Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.
Sci Rep. 2013;3:1351. doi: 10.1038/srep01351.
Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.
Nm23-H1 是神经母细胞瘤发病机制中具有重要作用的候选基因之一。H-Prune 是最具特征性的 Nm23-H1 结合伴侣，其过表达已在不同的人类癌症中得到证实。我们的研究集中在 Nm23-H1/h-Prune 蛋白复合物在神经母细胞瘤中的作用。我们使用 NMR 光谱法对 h-Prune C 端进行构象分析，以确定与 Nm23-H1 相互作用的氨基酸。我们开发了一种竞争性渗透肽 (CPP) 来破坏 Nm23-H1/h-Prune 复合物的形成，并证明 CPP 导致细胞迁移能力受损、肿瘤生长和转移形成的实质性受损。对三个神经母细胞瘤队列进行的荟萃分析显示，Nm23-H1 是与神经母细胞瘤侵袭性高度相关的基因。我们还鉴定了另外两种表达水平受 CPP 显著影响的蛋白质（PTPRA 和 TRIM22）。这些数据为 CPP 在神经母细胞瘤治疗中的潜在临床应用提供了新的途径。
