Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion.

Giannelli G, Bergamini C, Fransvea E, Marinosci F, Quaranta V, Antonaci S
Lab Invest. 2001 81 (4): 613-27

PMID: 11304581

Hepatocellular carcinoma (HCC) is the most frequent malignant tumor of the liver; prognosis depends on the tendency to metastasize. Cancer cell invasion is regulated by proteolytic remodeling of extracellular matrix components and by integrin expression. We have shown that matrix metalloproteinase-2 (MMP-2) and membrane-type-1 matrix metalloproteinase (MT1-MMP) cleave Laminin-5 (Ln-5), stimulating cell migration. Here we report that all HCC cells express MT1-MMP, migrate on Ln-1 and Collagen IV, whereas only HCC cells that express alpha3beta1 integrin secrete detectable levels of gelatinases, migrate on Ln-5, and invade through a reconstituted basement membrane (BM). Migration on Ln-5 is blocked by BB-94, an MMP inhibitor, and by MIG1, a monoclonal antibody that hinders migration on MMP-2-cleaved Ln-5. Invasion through a reconstituted BM is also inhibited by BB-94. HCC alpha3beta1-negative cells migrate on Ln-1 and Collagen IV, but not on Ln-5, and do not invade through a reconstituted BM, although they express MT1-MMP. Anti-alpha3beta1 blocking antibodies inhibit gelatinase activation, cell motility, and cell invasion through MATRIGEL: In vivo, alpha3beta1 integrin and Ln-5 are expressed in HCC tissue but not in normal liver. In conclusion, our data suggest that both alpha3beta1 integrin and gelatinase activity are required for HCC migration and invasion.

MeSH Terms (21)

Basement Membrane Carcinoma, Hepatocellular Cell Adhesion Cell Adhesion Molecules Cell Movement Collagen Drug Combinations Extracellular Matrix Extracellular Matrix Proteins Humans Integrin alpha3beta1 Integrins Laminin Matrix Metalloproteinase 2 Matrix Metalloproteinases Matrix Metalloproteinases, Membrane-Associated Metalloendopeptidases Neoplasm Invasiveness Proteoglycans Tissue Inhibitor of Metalloproteinase-2 Tumor Cells, Cultured

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