Nucleoside diphosphate kinase A/nm23-H1 promotes metastasis of NB69-derived human neuroblastoma.
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.
Department of Medicine, University of California at San Diego, 4028 Basic Science Building, 9500 Gilman Drive, La Jolla, CA 92093-0688, USA.
Malin A E
MA
Almgren
K Cecilia E
KC
Henriksson
Jennifer
J
Fujimoto
Christina L
CL
Chang
D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D054778:NM23 Nucleoside Diphosphate Kinases; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D054778:NM23 Nucleoside Diphosphate Kinases; C517938:NME1 protein, human; C517939:Nme1 protein, mouse; D009701:Nucleoside-Diphosphate Kinase