Enhancing in vivo tumorigenicity of B16 melanoma by overexpressing interferon regulatory factor-2: resistance to endogenous IFN-gamma.
We investigated the role of interferon (IFN) regulatory factor-2 (IRF-2) as an oncoprotein in vivo, opposing endogenous IFN-gamma suppression of tumor growth. Using syngeneic IFN-gamma knockout mice, we show that endogenous IFN-gamma slows growth of the mouse melanoma cell line B16-F10 in immunocompetent mice, suggesting that tumor cell resistance to IFN-gamma may lead to greater tumorigenicity. IRF-2 is a nuclear transcription factor induced by IFN-gamma that represses numerous IFN-inducible genes, including genes that regulate cell growth, in opposition to the transcriptional activator IRF-1. B16-F10 has a marked growth inhibitory response to IFN-gamma in vitro and has very little IRF-2 induction compared with other murine tumor cell lines. We engineered B16-F10 cells to stably overexpress murine IRF-2. In vitro, these transfected cells showed a marked resistance to the growth-inhibitory effect of IFN-gamma. In normal mice the IRF-2-transfected cells grew much faster than control tumors. In syngeneic IFN-gamma knockout mice, control cells grew at a rate similar to that of IRF-2-transfected cells, implicating resistance to endogenous IFN-gamma as playing the major role in enhanced growth of IRF-2-transfected tumors in intact mice. These experiments demonstrate that (1) IRF-2 enhances B16 melanoma growth and increases resistance to IFN-gamma in vitro, and (2) IRF-2 opposes the growth suppression mediated by endogenous IFN-gamma in vivo.
Yim
J H
JH
Cytokine and Tumor Biology Laboratory, Department of Surgery, Washington School of Medicine, St. Louis, MO 63110-1093, USA.
Wu
S J
SJ
Lowney
J K
JK
Vander Velde
T L
TL
Doherty
G M
GM
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002999:Clone Cells / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006131:Growth Inhibitors / Q000378:metabolism; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000502:physiology*; D008546:Melanoma, Experimental / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D015513:Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D050836:Interferon Regulatory Factor-2; C494230:Irf2 protein, mouse; D015513:Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D007371:Interferon-gamma