Role of ?1 integrins in adhesion and invasion of hepatocellular carcinoma cells

Abstract

To investigate the role of integrins in hepatocellular carcinoma (HCC) invasion, we analyzed the relationship between the expression and activity of ␤1 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 ␤1 and ␣6 subunits, and various levels of ␣1, ␣2, ␣3, and ␣5 expression as determined by cell surface flow cytometry. Activity of ␤1 integrins was evaluated by cell adhesion to collagen, fibronectin, and laminin in the presence or absence of the stimulatory anti-␤1 monoclonal antibody ( Tumor invasion and metastasis are complex processes requiring the ability of tumor cells to interact with endothelial cells and extracellular matrix. The major cell surface receptors that mediate these interactions are integrins. They are heterodimeric transmembrane receptors consisting of ␣ and ␤ subunits, which produce more than 20 different heterodimers and bind specific ligands. 1,2 Each subunit is a glycoprotein with a large extracellular domain and a relatively small cytoplasmic domain. It has been shown that integrins can transduce signals and play principal roles in biological features of tumors, especially in growth, differentiation, and invasive and metastatic events of malignant cells. 2,3 Changes in expression of integrins have been linked to both tumor suppression and tumor progression in different human malignancies. 4,5 Several studies have described altered expression of ␤1 integrins in hepatocellular carcinoma (HCC). Reduced expression of ␣2, ␣3, and ␣5 subunits 6,7 and overexpression of ␣6 subunits of ␤1 integrins 8 have been shown in HCC with aggressive phenotypes. Nonpolarized aberrant distribution of ␤1 subunit has been shown to correlate with tumor growth rate, grade, and size in HCC. 9 These observations suggest important roles of ␤1 integrins in growth and invasiveness of HCC. Recently, several studies have indicated the modulation of expression and function of ␤1 integrins on HCC cells during metastatic events. Following the adhesion to vascular endothelial cells, HCC cells receive stimulation from cytokines produced by the endothelial cells. The resultant increase of ␣2␤1 integrin expression on HCC cells may facilitate migration of these cells to extravascular tissues. 10 On the contrary, the cell adhesion regulator, the gene of which is located on 16q, suppresses the process of integrin-mediated cell adhesion and has an inhibitory effect on the progression of HCC. 11

Autocrine motility factor enhances hepatoma cell invasion across the basement membrane through activation of β1 integrins

“…32 It has been demonstrated that certain cytokines activate integrins. 33 Masumoto et al 34 showed that activity of several ␤1 integrins was enhanced by the stimulation of integrin ␤1 subunit, and the level of ␤1 integrins activity correlated with the tumor cell-invasive ability in hepatoma cells. We have previously demonstrated that ␤1 integrins, such as integrins ␣1␤1, ␣2␤1, ␣3␤1, and ␣6␤1, are involved in the motility and adhesion to type IV collagen and laminin.…”

Transforming growth factor‐β1‐induced apoptosis is blocked by β1‐integrin‐mediated mitogen‐activated protein kinase activation in human hepatoma cells

“…In HCC, overexpression of integrins, including β1-integrin has been shown, [18][19][20] and several in vitro studies have demonstrated that the levels of constitutive activity of β1-integrins are correlated with invasive and metastatic activity of hepatoma cells. [37][38][39] Pollman et al 40) reported that ECM protected vascular endothelial cells from TGF-β1-induced apoptosis, and this anti-apoptotic effect of ECM was mimicked by activation of β1-integrin. Consistent with this observation, we have demonstrated that β1-integrin protects hepatoma cells from chemotherapy-induced apoptosis, 23) indicating that β1-integrin functions as a survival factor in hepatoma cells.…”

Downregulation of spleen tyrosine kinase in hepatocellular carcinoma by promoter CpG island hypermethylation and its potential role in carcinogenesis

“…Integrins are the major cell surface receptors that mediate these interactions, and activity and expression of b1-integrins are associated with the invasive ability of HCC cells. 27 Several reports have shown that in airway epithelial cells and breast cancer cells, SYK is phosphorylated at several tyrosine residues, including Y342, and activated through b1-integrins signaling. 13,15 b1-integrins are highly expressed in HCC cell lines, including Hep3B and Huh7.…”