RNAi targeting urokinase‐type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo

It has been admitted that urokinase‐type plasminogen activator receptor (u‐PAR) is overexpressed in many human malignant tumors including oral squamous cell carcinoma (OSCC) and plays an important role in a variety of cancer key cellular events as a versatile signaling orchestrator. In our study, a retroviral vector expressing u‐PAR‐specific siRNA was injected into OSCC xenografts of nude mice to observe its inhibitory effects on OSCC. Our data demonstrate that siRNA targeting u‐PAR markedly suppressed tumor growth, reduced the expression of proliferation‐related gene, Ki‐67 and increased cell apoptosis, accompanying with the efficient and specific inhibition of endogenous u‐PAR expression in OSCC. More importantly, the mRNA and protein expression of MMP‐2, MMP‐9, VEGF‐C, VEGF‐D and VEGFR‐3 that are intimately involved in oral cancer invasion and metastasis, was simultaneously downregulated significantly as determined by quantitative real‐time RT‐PCR, Western blot and immunohistochemistry; and Gelatin and fibrin zymography showed that MMP‐9, MMP‐2 and u‐PA enzymatic activities were significantly reduced in u‐PAR‐specific siRNA group, compared to those in control groups. In addition, the expression of MDR‐1 gene related to drug resistance was obviously inhibited by silencing of u‐PAR. These findings suggest that RNAi targeting u‐PAR could effectively inhibit the metastasis and progression of OSCC in vivo. Thus, it may be used as a potent and specific therapy for oral cancer, especially in inhibiting and preventing cancer cell invasion and metastasis. © 2009 UICC