Haber M, Bordow S B, Gilbert J, Madafiglio J, Kavallaris M, Marshall G M, Mechetner E B, Fruehauf J P, Tee L, Cohn S L, Salwen H, Schmidt M L, Norris M D
Children's Cancer Research Institute, Sydney Children's Hospital, Australia.
Oncogene. 1999 Apr 29;18(17):2777-82. doi: 10.1038/sj.onc.1202859.
We have recently shown a close correlation between expression of the Multidrug Resistance-associated Protein (MRP) gene and the MYCN oncogene and provided evidence that high MRP expression is a powerful independent predictor of poor outcome in neuroblastoma (Norris et al., New Engl. J. Med., 334, 231-238, 1996). The effect of MYCN down-regulation on MRP expression and response to cytotoxic drugs was investigated in NBL-S neuroblastoma cells transfected with MYCN antisense RNA constructs. Concomitant with MYCN down-regulation, the level of MRP expression was decreased in the NBAS-4 and NBAS-5 antisense transfectants. These cells demonstrated significantly increased sensitivity to the high affinity MRP substrates vincristine, doxorubicin, sodium arsenate and potassium antimony tartrate, but not to the poor MRP substrates, taxol or cisplatin. Similarly, transfection of full-length MYCN cDNA into SH-EP neuroblastoma cells resulted in increased MRP expression and significantly increased resistance specifically to MRP substrates. The results provide evidence for the MYCN oncogene influencing cytotoxic drug response via regulation of MRP gene expression. Our data also provide a link between the malignant and chemoresistant phenotypes of this childhood malignancy.
我们最近发现多药耐药相关蛋白（MRP）基因的表达与MYCN癌基因之间存在密切关联，并提供证据表明高MRP表达是神经母细胞瘤预后不良的有力独立预测指标（Norris等人，《新英格兰医学杂志》，334, 231 - 238, 1996）。在用MYCN反义RNA构建体转染的NBL - S神经母细胞瘤细胞中，研究了MYCN下调对MRP表达和细胞毒性药物反应的影响。与MYCN下调同时发生的是，NBAS - 4和NBAS - 5反义转染细胞中MRP表达水平降低。这些细胞对高亲和力MRP底物长春新碱、阿霉素、砷酸钠和酒石酸锑钾的敏感性显著增加，但对差的MRP底物紫杉醇或顺铂不敏感。同样，将全长MYCN cDNA转染到SH - EP神经母细胞瘤细胞中导致MRP表达增加，并且对MRP底物的抗性显著增加。这些结果为MYCN癌基因通过调节MRP基因表达影响细胞毒性药物反应提供了证据。我们的数据还在这种儿童恶性肿瘤的恶性和化疗耐药表型之间建立了联系。
