ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
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DOI：
10.1158/0008-5472.can-08-2976
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发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Camargo, Anamaria A.
中科院分区：
文献类型：
--
作者：
Verbisck, Newton V.;Costa, Erico T.;Camargo, Anamaria A.
ADAM 23基因在不同类型的肿瘤中经常沉默，并且在乳腺肿瘤中，沉默与肿瘤进展相关，这表明它可能与转移表型的获得相关。ADAM 23主要通过去整合素结构域发挥其功能，因为其金属蛋白酶结构域是无活性的。对ADAM 23与整联蛋白结合的分析揭示了与α（v）β（3）整联蛋白的特异性相互作用，其由去整联蛋白结构域介导。已在不同类型的肿瘤中观察到α（v）β（3）整联蛋白的改变的表达，并且已显示该整联蛋白以活化形式的表达促进转移形成。在这里，我们研究了在转移进展过程中，ADAM 23和α（v）β（3）整合素之间的相互作用可能负向调节α（v）β（3）激活的可能性。在MDA-MB-435细胞系中使用短发夹RNA敲低ADAM 23表达，MDA-MB-435细胞系已被广泛用作α（v）β（3）整联蛋白激活的模型。ADAM 23的消融使α（v）β（3）整联蛋白活化增强至少2- 4倍，并且ADAM 23敲除细胞显示增强的迁移和与经典α（v）β（3）整联蛋白配体的粘附。在免疫缺陷小鼠中，ADAM 23表达的消除也增强了肺肿瘤细胞的停滞。为了用临床证据补充我们的发现，我们发现在94例原发性乳腺肿瘤中，DNA启动子高甲基化导致的ADAM 23基因沉默与较低的无远处转移和疾病特异性生存率显著相关，并且是疾病预后不良的独立预后因素。我们的研究结果强烈支持了在转移进展过程中，ADAM 23通过负性调节α（v）β（3）整合素活化而发挥的功能作用。[Cancer Res 2009;69（13）：5546-52]
The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with alpha(v)beta(3) integrin mediated by the disintegrin domain. Altered expression of alpha(v)beta(3) integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and alpha(v)beta(3) integrin might negatively modulate alpha(v)beta(3) activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for alpha(v)beta(3) integrin activation. Ablation of ADAM23 enhanced alpha(v)beta(3) integrin activation by at least 2- to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic alpha(v)beta(3) integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating alpha(v)beta(3) integrin activation. [Cancer Res 2009;69(13):5546-52]