Ribeiro Diogo, Klarqvist Marcus D R, Westermark Ulrica K, Oliynyk Ganna, Dzieran Johanna, Kock Anna, Savatier Banares Carolina, Hertwig Falk, Johnsen John Inge, Fischer Matthias, Kogner Per, Lovén Jakob, Arsenian Henriksson Marie
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
Cell Rep. 2016 Jul 26;16(4):979-993. doi: 10.1016/j.celrep.2016.06.052. Epub 2016 Jul 7.
MYCN amplification and MYC signaling are associated with high-risk neuroblastoma with poor prognosis. Treating these tumors remains challenging, although therapeutic approaches stimulating differentiation have generated considerable interest. We have previously shown that the MYCN-regulated miR-17∼92 cluster inhibits neuroblastoma differentiation by repressing estrogen receptor alpha. Here, we demonstrate that this microRNA (miRNA) cluster selectively targets several members of the nuclear hormone receptor (NHR) superfamily, and we present a unique NHR signature associated with the survival of neuroblastoma patients. We found that suppressing glucocorticoid receptor (GR) expression in MYCN-driven patient and mouse tumors was associated with an undifferentiated phenotype and decreased survival. Importantly, MYCN inhibition and subsequent reactivation of GR signaling promotes neural differentiation and reduces tumor burden. Our findings reveal a key role for the miR-17∼92-regulated NHRs in neuroblastoma biology, thereby providing a potential differentiation approach for treating neuroblastoma patients.
MYCN基因扩增和MYC信号传导与预后不良的高危神经母细胞瘤相关。尽管刺激分化的治疗方法已引起广泛关注，但治疗这些肿瘤仍然具有挑战性。我们之前已经表明，MYCN调控的miR-17∼92簇通过抑制雌激素受体α来抑制神经母细胞瘤的分化。在此，我们证明该微小RNA（miRNA）簇选择性靶向核激素受体（NHR）超家族的几个成员，并呈现出与神经母细胞瘤患者生存相关的独特NHR特征。我们发现，在MYCN驱动的患者肿瘤和小鼠肿瘤中抑制糖皮质激素受体（GR）表达与未分化表型和生存率降低相关。重要的是，抑制MYCN并随后重新激活GR信号传导可促进神经分化并减轻肿瘤负担。我们的数据揭示了miR-17∼92调控的NHR在神经母细胞瘤生物学中的关键作用，从而为治疗神经母细胞瘤患者提供了一种潜在的分化方法。
