Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota.
Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York.
Cancer Res. 2021 Jun 1;81(11):2995-3007. doi: 10.1158/0008-5472.CAN-20-1890. Epub 2021 Feb 18.
One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the oncogene. However, only a limited number of regulatory proteins that contribute to this complex -mediated process have been elucidated. Here we show that the () gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. expression was also suppressed in -amplified neuroblastoma lacking 17p deletion. deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of . Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with overexpression identified that deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of overexpression. SIGNIFICANCE: Heterozygous deletion or -mediated repression of in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma..
神经母细胞瘤治愈治疗的最大障碍之一是其在诊断前经常发生转移性生长，特别是在由癌基因扩增驱动的情况下。然而，只有少数调节蛋白已被阐明有助于这一复杂的中介过程。在这里，我们表明，位于染色体 17p13.1 带的（）基因在高风险 MYCN 驱动的神经母细胞瘤中优先缺失。在缺乏 17p 缺失的扩增神经母细胞瘤中，也抑制了的表达。在过表达或扩增的神经母细胞瘤的斑马鱼和哺乳动物模型中，缺陷导致转移加速。对过表达的斑马鱼神经母细胞瘤肿瘤的表达谱和超微结构的分析表明，缺陷导致（i）参与细胞-细胞相互作用的基因下调，（ii）肿瘤细胞之间接触的丧失，这是加速转移的关键决定因素，以及（iii）MYCN 蛋白水平升高。这些结果提供了第一个遗传证据，表明在过表达的情况下， 耗竭是导致神经母细胞瘤转移的级联事件中的一个关键早期步骤。意义：神经母细胞瘤中杂合缺失或 -介导的 抑制释放了肿瘤细胞分散和迁移到远处部位的重要制动器，为 MYCN 驱动的神经母细胞瘤中的肿瘤转移提供了一种新的机制。
