Department of Cancer Biology and the Cancer Center
1-Phosphatidylinositol 3-Kinase; Adaptor Proteins, Signal Transducing; Animals; Antigens, CD29; CHO Cells; Cell Adhesion; Cricetinae; Cytoplasm; Humans; Insulin-Like Growth Factor II; Intracellular Signaling Peptides and Proteins; Laminin; Male; Mice; Phosphoproteins; Prostatic Neoplasms; Protein Phosphatase 2; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases; RNA, Messenger; Transfection; Up-Regulation
The interactions between cancer cells and the extracellular matrix (ECM) regulate cancer progression. The beta1C and beta1A integrins, two cytoplasmic variants of the beta1 integrin subfamily, are differentially expressed in prostate cancer. Using gene expression analysis, we show here that the beta1C 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, beta1A does not affect IGF-II levels. We provide evidence that beta1C-mediated up-regulation of IGF-II levels increases adhesion to Laminin-1, a basement membrane protein down-regulated in prostate cancer, and that the beta1C 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 beta1 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 beta1C 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 beta1C will be sufficient to revert a neoplastic phenotype to a nonproliferative and highly adherent normal phenotype.
DOI of Published Version
Cancer Res. 2006 Jan 1;66(1):331-42. Link to article on publisher's site
Goel, Hira Lal; Moro, Loredana; King, Michael; Teider, Natalia; Centrella, Michael; McCarthy, Thomas L.; Holgado-Madruga, Marina; Wong, Albert J.; Marra, Ersilia; and Languino, Lucia R., "Beta1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment" (2006). Open Access Articles. 347.