Interference of macrophage migration inhibitory factor expression in a mouse melanoma inhibits tumor establishment by up-regulating thrombospondin-1.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with proinflammatory, proangiogenic, and protumorigenic properties. The molecular mechanisms underlying the role of MIF in tumorigenesis and angiogenesis are not well understood. To address these roles, an interfering MIF (iMIF) RNA was stably introduced into the B16-F10 mouse melanoma cell line, reducing MIF mRNA expression 1.6-fold and MIF protein expression 2.8-fold relative to control cells. When iMIF cells were subcutaneously injected into C57BL/6 mice, tumor establishment was significantly delayed and there was a marked absence of intratumoral vasculature in iMIF tumors relative to controls. A comparative gene expression analysis of iMIF and control melanoma cell lines revealed that thrombospondin-1 (TSP-1) mRNA expression was up-regulated 88-fold in the iMIF cells by real-time PCR. A 2-fold increase in TSP-1 protein levels was observed in iMIF cell culture supernatants. These results strongly suggest that the delayed tumor establishment and reduced vasculature in iMIF melanomas are linked to the up-regulation of the antiangiogenic TSP-1. They further define a novel function of MIF as a regulator of TSP-1 in a mouse melanoma model.
Culp
W David
WD
National Eye Institute, Bethesda, MD, USA.
Tsagozis
Panagiotis
P
Burgio
Michael
M
Russell
Paul
P
Pisa
Pavel
P
Garland
Donita
D
D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000502:physiology; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D012983:Soft Tissue Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D040521:Subcutaneous Tissue; D019700:Thrombospondin 1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse