receptor binding protein 2-associated binder-1/SH2-containing protein-tyrosine phosphatase 2/phosphatidylinositol 3-kinase pathway. Thus, the concurrent local loss of beta(1C) integrin, of its ligand Laminin-1, and of IGF-II in the tumor microenvironment may promote prostate cancer cell invasion and metastasis by reducing cancer cell adhesive properties. It is, therefore, conceivable that reexpression of beta(1C) will be sufficient to revert a neoplastic phenotype to a nonproliferative and highly adherent normal phenotype.