Lau Diana T, Flemming Claudia L, Gherardi Samuele, Perini Giovanni, Oberthuer André, Fischer Matthias, Juraeva Dilafruz, Brors Benedikt, Xue Chengyuan, Norris Murray D, Marshall Glenn M, Haber Michelle, Fletcher Jamie I, Ashton Lesley J
Children's Cancer Institute Australia, Lowy Cancer Research Centre, Randwick, NSW, Australia.
Department of Biology, University of Bologna, Bologna, Italy.
Oncotarget. 2015 Jun 20;6(17):15510-23. doi: 10.18632/oncotarget.3732.
MYCN amplification occurs in 20% of neuroblastomas and is strongly related to poor clinical outcome. We have identified folate-mediated one-carbon metabolism as highly upregulated in neuroblastoma tumors with MYCN amplification and have validated this finding experimentally by showing that MYCN amplified neuroblastoma cell lines have a higher requirement for folate and are significantly more sensitive to the antifolate methotrexate than cell lines without MYCN amplification. We have demonstrated that methotrexate uptake in neuroblastoma cells is mediated principally by the reduced folate carrier (RFC; SLC19A1), that SLC19A1 and MYCN expression are highly correlated in both patient tumors and cell lines, and that SLC19A1 is a direct transcriptional target of N-Myc. Finally, we assessed the relationship between SLC19A1 expression and patient survival in two independent primary tumor cohorts and found that SLC19A1 expression was associated with increased risk of relapse or death, and that SLC19A1 expression retained prognostic significance independent of age, disease stage and MYCN amplification. This study adds upregulation of folate-mediated one-carbon metabolism to the known consequences of MYCN amplification, and suggests that this pathway might be targeted in poor outcome tumors with MYCN amplification and high SLC19A1 expression.
MYCN基因扩增在20%的神经母细胞瘤中出现，且与不良临床预后密切相关。我们发现，在发生MYCN基因扩增的神经母细胞瘤肿瘤中，叶酸介导的一碳代谢高度上调，并通过实验验证了这一发现，即MYCN基因扩增的神经母细胞瘤细胞系对叶酸的需求更高，且与无MYCN基因扩增的细胞系相比，对抗叶酸药物甲氨蝶呤更为敏感。我们已经证明，神经母细胞瘤细胞对甲氨蝶呤的摄取主要由还原型叶酸载体（RFC；SLC19A1）介导，在患者肿瘤和细胞系中，SLC19A1与MYCN的表达高度相关，且SLC19A1是N-Myc的直接转录靶点。最后，我们在两个独立的原发性肿瘤队列中评估了SLC19A1表达与患者生存之间的关系，发现SLC19A1表达与复发或死亡风险增加相关，且SLC19A1表达具有独立于年龄、疾病分期和MYCN基因扩增的预后意义。本研究将叶酸介导的一碳代谢上调添加到MYCN基因扩增的已知后果中，并表明该途径可能是MYCN基因扩增且SLC19A1高表达的预后不良肿瘤的靶向目标。
