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Functional role of MIA in melanocytes and early development of melanoma

Oncogene volume 23, pages 6115–6124 (2004)Cite this article

Abstract

The protein MIA (melanoma inhibitory activity) is highly expressed in malignant melanomas but not in melanocytes. Furthermore, expression of MIA correlates with tumor progression in vivo. Here, MIA-dependent changes of gene expression after long-term inhibition of MIA expression in the human melanoma cell line HMB2 were investigated. Primarily, we observed characteristic changes in cell morphology, and also found re-established cell–cell contacts in MIA-deficient cell clones grown in monolayer culture. Real-time reverse transcription–polymerase chain reaction (RT–PCR) showed a downregulation of N-cadherin expression and a reinduction of E-cadherin expression in the MIA-deficient cell clones. Further, both cancer cDNA array and protein arrays verified a marked downregulation of several other melanoma-associated genes (e.g. membrane-type 1 matrix metalloproteinase tissue-type plasminogen activator integrin β3, secreted protein acidic and rich in cysteins and fibronectin) in the MIA-deficient melanoma cells, confirmed by real-time RT–PCR and Western blotting. As all these molecules are associated with migration, the effect of MIA on migration of human primary melanocytes was analysed. In the presence of MIA, we observed enhanced migratory ability of melanocytic cells, induction of melanoma-associated genes as well as inhibition of apoptosis due to anoikis. These results suggest that expression of MIA promotes melanoma progression by inducing further melanoma-associated genes.

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Abbreviations

Apaf-1:

apoptotic protease activating factor 1

BSA:

bovine serum albumin

DMEM:

Dulbecco's modified Eagle medium

dNTP's:

deoxynucleoside triphosphates

DTT:

dithiothreitol

E2F-1:

E2F transcription factor 1

EDTA:

ethylenediaminetetraacetic acid

ELISA:

enzyme-linked immunosorbant assay

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

INR:

internally normalized ratio

MGM-3:

melanocyte growth medium no. 3

MIA:

melanoma inhibitory activity

MT1-MMP:

membrane-type 1 matrix metalloproteinase

NBT/BCIP:

nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl phoshate

NMR:

nuclear magnetic resonance

ns:

non specific

PBS:

phosphate-buffered saline

PHM:

primary human melanocytes

PVDF:

polyvenylidene fluoride

RIPA:

radioimmunoprecipitation assay buffer

rMIA:

recombinant MIA protein

RT–PCR:

reverse transcription–polymerase chain reaction

SDS-PAGE:

sodium dodecyl sulfate–polyacrylamide gel

SPARC:

secreted protein acidic and rich in cysteins

t-PA:

tissue-type plasminogen activator

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Acknowledgements

We are indebted to Claudia Abschlag, Jacqueline Schlegel, Astrid Fuβ and Kalle Guenther for technical assistance. This work was supported by grants from the Wilhelm Sander Foundation and the Deutsche Krebshilfe to AB.

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  1. Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, D-93053, Germany

    Ina Poser, Jutta Tatzel, Silke Kuphal & Anja K Bosserhoff

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  1. Ina Poser
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Correspondence to Anja K Bosserhoff.

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Poser, I., Tatzel, J., Kuphal, S. et al. Functional role of MIA in melanocytes and early development of melanoma. Oncogene 23, 6115–6124 (2004). https://doi.org/10.1038/sj.onc.1207797

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