An immortalization-dependent switch in integrin function up-regulates MMP-9 to enhance tumor cell invasion.
An immortalization-dependent switch in integrin function up-regulates MMP-9 to enhance tumor cell invasion.
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DOI：
10.1158/0008-5472.can-08-1080
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
DiPersio CM
中科院分区：
文献类型：
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作者：
Lamar JM;Pumiglia KM;DiPersio CM
整合素是细胞粘附到细胞外基质的主要受体，在肿瘤进展过程中发挥着重要作用。然而，目前尚不清楚癌症发展过程中发生的遗传病变是否会导致整合素功能改变，以及整合素功能的变化如何促进随后的癌症进展。 p53 的功能丧失突变和 H-Ras 的激活突变（分别使上皮细胞永生化和转化）是鳞状细胞癌 (SCC) 的常见因果事件。这两种基因损伤产生的表型促进鳞状细胞癌的进展，因此是抗癌治疗的潜在目标。我们开发了角质形成细胞转化模型系统，使我们能够研究 p53 突变和致癌 Ras 突变在获得促进鳞状细胞癌进展的整合素 α3β1 调节表型中的各自作用。使用该模型，我们发现 p53 缺失突变导致的角质形成细胞永生化会导致 α3β1 功能发生转变，从而诱导致瘤细胞中的 MMP-9 基因表达。 MMP-9 的这种获得性 α3β1 依赖性调节在随后的致癌 Ras 转化过程中得以维持，并促进了致瘤角质形成细胞的侵袭。我们的结果表明，p53 功能的丧失会导致鳞状细胞癌进展期间发生的整合素介导的基因调控发生变化，并在肿瘤细胞侵袭中发挥关键作用。
Integrins, the major receptors for cell adhesion to the extracellular matrix, play important roles during tumor progression. However, it is still unclear whether genetic lesions that occur during carcinoma development can lead to altered integrin function, and how changes in integrin function contribute to subsequent carcinoma progression. Loss-of-function mutations in p53 and activating mutations in H-Ras, which immortalize and transform epithelial cells respectively, are common causal events in squamous cell carcinoma (SCC). Phenotypes resulting from these two genetic lesions promote SCC progression, and are therefore potential targets for anti-cancer therapies. We developed a model system of keratinocyte transformation that has allowed us to investigate the individual roles of p53 mutation and oncogenic Ras mutation in the acquisition of integrin α3β1-regulated phenotypes that promote SCC progression. Using this model, we show that keratinocyte immortalization by p53-null mutation causes a switch in α3β1 function that induces MMP-9 gene expression in tumorigenic cells. This acquired α3β1-dependent regulation of MMP-9 was maintained during subsequent transformation by oncogenic Ras, and it promoted invasion of tumorigenic keratinocytes. Our results show that loss of p53 function leads to changes in integrin-mediated gene regulation that occur during SCC progression and play a critical role in tumor cell invasion.