Carcinogenesis Advance Access originally published online on May 16, 2006
Carcinogenesis 2006 27(11):2157-2169; doi:10.1093/carcin/bgl045
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The function of melanotransferrin: a role in melanoma cell proliferation and tumorigenesis
Children's Cancer Institute Australia for Medical Research, Iron Metabolism and Chelation Program P.O. Box 81, High Street, Randwick, Sydney, New South Wales, 2031 Australia
1 The Heart Research Institute 145 Missenden Road, Camperdown, Sydney, New South Wales, 2050 Australia
*To whom correspondence should be addressed at: Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales, 2006 Australia. Tel: +61-2-9036-6548; Fax: +61-2-9036-6549; Email: d.richardson{at}pathology.usyd.edu.au
Melanotransferrin (MTf) or melanoma tumor antigen p97 is an iron (Fe) binding transferrin homolog expressed highly on melanomas and at lower levels on normal tissues. It has been suggested that MTf is involved in a variety of processes such as Fe metabolism and cellular differentiation. Considering the crucial role of Fe in many metabolic pathways, for example, DNA synthesis, it is important to understand the function of MTf. To define the roles of MTf, two models were developed: (i) an MTf knockout (MTf–/–) mouse and (ii) downregulation of MTf expression in melanoma cells by post-transcriptional gene silencing (PTGS). Examination of the MTf–/– mice demonstrated no differences compared with wild-type littermates. However, microarray analysis showed differential expression of molecules involved in proliferation such as Mef2a, Tcf4, Gls and Apod in MTf–/– mice compared with MTf+/+ littermates. Considering the role of MTf in melanoma cells, PTGS was used to downregulate MTf mRNA and protein levels by >90 and >80%, respectively. This resulted in inhibition of proliferation and migration. As found in MTf–/– mice, in melanoma cells with suppressed MTf expression, hMEF2A and hTCF4 were upregulated compared with parental cells. Furthermore, when melanoma cells with decreased MTf expression were injected into nude mice, tumor growth was markedly reduced, suggesting a role for MTf in proliferation and tumorigenesis.
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