title: RNAi targeting urokinase-type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo.
abstract: 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.
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Yaling
authors.initials: Y
authors.lastname: Tang
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liang
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Guiquan
authors.initials: G
authors.lastname: Zhu
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Chunxu
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000235:genetics*; D034622:RNA Interference; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D055293:Receptors, Urokinase Plasminogen Activator