Robinson Samantha J, Healy Eugene
Dermatopharmacology, University of Southampton, Southampton General Hospital, UK.
Oncogene. 2002 Nov 14;21(52):8037-46. doi: 10.1038/sj.onc.1205913.
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 (alphaMSH, the ligand for MC1R), therefore MC1R variants could alter the autocrine effects of alphaMSH 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, alphaMSH 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, alphaMSH 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 alphaMSH in the wild type transfectants whereas this was not observed in the variant transfected clones; binding to laminin was not affected by alphaMSH 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.
色素沉着是个体对皮肤黑色素瘤易感性的一个重要决定因素，皮肤白皙的个体患这种肿瘤的风险最高。黑皮质素1受体（MC1R）基因变异会改变体内色素合成，并与人类的红发和白皙皮肤存在因果关系。MC1R变异在黑色素瘤患者中更为常见，并增加了散发性和家族性病例中患这种肿瘤的风险。MC1R变异可能由于皮肤色素沉着的改变（对紫外线辐射的防护较少）而导致黑色素瘤易感性增加。然而，黑色素瘤细胞会合成并释放α-黑素细胞刺激素（αMSH，MC1R的配体），因此MC1R变异可能会改变αMSH对黑色素瘤细胞行为的自分泌作用，从而通过非色素相关机制影响黑色素瘤的早期发生和进展。在Mc1r功能缺失的B16G4F黑色素瘤细胞中，稳定转染野生型和变异型（Arg151Cys、Arg160Trp和Asp294His）人类MC1R。在每个细胞的MC1受体数量相似的情况下，αMSH可增加野生型MC1R转染的黑色素瘤细胞内的环磷酸腺苷（cAMP），但在变异型MC1R转染的克隆中，cAMP反应受损。在生长抑制实验中，αMSH显著降低了野生型MC1R转染细胞的生长，但对变异型MC1R转染的细胞没有影响。此外，αMSH使野生型转染细胞与纤连蛋白的结合显著减少，而在变异型转染克隆中未观察到这种现象；在该细胞系中，αMSH对与层粘连蛋白的结合没有影响。这些结果为MC1R变异导致的黑色素瘤细胞行为差异提供了证据，并提示了一种替代的非色素相关机制，通过该机制MC1R变异可能会改变黑色素瘤的易感性或进展。
