Midkine promotes tetraspanin–integrin interaction and induces FAK-Stat1α pathway contributing to migration/invasiveness of human head and neck squamous cell carcinoma cells

The heparin-binding growth factor, MK, promoting tumorigenesis and survival was found to associate with α6β1 integrins. We showed for the first time that MK interacted with TSPAN1 and facilitated the association between TSPAN1 and integrin α6β1 proteins in head and neck squamous cell carcinoma (HNSCC) cells. We found that MK mediated an integrin-dependent tyrosine phosphorylation of FAK and activation of paxillin and Stat1α pathways. As result, downstream target genes implicated in cell migration and invasiveness (e.g. MMP-2 and MMP-26) were overexpressed. We observed that RNAi silencing of the critical signaling intermediates led to decrease of MK-induced migration/invasiveness of HNSCC cells. The major finding of this study is a novel MK-triggered signaling mechanism implicated in migration and invasiveness of HNSCC cells.