Human hepatocellular carcinoma (HCC) cells require both α3β1 integrin and matrix metalloproteinases activity for migration and invasion

被引:133
作者
Giannelli, G
Bergamini, C
Fransvea, E
Marinosci, F
Quaranta, V
Antonaci, S
机构
[1] Univ Bari, Sch Med, Dept Internal Med Immunol & Infect Dis, Sect Internal Med, Bari, Italy
[2] Scripps Res Inst, Dept Cell Biol, La Jolla, CA USA
关键词
D O I
10.1038/labinvest.3780270
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 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 monoclonal antibody that hinders migration on MMP-2-cleaved Ln-5. Invasion through a reconstituted BM is also inhibited by BB-94. HCC alpha3 beta1-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-alpha3 beta1 blocking antibodies inhibit gelatinase activation, cell motility, and cell invasion through Matrigel. In vivo, alpha3 beta1 integrin and Ln-5 are expressed in HCC tissue but not in normal liver. In conclusion, our data suggest that both alpha3 beta1 integrin and gelatinase activity are required for HCC migration and invasion.
引用
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页码:613 / 627
页数:15
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