Heparin-binding epidermal growth factor-like growth factor is a potent regulator of invasion activity in oral squamous cell carcinoma

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF)has been shown to stimulate the growth of various cell types in an autocrine orparacrine manner. Although HB-EGF is widely expressed in tumors when comparedwith normal tissue, its contribution to cancer progression remains obscure. Theobjective of this study was to explore the effects of HB-EGF on proliferation,invasion activity and MMP-9 levels of an oral squamous cell carcinoma cell line,HSC3, in vitro. MTT assays, Matrigel invasion assays and RT-PCR in combinationwith RNA interference (RNAi) were used in this study. An RNAi-mediated decreasein HB-EGF expression reduced invasion activity and MMP-9 mRNA levels, but notproliferation, in HSC3 cells. The addition of purified HB-EGF to cell culturemedium upregulated MMP-9 mRNA levels in HSC3 cells. Furthermore, the TACE inhibitorTAPI-2 or EGFR inhibitor AG1478 decreased MMP-9 mRNA levels in HSC3 cells. Thesedata indicate that HB-EGF released from HSC3 cells by TACE stimulates EGFR inan autocrine manner, which in turn activates invasion activity via MMP-9 upregulation.