Abstract
SCC-S2/GG2-1/NDED (approved gene symbol TNFAIP8) is a transcription factor NF-kappaB-inducible, antiapoptotic, and oncogenic molecule. In this study, we examined the role of SCC-S2 in invasion and experimental metastasis. We demonstrate that expression of SCC-S2 cDNA in MDA-MB 435 human breast cancer cells is associated with enhanced invasion in vitro and increased frequency of pulmonary colonization of tumor cells in athymic mice. Systemic treatment of athymic mice with a cationic liposomal formulation of SCC-S2 antisense oligo led to decreased incidence of pulmonary metastasis and inhibition of SCC-S2 expression in vivo. Antisense inhibition of endogenous SCC-S2 expression correlated with decreased expression of VEGF receptor-2 in tumor cells and human lung microvascular endothelial cells and loss of endothelial cell viability. In addition, downregulation of SCC-S2 expression in tumor cells was associated with decreased expression of known metastasis-related molecules MMP-1 and MMP-9. These results demonstrate a novel role for SCC-S2 in tumor progression, involving multiple effectors, and provide a basis for SCC-S2-targeted cancer gene therapy.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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Breast Neoplasms / pathology*
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Cell Line, Tumor
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Female
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Gene Expression Regulation, Enzymologic*
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Gene Expression Regulation, Neoplastic*
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Humans
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Liposomes
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / secondary
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Matrix Metalloproteinase 1 / genetics
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Matrix Metalloproteinase 1 / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Metalloproteases / genetics
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Metalloproteases / metabolism*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Invasiveness
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Neoplasm Metastasis / drug therapy
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Neoplasm Transplantation
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Oligonucleotides, Antisense / therapeutic use
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Proteins / genetics
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Proteins / metabolism*
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Transplantation, Heterologous
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Liposomes
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Oligonucleotides, Antisense
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Proteins
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TNFAIP8 protein, human
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Vascular Endothelial Growth Factor Receptor-2
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Metalloproteases
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase 1