Thoracic Disease Research Unit, Division of Pulmonary & Critical Care Medicine, Mayo Clinic, Rochester 55905, MN, USA.
Oncogene. 2013 Jan 10;32(2):141-50. doi: 10.1038/onc.2012.41. Epub 2012 Feb 27.
The integrin α9β1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that α9β1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As α9β1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that α9β1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation. These findings were consistent in cells in which: α9β1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing α9β1. These in vitro results are biologically significant as α9β1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9β1 expression or when integrin expression is suppressed. Furthermore, integrin α9β1 is expressed in primary human small cell lung cancer and patients having a high expression of α9β1 demonstrated significantly worse long-term survival compared with patients with low α9β1 expression. These findings highlight a novel mechanism of integrin α9β1 function in human cancer.
整合素 α9β1 结合多种细胞外基质成分，介导细胞黏附、迁移和组织浸润。尽管它在包括内皮细胞在内的多种正常人类细胞中表达，但也在癌细胞中表达。我们之前已经表明，α9β1 结合 VEGF-A 以促进血管生成，这是肿瘤微环境的重要组成部分。由于 α9β1 诱导癌细胞迁移加速，我们希望确定它在癌症生长和转移中的作用。在这项研究中，我们表明 α9β1 表达诱导与上皮-间充质转化一致的分子变化。此外，我们发现 α9β1 与 β-连环蛋白和 E-钙黏蛋白形成三元蛋白复合物，该复合物在整合素激活和随后的 src 和 β-连环蛋白磷酸化后解离。这些发现与以下细胞中的发现一致：α9β1 被外源过表达，或者当内源性表达 α9β1 的癌细胞中其表达被抑制时。这些体外结果具有生物学意义，因为与没有 α9β1 表达或抑制整合素表达的细胞相比，表达 α9β1 的癌细胞在小鼠中诱导更大的肿瘤生长和转移。此外，整合素 α9β1 在原发性人类小细胞肺癌中表达，并且高表达 α9β1 的患者与低表达 α9β1 的患者相比，长期生存明显更差。这些发现强调了整合素 α9β1 在人类癌症中的一种新的功能机制。
