Abstract
Pigmentation is a significant determinant of individual susceptibility to cutaneous melanoma, with fair skinned subjects at highest risk of developing this neoplasm. Melanocortin 1 receptor (MC1R) gene variants alter pigment synthesis in vivo, and are causally associated with red hair and fair skin in humans. MC1R variants are more frequent in subjects with melanoma, and increase the risk of developing this tumour in sporadic and familial cases. MC1R variants may predispose to melanoma as a result of alterations in skin pigmentation (which affords less protection against incident ultraviolet radiation). However, melanoma cells synthesize and release alpha-melanocyte stimulating hormone (αMSH, the ligand for MC1R), therefore MC1R variants could alter the autocrine effects of αMSH on melanoma cell behaviour, thereby affecting early melanoma development and progression via non-pigmentary mechanisms. B16G4F melanoma cells, which are functionally null at Mc1r, were stably transfected with wild type and variant (Arg151Cys, Arg160Trp, and Asp294His) human MC1R. At similar MC1 receptor numbers per cell, αMSH increased intracellular cAMP in wild type MC1R transfected melanoma cells, but the cAMP response was compromised in the variant MC1R transfected clones. In growth inhibition experiments, αMSH significantly reduced growth of wild type MC1R transfected cells, but had no effect on cells transfected with variant MC1R. In addition, binding to fibronectin was significantly reduced by αMSH in the wild type transfectants whereas this was not observed in the variant transfected clones; binding to laminin was not affected by αMSH in this cell line. These results provide evidence for differences in melanoma cell behaviour secondary to MC1R variants, and suggest an alternative non-pigmentary mechanism whereby MC1R variants could modify melanoma susceptibility or progression.
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Acknowledgements
We are grateful to A Eberle for providing the B16G4F cell line, to S Phillips and JL Rees for providing the original pCR3.1 plasmids with wild type and variant MC1R, and to P Friedmann and LM Holden-Dye for helpful advice. The work was supported by grants from the Medical Research Council, the Wessex Medical Trust (HOPE), and the British Medical Association. E Healy is a Medical Research Council Senior Clinical Fellow.
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Robinson, S., Healy, E. Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix. Oncogene 21, 8037–8046 (2002). https://doi.org/10.1038/sj.onc.1205913
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DOI: https://doi.org/10.1038/sj.onc.1205913
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