Inhibition of chemokine receptor expression on uveal melanomas by CXCR4 siRNA and its effect on uveal melanoma liver metastases

Haochuan Li, Wanhua Yang, Peter W. Chen, Hassan Alizadeh, Jerry Y. Niederkorn

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

To determine whether 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 siRNA and tested in vitro for chemo-tactic 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. Similarly, blocking CXCR4 gene expression by transfection with CXCR4 siRNA inhibited both the chemotactic and the 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.

Original languageEnglish (US)
Pages (from-to)5522-5528
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number12
DOIs
StatePublished - Dec 2009

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Chemokine Receptors
Small Interfering RNA
Neoplasm Metastasis
Liver
Transfection
Inhibition (Psychology)
Uveal melanoma
Ligands
Inbred NOD Mouse
SCID Mice
Essential Genes
Capsules
Anti-Idiotypic Antibodies
Melanoma
Spleen
Gene Expression

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Inhibition of chemokine receptor expression on uveal melanomas by CXCR4 siRNA and its effect on uveal melanoma liver metastases. / Li, Haochuan; Yang, Wanhua; Chen, Peter W.; Alizadeh, Hassan; Niederkorn, Jerry Y.

In: Investigative Ophthalmology and Visual Science, Vol. 50, No. 12, 12.2009, p. 5522-5528.

Research output: Contribution to journalArticle

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abstract = "To determine whether 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 siRNA and tested in vitro for chemo-tactic 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. Similarly, blocking CXCR4 gene expression by transfection with CXCR4 siRNA inhibited both the chemotactic and the 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.",
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AU - Niederkorn, Jerry Y.

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N2 - To determine whether 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 siRNA and tested in vitro for chemo-tactic 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. Similarly, blocking CXCR4 gene expression by transfection with CXCR4 siRNA inhibited both the chemotactic and the 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.

AB - To determine whether 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 siRNA and tested in vitro for chemo-tactic 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. Similarly, blocking CXCR4 gene expression by transfection with CXCR4 siRNA inhibited both the chemotactic and the 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.

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