Human hepatocellular carcinoma (HCC) cells require both alpha 3 beta 1 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 invasi on is regulated by proteolytic remodeling of extracellular matrix component s and by integrin expression. We have shown that matrix metalloproteinase-2 (MMP-2) and membrane-type-1 matrix metalloproteinase (MT1-MMP) cleave Lami nin-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 t hat express alpha3 beta1 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 m onoclonal antibody that hinders migration on MMP-2-cleaved Ln-5. Invasion t hrough a reconstituted BM is also inhibited by BB-94. HCC alpha3 beta1-nega tive cells migrate on Ln-1 and Collagen IV, but not on Ln-5, and do not inv ade through a reconstituted BM, although they express MT1-MMP. Anti-alpha3 beta1 blocking antibodies inhibit gelatinase activation, cell motility, and cell invasion through Matrigel. In vivo, alpha3 beta1 integrin and Ln-5 ar e expressed in HCC tissue but not in normal liver. In conclusion, our data suggest that both alpha3 beta1 integrin and gelatinase activity are require d for HCC migration and invasion.