Background : EMMPRIN, an important modulator of tumor microenvironment cross-talk is linked to tumor cell invasion, anchorage-independent growth and angiogenesis. Recently, we reported that development of OIN coincides with a dramatic increase in EMMPRIN levels both in vitro and in vivo. Dysregulation of EGFR signaling plays a central role in the development and progression of OIN. Hence, EGFR-targeted therapy is being proposed to prevent the progression of OIN to oral cancer. Aim : The purpose of this study was to explore the effects of EGFR-ligand Amphiregulin (AR) on the EMMPRIN expression in OIN cells and to determine if EGFR-tyrosine kinase inhibitor (EGFR-TKI) ZD1839 blocks EGFR signaling pathways in OIN cells and inhibit their growth and EMMPRIN expression. Results : OIN cell line MSK-Leuk1 was derived from an OIN lesion adjacent to tongue squamous cell carcinoma. Treatment of growth factor-starved OIN cells with AR also enhanced EMMPRIN mRNA and protein expression levels and stimulated their growth in a dose and time dependent fashion (10 - 200 ng/ml; 24-48 hrs). Treatment of OIN cells with AR induced phosphorylation of ERK1/2 and JNK activation without significant p38 activation. ZD1839 (1 µM) inhibited AR-dependent phosphorylation of ERK 1/2 in OIN cells almost identical to the inhibitory activity shown by PD98059, an ERK pathway inhibitor. Pre-treatment of growth factor-starved OIN cells with either ZD1839 (1 μm) or PD98059 (20 μm) markedly (>50%) reduced AR-induced EMMPRIN expression. Parallel experiments revealed that ZD1839 (1 μm) strongly inhibited growth factor-induced proliferation of OIN cells in dose-dependent fashion without significant increase in their apoptosis rate (% cells positive for cleaved caspase 3). Conclusion : Transactivation of EGFR by AR upregulates EMMPRIN expression in OIN cells predominantly via Erk1/2 signaling pathway. EGFR-TKI ZD1839 inhibits AR-induced EMMPRIN expression in OIN cells by blocking EGFR-mediated Erk activation. Thus, EMMPRIN would be an ideal predictor of EGFR-TKI mediated therapeutic response in OIN.
- American Association for Cancer Research