Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Semin Cancer Biol. 2011 Oct;21(4):256-66. doi: 10.1016/j.semcancer.2011.08.001. Epub 2011 Aug 9.
Childhood neuroblastoma exhibits a heterogeneous clinical behavior ranging from low-risk tumors with the ability to spontaneously differentiate and regress, to high-risk tumors causing the highest number of cancer related deaths in infants. Amplification of the MYCN oncogene is one of the few prediction markers for adverse outcome. This gene encodes the MYCN transcriptional regulator predominantly expressed in the developing peripheral neural crest. MYCN is vital for proliferation, migration and stem cell homeostasis while decreased levels are associated with terminal neuronal differentiation. Interestingly, high-risk tumors without MYCN amplification frequently display increased c-MYC expression and/or activation of MYC signaling pathways. On the other hand, downregulation of MYCN leads to decreased proliferation and differentiation, emphasizing the importance of MYC signaling in neuroblastoma biology. Furthermore, expression of the neurotrophin receptor TrkA is associated with good prognosis, the ability to differentiate and spontaneous regression while expression of the related TrkB receptor is correlated with bad prognosis and MYCN amplification. Here we discuss the role of MYCN in neuroblastoma with a special focus on the contribution of elevated MYCN signaling for an aggressive and undifferentiated phenotype as well as the potential of using MYCN as a therapeutic target.
儿童神经母细胞瘤表现出异质性的临床行为，从具有自发分化和消退能力的低风险肿瘤到导致婴儿癌症相关死亡人数最多的高风险肿瘤。MYCN 癌基因扩增是少数不良预后的预测标志物之一。该基因编码 MYCN 转录调节剂，主要在发育中的周围神经嵴中表达。MYCN 对于增殖、迁移和干细胞稳态至关重要，而水平降低则与终末神经元分化有关。有趣的是，没有 MYCN 扩增的高危肿瘤经常显示出 c-MYC 表达增加和/或 MYC 信号通路的激活。另一方面，MYCN 的下调导致增殖和分化减少，强调了 MYC 信号在神经母细胞瘤生物学中的重要性。此外，神经营养因子受体 TrkA 的表达与良好的预后、分化和自发消退能力相关，而相关的 TrkB 受体的表达与不良预后和 MYCN 扩增相关。在这里，我们讨论了 MYCN 在神经母细胞瘤中的作用，特别关注升高的 MYCN 信号对侵袭性和未分化表型的贡献，以及将 MYCN 用作治疗靶点的潜力。
