Inhibition of Chemokine Receptor Expression on Uveal Melanomas by CXCR4 siRNA Blocks Tumor Cell Invasion and Liver Metastasis of Uveal Melanoma Cells
Haochuan Li 1,
Wanhua Yang 1,
Peter W. Chen 1,
Hassan Alizadeh 1,
and
Jerry Y. Niederkorn 2*
1 Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
2 Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390-9057, United States
* To whom correspondence should be addressed. E-mail: jerry.niederkorn{at}utsouthwestern.edu.
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Abstract |
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Purpose: To determine if blocking the expression of the chemokine receptor CXCR4 using siRNA inhibits chemotactic responses of human uveal melanoma cells to liver-derived factors and prevents liver metastases.
Methods: Human uveal melanoma cells were transfected with CXCR4 siRNA or control RNA and tested in vitro for chemotactic and invasive behavior in response to soluble factors produced by human liver cells. The effect of CXCR4 siRNA transfection on the formation of liver metastases was tested by injecting transfected melanoma cells into the spleen capsules of NOD-SCID mice and metastases were quantified by measuring the human housekeeping gene, hHPRT, in livers.
Results: Blocking CXCR4 interaction with its ligand using anti-CXCL12 antibody resulted in a significant reduction in the chemotactic responses of uveal melanoma cells to soluble factors produced by human liver cells. Likewise, blocking CXCR4 gene expression by transfection with CXCR4 siRNA inhibited both the chemotactic and invasive properties of uveal melanoma cells exposed to factors produced by human livers. Uveal melanoma cells transfected with CXCR4 siRNA produced fewer liver metastases than untreated uveal melanoma cells or uveal melanoma cells transfected with control siRNA.
Conclusions: CXCR4 is a key chemokine receptor that may account for the organ-specific homing of human uveal melanomas to the liver, which contains significant quantities of CXCL2, the only known ligand for CXCR4. CXCR4 is a potential therapeutic target for preventing the initial establishment of liver metastases, but has limited application for use in advanced liver tumors.
Key Words:
melanoma, chemotaxis, immunotherapy
