Identification of integrins α6 and β7 as c‐Jun‐ and transformation‐relevant genes in highly invasive fibrosarcoma cells

Understanding the mechanisms of tumor cell invasion is essential for our attempts to prevent cancer deaths. We screened by DNAmicroarrays 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 α6 and β7, cathepsin L and thymosin β4, all upregulated in the AdoMetDC‐transformed cells and downregulated upon reversal of transformation by TAM67 or c‐Jun shRNA. The upregulation of integrin α6 subunit, pairing with integrin β1, endowed the transformed cells with the capability to attach to basement membrane laminin and to spread. Further, inhibition of integrin α6 or β1 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 α6 staining in high‐grade human fibrosarcomas. Our data show that c‐Jun can regulate all three key steps of invasion: cell adhesion (integrin α6), basement membrane/extracellular matrix degradation (cathepsin L) and cell migration (thymosin β4). In addition, this is the first study to associate integrin β7, 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 α6β1 in fibrosarcoma cell invasion/spreading allures testing antagonists to integrin α6β1, alone or combined with inhibitors of cathepsin L and thymosin β4, as chemotherapeutic agents. © 2009 UICC