Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion.
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.
Giannelli
G
G
Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy. g.giannelli@intmed.uniba.it
Bergamini
C
C
Fransvea
E
E
Marinosci
F
F
Quaranta
V
V
Antonaci
S
S
D001485:Basement Membrane / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000502:physiology*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D003094:Collagen; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins; D039201:Integrin alpha3beta1; D016023:Integrins; D007797:Laminin; D020778:Matrix Metalloproteinase 2; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D011509:Proteoglycans; D019716:Tissue Inhibitor of Metalloproteinase-2; D000097794:Kalinin; C059485:matrigel