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H. Li, W. Yang, H. Alizadeh, P. W. Chen, J. Y. Niederkorn; Inhibition of Uveal Melanoma Metastasis by Suppression of CXCR4 Expression. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3391.
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We previously demonstrated that primary uveal melanoma cells express high levels of the chemokine receptor CXCR4, when compared to metastatic uveal melanoma cells. Moreover, metastatic uveal melanoma lesions in the livers of nude mice developing from intracameral injections of primary uveal melanoma cells express less CXCR4 relative to the primary tumor cells. We hypothesize that expression of CXCR4 determines the invasive and metastatic properties of uveal melanoma cells, and suppression of CXCR4 expression reduces the metastatic potential of primary uveal melanomas.
OCM3 uveal melanoma cells transfected with either CXCR4 siRNA or control siRNA were injected into beige/nude mice. In vitro effects of CXCR4 siRNA transfection on gene transcription and expression were evaluated by RT-PCR, flow cytometry, transwell migration assays, and matrigel invasion assays. The viability of transfected cells was evaluated by 3H-thymidine incorporation. In vivo effects of CXCR4 siRNA transfection was assessed by immunohistochemistry of liver sections and qPCR for the human HPRT gene expression.
Migration of uveal melanoma cells toward human liver extracts was inhibited by blocking with an anti-CXCL12 monoclonal antibody (p < 0.05 to p< 0.01). Transfection of CXCR4 siRNA reduced CXCR4 gene transcription and protein expression in OCM3 uveal melanoma cells (p <0.05 to 0.001). CXCR4 siRNA transfection also reduced the chemotaxis and invasion of OCM3 cells stimulated by human liver cell extract (p<0.01 to P<0.001). Compared to the control siRNA group, significant decreases in liver metastasis were found in the CXCR4 siRNA group (p=0.027) in three separate in vivo experiments. There were no significant differences in the viability of OCM3 cells after CXCR4 siRNA or control siRNA transfection.
The inhibition of CXCR4 gene expression by siRNA transfection reduces migration and invasiveness of uveal melanoma cells. Moreover, CXCR4 inhibition reduces the incidence of metastasis of uveal melanoma cells to the liver, suggesting that siRNA silencing of CXCR4 may be used as a potential strategy to prevent uveal melanoma metastasis.
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