Role of β1 Integrins in Adhesion and Invasion of Hepatocellular Carcinoma Cells

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Abstract
To investigate the role of integrins in hepatocellular carcinoma (HCC) invasion, we analyzed the relationship between the expression and activity of β1 integrins and the invasive ability of multiple HCC cell lines. Human HCC cell lines, PLC/PRF/5, Hep3B, HepG2, HLE, HuH7, and C3A cells, had high expression of β1 and α6 subunits, and various levels of α1, α2, α3, and α5 expression as determined by cell surface flow cytometry. Activity of β1 integrins was evaluated by cell adhesion to collagen, fibronectin, and laminin in the presence or absence of the stimulatory anti–β1 monoclonal antibody (mAb) TS2/16. Different types of HCC cells showed various levels of constitutive activity of β1 integrins as assessed by the TS2/16 requirement in cell adhesion. TS2/16 rapidly stimulated constitutively inactive or partially active β1 integrins to fully active states, and as the result, the levels of cell adhesion to each ligand correlated with the expression levels of corresponding β1 integrins. Thus, in the presence of TS2/16 stimulation, the levels of cell adhesion to collagen, fibronectin, and laminin correlated predominantly with the expression levels of α2, α5, and α6, respectively. Remarkably, as a result of in vitro chemoinvasion assay, the levels of constitutive activity of β1 integrins correlated with the invasive ability of HCC cells. The inhibitory anti–β1 mAb 13 almost completely blocked the invasion of PLC/PRF/5 and Hep3B cells that are the most invasive HCC cell lines. Alternatively, the stimulatory anti–β1 mAb TS2/16 strongly inhibited the invasion. These results not only show an essential role of β1 integrins in invasion of HCC cells but also suggest subtle regulatory mechanisms of cell invasion.

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