Nucleoside diphosphate kinase A/nm23-H1 promotes metastasis of NB69-derived human neuroblastoma.
Nucleoside diphosphate kinase A/nm23-H1 promotes metastasis of NB69-derived human neuroblastoma.
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DOI：
10.1158/1541-7786.387.2.7
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发表时间：
2004-07
期刊：
影响因子：
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通讯作者：
Malin A. E. Almgren;K. Henriksson;J. Fujimoto;C. Chang
中科院分区：
文献类型：
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作者：
Malin A. E. Almgren;K. Henriksson;J. Fujimoto;C. Chang
核苷二磷酸激酶A （NDPK-A）由nm23-H1基因编码，在某些人类肿瘤（如乳腺癌）中起转移抑制作用。然而，也有证据表明NDPK-A在包括神经母细胞瘤在内的其他人类肿瘤中作为转移启动子起作用。事实上，在14% - 30%的晚期神经母细胞瘤患者中已经检测到nm23-H1和NDPK-A的S120G突变（NDPK-A(S120G)）的扩增和过表达。为了验证NDPK-A是否促进神经母细胞瘤的转移，我们建立了稳定的转染剂和人神经母细胞瘤NB69细胞系的原位异种移植动物模型。我们证明，过表达的NDPK-A或NDPK-A（S120G）增加了动物肺中神经母细胞瘤转移的发生率和定植，但对原发肿瘤的发展没有显著影响。在体外，这些与转移相关的NDPK-A畸变消除了视黄酸诱导的神经元分化，同时提高了NB69衍生物的克隆效率、细胞存活率和集落形成。此外，NDPK-A（S120G）降低了细胞粘附，增加了细胞迁移。与野生型相比，NDPK-A（S120G）在促进神经母细胞瘤转移方面更有效。我们的研究结果首次证明NDPK-A至少在源自NB69细胞的人神经母细胞瘤中起转移促进作用。研究结果不仅提示NDPK-A在神经母细胞瘤患者中的预后价值，也提示针对不同肿瘤类型的患者进行NDPK-A靶向治疗。
Nucleoside diphosphate kinase A (NDPK-A), encoded by the nm23-H1 gene, acts as a metastasis suppressor in certain human tumors such as breast carcinoma. However, evidence also points to NDPK-A functioning as a metastasis promoter in other human tumors including neuroblastoma. In fact, amplification and overexpression of nm23-H1 as well as S120G mutation of NDPK-A (NDPK-A(S120G)) have been detected in 14% to 30% of patients with advanced stages of neuroblastoma. To test whether NDPK-A promotes neuroblastoma metastasis, we established stable transfectants and an orthotopic xenograft animal model from the human neuroblastoma NB69 cell line. We demonstrate that overexpressed NDPK-A or NDPK-A(S120G) increased both incidence and colonization of neuroblastoma metastasis in animal lungs without significantly affecting primary tumor development. In vitro, these metastasis-associated NDPK-A aberrations abrogated retinoic acid-induced neuronal differentiation while increasing cloning efficiency, cell survival, and colony formation of NB69 derivatives. Furthermore, NDPK-A(S120G) reduced cell adhesion and increased cell migration. Compared with its wild-type, NDPK-A(S120G) appears more effective in promoting neuroblastoma metastasis. Our results provide the first evidence that NDPK-A behaves as a metastasis promoter at least in human neuroblastoma derived from NB69 cells. The findings not only suggest a prognostic value of NDPK-A in neuroblastoma patients but also caution NDPK-A-targeted treatment for patients with different tumor types.