Functional differences between integrin α4 and integrins α5/αv in modulating the motility of human oral squamous carcinoma cells in response to the V region and heparin-binding domain of fibronectin

Abstract

The high-affinity heparin-binding domain and the V region of fibronectin (FN) mediate invasion and migration of human oral squamous cell carcinoma (SCC) cells. We investigated the role of the α4, α5, and αv integrin receptors—which are central to mediating interactions with these domains of FN—in regulating SCC cell migration. SCC cells expressed the α4, α5, and αv integrin subunits on their surface, although α4 expression was low. Treatment with recombinant FN proteins containing an alternatively spliced V region (V+) and either an unmutated (H+) or a mutated, nonfunctional high-affinity heparin-binding domain (H−) increased expression of α5 and αv and cell motility. Antisense α5 or αv oligonucleotides inhibited cell motility stimulated by FN proteins, as did blocking antibodies to α5 or αv. Blocking antibodies to α5 increased αv and α4 levels, and blocking antibodies to αv increased the levels of α5 and α4, without increasing cell motility. In contrast, an antisense α4 oligonucleotide and α4-blocking antibodies increased cell motility, especially migration stimulated by V+H+ and V+H− FN proteins. α4-Blocking antibodies alone increased motility, probably by inducing α5 and αv expression. Transfection with α4 cDNA decreased cell motility and α5 and αv expression. Thus, the increased motility induced by the FN protein is probably mediated by αv and α5, whereas α4 downregulates this process in a transdominant fashion.