Overexpression of Discoidin Domain Receptor 1 (DDR1) in oral squamous cell carcinoma

[[abstract]]Overexpression and mutation of protein tyrosine kinases (PTKs) are observed in a variety of human cancers, which are associated with poor prognosis. To identify PTKs that are overexpressed in oral cancer, the expressions of eighty-three PTKs in four Taiwanese oral squamous cell carcinoma (OSCC) lines and a pooled cDNA reference were compared by quantitative RT-PCR analysis. Among several hits, we found DDR1 was consistently over-represented in a panel of OSCC cell lines. In addition, by immunohistochemistry analysis of clinical OSCC specimens, we observed that DDR1 concentrations were positively correlated with tumor grades. Similarly, results from microarray analysis of forty tumor/normal-paired oral cancer biopsies revealed an average ~1.5-fold elevation of DDR1 expressions in the tumor parts relative to the normal parts. DDR1 is a non-integrin collagen receptor that has been implicated in a variety of malignancies including breast, prostate, brain, and hepatocellular carcinomas. By using shRNA-mediated depletion of DDR1 in OSCC cells, we found that DDR1 signaling pathway, including phosphorylation of AKT, phosphorylation of ERK1/2 and Bcl-2 expression, plays a critical role in OSCC cell growth. Furthermore, results of immunoprecipitationwestern blot analysis showed that the overexpressed DDR1 was tyrosinephosphorylated and known ligands of DDR1 (collagens I and IV) did not further enhance its phosphorylation state, indicating that DDR1 in these OSCC cells is constitutively-active and is ligand-independent. Finally, imatinib mesylate (Glivec/ Gleevec), a potent DDR1 inhibitor, was found to inhibit the growth of OSCC cells in a dose- and time-dependent manner. This result reinforces the role of DDR1 in OSCC cell survival. Collectively, our data suggest that DDR1 could be a novel therapeutic target for oral cancer treatment