Abstract
NDPK-A, encoded by nm23-H1 (also known as NME1) was the first metastasis suppressor discovered. Much of the attention has been focused on the metastasis-suppressing role of NDPK-A in human tumors, including breast carcinoma and melanoma. However, compelling evidence points to a metastasis-promoting role of NDPK-A in certain tumors such as neuroblastoma and lymphoma. To balance attention on this contrariety of NDPK-A in different cancer types, this review addresses the metastasis-promoting role of NDPK-A in neuroblastoma. Neuroblastoma is an embryonic tumor, arising from neural crest cells that fail to differentiate into the sympathetic nervous system. We summarize and discuss nm23-H1 genetics and the prognosis of neuroblastoma, structural and functional changes associated with the S120G mutation of NDPK-A, as well as the evidence supporting the role of NDPK-A as a metastasis promoter. Also discussed are the NDPK-A relevant molecular determinants of neuroblastoma metastasis, and metastasis-relevant neural crest development. Because of NDPK-A’s dichotomous role in tumor metastasis as both a suppressor and a promoter, tumor genome/exome profiles are necessary to identify the molecular drivers of metastasis in the NDPK-A network for developing tumor-specific therapies.
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Metastasis remains as the major cause of death in cancer patients, accounting for ~90% of cancer mortality. To metastasize, tumor cells need to successfully complete every step in the metastatic cascade, including detachment from the primary tumor, migration and invasion to local tissues, survival in the circulatory and lymphatic systems, and colonization at a distal organ(s) of the human body.
The tumor metastasis field has greatly advanced since the discovery, three decades ago, of the first metastasis suppressor gene, nm23-H1 (also known as NME1).1 The nm23-H1 gene encodes nucleoside diphosphate kinase A (NDPK-A, also termed as NM23-H1 and NME1),2 which belongs to the human NDPK family, currently consisting of ten members. Much of the attention has focused on the metastasis-suppressing role of NDPK-A in human tumors including breast carcinoma and melanoma. However, compelling evidence points to an opposite role for NDPK-A as a metastasis promoter in certain tumor types, such as neuroblastoma and lymphoma. To clarify this dichotomous trait of NDPK-A, this review will address the metastasis-promoting role of NDPK-A in neuroblastoma.
THE CLINICAL RELEVANCE OF NDPK-A TO TUMOR METASTATSIS
After a seminal report by Steeg et al,1 the clinical relevance of NDPK-A in tumor metastasis has been extensively studied. Results from most of these studies are summarized in Tables 1 and 2. A negative correlation between the protein and/or RNA levels of NDPK-A and metastatic potential is displayed by many cancer types, including breast, head and neck, liver and ovarian cancers (Tables 1 and 2). This negative correlation suggests a metastasis-suppressing role for NDPK-A (see the review by Steeg in this issue). For colorectal, gastric and lung cancers, however, the role of NDPK-A in tumor metastasis remains uncertain because of contradictory correlations (Tables 1 and 2). Conversely, a positive correlation between the protein and/or RNA levels of NDPK-A and metastatic potential occurs in neuroblastoma and lymphoma, suggesting a metastasis-promoting role of NDPK-A (Tables 1 and 2).
The dichotomous role of NDPK-A in tumor metastasis is likely due to the unique genetic makeup of different human cancer types. In addition to the different molecules and pathways affected, pediatric tumors such as neuroblastoma generally contain fewer mutations than adult tumors such as breast carcinoma, which display 10–20 and 25–130 non-synonymous mutations per tumor, respectively.3, 4 To address this contrariety of NDPK-A, we focus on its metastasis-promoting role in neuroblastoma by starting with the nm23-H1 genetics unique to this disease.
NM23-H1 GENETICS AND PROGNOSIS OF NEUROBLASTOMA
Neuroblastoma is the most common extracranial tumor of early childhood, accounting for 7% of all pediatric cancers.5 Neuroblastoma arises from multipotent neural crest cells that fail to differentiate into the sympathetic nervous system.6 Based on the International Neuroblastoma Staging System (INSS), limited stages (1 and 2) and advanced stages (3 and 4) of neuroblastoma are referred to as localized and metastatic tumors, respectively.7 The long-term survival rate for advanced stages of neuroblastoma patients is 40–50%.5
The genetics of nm23-H1 in neuroblastoma is more complicated than that in other tumors. An increased nm23-H1 copy number has been reported in 14% (13 of 95) to 23% (7 of 31) of neuroblastoma patients.8, 9 The nm23-H1 gene is mapped to chromosome 17q21.3.10 An increased nm23-H1 copy number therefore could be due to the gain of a chromosomal segment, 17q21-qter, which occurs in 54–65% of neuroblastoma patients and is associated with poor clinical outcomes.11, 12, 13
In addition to an increased gene copy number, high levels of nm23-H1 RNA and/or NDPK-A protein also occur in advanced neuroblastomas, and which are associated with poor prognosis.8, 9, 14, 15, 16 A high level of NDPK-A can occur in advanced neuroblastomas with or without MYCN amplification.14 MYCN amplification is a frequent genetic alteration, occurring in ~20% of patients with advanced neuroblastoma.6 The ability of MYCN to upregulate nm23-H1 expression17 can contribute to a high NDPK-A level in this subset of neuroblastomas. Intriguingly, neuroblastoma patients with MYCN amplification display a higher serum NDPK-A level than those without MYCN amplification.18 Serum NDPK-A suggests a secreted form, similar to that reported in myeloid leukemia.19
Although nm23-H1 mutations are rare, a serine 120→glycine (S120G) mutation of NDPK-A has been reported in 21% (6 of 28) of advanced neuroblastomas, but not in any of 22 limited-stage tumors.20 This S120G mutation appears to be specific to neuroblastoma as it was not detected in 26 breast carcinoma patients nor in 17 patients with acute leukemia.20 This mutation can be inherited or occur somatically, and also can occur with or without nm23-H1 amplification (3–10 copies).20 Moreover, the S120G mutation of NDPK-A can arise in advanced neuroblastomas with or without MYCN amplification.20 This genetic heterogeneity likely complicates the interpretation of NDPK-A’s role in tumor metastasis.
On the basis of a differential expression of genes between favorable and unfavorable (ie, advanced) neuroblastomas, NME1 (also known as nm23-H1), CHD5 and PAFAH1B1 genes are proposed as a prognostic signature for risk stratification of neuroblastoma patients.21
NDPK-A OR NDPK-AS120G ENHANCES NEUROBLASTOMA CELL INVASIVENESS
Metastasis-associated cellular processes include decreased cell adhesion as well as increased cell survival, migration, invasion, and colonization. For simplicity here, these cellular processes are collectively termed cell invasiveness. It is noteworthy that cell proliferation and death are generally considered as tumorigenesis- and not metastasis-associated processes.
For NDPK-A to be a bona fide metastasis promoter in neuroblastoma, it is expected to increase the invasiveness but not the proliferation of neuroblastoma cells. This is indeed the case for human neuroblastoma NB69 cells that express ectopic NDPK-A or NDPK-AS120G.22 NDPK-A or NDPK-AS120G readily increases the invasiveness of NB69 cells, as measured by serum-independent survival, cloning efficiency, cell migration, and colony formation on soft agar.22 On the other hand, ectopically expressed NDPK-A or NDPK-AS120G does not affect the proliferation of NB69 cells under normal growth conditions.22 A similar migration-enhancing effect of NDPK-A or NDPK-AS120G is also observed in another human neuroblastoma cell line, SH-SY5Y (unpublished data). These two neuroblastoma cell lines do not exhibit MYCN amplification, which therefore excludes the possibility of interference by MYCN in the cell invasiveness-enhancing role of NDPK-A.
Compared with the wild type, ectopically expressed NDPK-AS120G level is lower but more potent in enhancing the invasiveness of NB6922 and SH-SY5Y cells (unpublished data). A lower level of NDPK-AS120G is not due to protein instability because a similar half-life is observed between the mutant and its wild type.23 This indicates that S120G may be a gain-of-function mutation.
A gain-of-function for S120G mutation is further observed in human cancer cell lines, in which NDPK-A behaves as a metastasis suppressor. NDPK-AS120G increases, whereas the wild type inhibits, the migration of human breast cancer MDA-MB-435 cells.24 In human prostate carcinoma DU145 cells, the S120G mutation abrogates the ability of NDPK-A to inhibit cell colonization and invasion.25 It seems reasonable to speculate that the genetic background unique to neuroblastoma, breast, and prostate carcinomas might dictate the role of wild-type NDPK-A in cell invasiveness. However, an apparent gain-of-function of S120G mutation renders NDPK-A with a better ability to enhance cell invasiveness regardless of tumor origins.
NDPK-A OR NDPK-AS120G PROMOTES NEUROBLASTOMA METASTASIS
Approximately 50% of human neuroblastomas originate from the adrenal gland,26 which serves as an ideal orthotopic site for a xenograft animal model of neuroblastoma metastasis. A fluorescent orthotopic xenograft model developed in SCID mice not only recapitulates human neuroblastoma, but also allows sensitive detection of GFP-labeled primary and metastatic tumors in mice.27 In this orthotopic xenograft model, NDPK-A- or NDPK-AS120G-expressing NB69 cells increase both the incidence and colonization of neuroblastoma metastasis in animal lungs without significantly affecting primary tumor development.22 Compared with the wild-type, NDPK-AS120G is more effective in promoting neuroblastoma metastasis in mice, consistent with their abilities in cell invasiveness.22 The lymphatic system appears to be one route for neuroblastoma cell dissemination because of accumulation of GFP-labeled NB69 cells in the inguinal lymph node of xenograft mice.27
As the xenograft mouse model is difficult to use for monitoring the behaviors of moving tumor cells, a xenograft zebrafish model has been developed, which is able to show that NDPK-A or NDPK-AS120G enhances the ability of NB69 cells to extravasate the fish tail vein (unpublished data). The extravasation-enhancing ability in xenograft zebrafish is consistent with the metastasis-promoting ability of NDPK-A or NDPK-AS120G in xenograft mice.22 Extravasation is essential for migrating tumor cells to gain access to other organs, an end point that is difficult to measure in the xenograft mouse model. Because of economic, physiological, and real-time observational advantages of zebrafish, this xenograft model will facilitate mechanistic and therapeutic studies of extravasation regulated by NDPK-A.
STRUCTURAL AND FUNCTIONAL CHANGES OF NDPK-AS120G
The molecular mechanism by which NDPK-A or NDPK-AS120G contributes to neuroblastoma metastasis remains unknown. Nevertheless, this mechanism is likely associated with S120G-associated structural and functional changes. Phosphotransferase activity is a well-established function of NDPK, including NDPK-A.28 Histidine 118 (H118) is an active site, and the H118-phosphorylated intermediate is essential for the transfer of the terminal phosphate from a triphosphate nucleotide (eg, ATP) to a diphosphate nucleotide (eg, UDP) via a 'ping-pong' mechanism.28, 29
Among all the NDPK family members from different organisms, the S120 residue is highly conserved. The NDPK-AS120G recombinant protein displays ~50% lower phosphotransferase activity than the wild-type recombinant protein in vitro.23 The same mutation when introduced to NDPK of D ictyostelium discoideum results in an 80% loss of the activity.30 The reduction of NDPK-AS120G activity is caused by the instability of its phosphorylated intermediate, as there are no defects in the phosphate incorporation of the H118 residue nor in the phosphate transfer from NDPK-AS120G to UDP.23 In human neuroblastoma tissues, a decrease in the phosphotransferase activity of NDPK-AS120G apparently is compensated for by other NDPK family members, such as nm23-H2-encoded NDPK-B.23, 31 Therefore, function(s) other than the phosphotransferase activity of NDPK-AS120G likely account for its metastasis-promoting role in neuroblastoma.
All known eukaryotic NDPKs, including NDPK-A, exist in a hexameric quaternary structure via assembling identical dimers.2, 32 However, NDPK-AS120G affects the subunit assembly and results in 17% dimeric structures, which is approximately sixfold higher than the wild type, but only when disulfide bonds are reduced.23 This indicates the susceptibility of the NDPK-AS120G structure to the intracellular redox state. Moreover, NDPK-AS120G reduces its enzyme stability when subjected to heat and urea,23, 33 and exhibits a protein-folding defect.33 This folding defect can be corrected when NDPK-AS120G is phosphorylated by ATP or by phosphoramidate.34 When forming a complex with ADP, no significant structural changes are observed between NDPK-AS120G and the wild-type.35
In addition to affecting the subunit assembly, the S120G mutation changes the interaction of NDPK-A with other cellular proteins. NDPK-AS120G, in contrast to the wild type, interacts with the 28-kDa protein23 but not with PRUNE.36 NDPK-AS120G also appears to indirectly alter protein-protein interaction. For example, the S120G mutation abolishes the ability of NDPK-A to suppress desensitization of the muscarinic potassium current.37 Extracellular recombinant NDPK-AS120G is more efficient than the wild type in supporting the colony formation of undifferentiated human embryonic stem cells.38
NDPK-A-RELEVANT MOLECULAR DETERMINANTS OF NEUROBLASTOMA METASTASIS
For NDPK-A to be a metastasis promoter in neuroblastoma, certain interacting proteins of NDPK-A39 may be the molecular determinants of neuroblastoma metastasis. Data from genome- and exome-wide sequencing studies are useful for identifying these molecular determinants. It has been reported that recurrent mutations affect pathways such as focal adhesions, Rac/Rho, RAS-MAPK, and YAP in advanced and relapsed neuroblastomas.3, 40, 41, 42 Among these pathways, the Rac/Rho pathway is pertinent to the current knowledge of the NDPK-A network.
Rac, Rho, and Cdc42 are well-studied members of the Rho GTPase family, which is a part of the Ras superfamily.43 Rho GTPases regulate cytoskeletal rearrangement, essential for cell migration, invasion, and neuritogenesis,43 and are relevant to neuroblastoma metastasis.
High-frequency recurrent mutations of Tiam1 have been detected in one but not a second study of advanced neuroblastomas due to a low mutation frequency.3, 44 As an interacting protein of NDPK-A,45 Tiam1 functions as a Rac1-specific guanine nucleotide exchange factor46, 47 and participates in neuritogenesis, cell invasiveness, and tumor progression.48 In addition to several genes involved in neuronal growth cone stabilization, Tiam1 and other regulators of the Rac/Rho pathway are also mutated, implicating defects in neuritogenesis.3
Data of chromosomal aberrations in advanced neuroblastoma are also useful for identifying molecules and pathways in the NDPK-A network. The loss of heterozygosity of 1p36 occurs in 23–35% high-risk neuroblastomas.6 One of the genes is located on 1p36 is Cdc42, and its gene product interacts with NDPK-A.49 In MYCN non-amplified neuroblastomas, overexpressed NDPK-A binds to Cdc42 and prevents the induction of neuronal differentiation.50 In advanced neuroblastomas with MYCN amplification, MYCN inhibits neuritogenesis by downregulating Cdc42 expression.50
METASTASIS-RELEVANT NEURAL CREST DEVELOPMENT
Neuroblastoma originates from multipotent neural crest cells committed to the lineage of sympathetic neurons. At the end of the first trimester in humans, neural crest cells are induced to undergo an epithelial-to-mesenchymal transition (EMT), delaminate from the neural tube and migrate through surrounding tissues before arriving at their final destination for terminal differentiation.51 Neural crest development thus shares common mechanisms with tumor metastasis, including EMT, migration, and invasion.52
NDPK-A is highly expressed in the first-trimester placenta in humans, whereas it is downregulated in second- and third-trimester placentas.53 The high level of NDPK-A seen in advanced neuroblastoma indicates deregulation of nm23-H1 expression. If nm23-H1 deregulation occurs during embryogenesis, it will arrest neural crest cells in less differentiated, yet highly migratory and invasive stages, leading to more aggressive neuroblastoma. Ectopically expressed NDPK-A or NDPK-AS120G inhibits neuronal differentiation of NB69 cells upon induction with retinoic acid.22 Such an arrest of the neural crest may occur indirectly via the ability of NDPK-A to bind the c-myc promoter and reduce its transcription (unpublished data), considering that c-Myc is required for neural crest specification.54, 55 Alternatively, NDPK-A-mediated reduction of c-myc transcription possibly increases neuroblastoma metastasis because c-Myc suppresses the metastasis of human breast carcinoma.56
Understanding the developmental functions of NDPK orthologs in different organisms (see review by Ćetković et al in this issue) will clarify the underlying mechanisms of tumor metastasis.
CONCLUDING REMARKS
A prognostic signature, consisting of nm23-H1 and two other genes, has been proposed for risk stratification of neuroblastoma patients. NDPK-A is encoded by nm23-H1 and acts as a metastasis promoter in neuroblastoma (eg, an embryonic tumor), unlike its metastasis-suppressing role found in many adult tumors such as breast and prostate carcinoma. Overexpression and the S120G mutation of NDPK-A, likely driving forces of neuroblastoma metastasis (Figure 1), occur in patients with advanced neuroblastoma. Relative to the wild type, NDPK-AS120G is more effective in promoting cell invasiveness and metastasis of neuroblastoma in vitro and in vivo. NDPK-AS120G appears to be a gain-of-function mutation because it increases, whereas the wild-type suppresses, the invasiveness of breast and prostate carcinoma cells. An apparent gain-of-function of the S120G mutation of NDPK-A is likely caused by a protein-folding defect, which affects its protein-protein interactions.
The molecular mechanism(s) by which NDPK-A promotes neuroblastoma metastasis remains elusive. Future studies will be facilitated by identifying molecules and pathways that are frequently altered in advanced neuroblastoma. Because developmental and metastatic processes share common mechanisms, understanding the functions of NDPK orthologs in neural crest development will shed light on neuroblastoma metastasis.
A promising targeted therapy for neuroblastoma is being developed based on a permeable peptide that disrupts the interaction of NDPK-A and PRUNE (reviewed by Ferrucci et al in this issue). This targeted therapy is, unfortunately, not useful for treating neuroblastoma patients harboring the S120G mutation because there is no interaction between NDPK-AS120G with PRUNE. Frequent disruption of Rho GTPases signaling pathways in advanced neuroblastoma suggests potential therapeutic strategies for preventing neuroblastoma metastasis. Because of NDPK-A’s dichotomous role in tumor metastasis as both a suppressor and a promoter, tumor genome/exome profiles are necessary to identify the molecular drivers of metastasis in the NDPK-A network for developing tumor-specific therapies.
References
Steeg PS, Bevilacqua G, Kopper L et al. Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 1988;80:200–204.
Gilles AM, Presecan E, Vonica A et al. Nucleoside diphosphate kinase from human erythrocytes. Structural characterization of the two polypeptide chains responsible for heterogeneity of the hexameric enzyme. J Biol Chem 1991;266:8784–8789.
Molenaar JJ, Koster J, Zwijnenburg DA et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 2012;483:589–593.
Vogelstein B, Papadopoulos N, Velculescu VE et al. Cancer genome landscapes. Science 2013;339:1546–1558.
Tolbert VP, Coggins GE, Maris JM . Genetic susceptibility to neuroblastoma. Curr Opin Genet Dev 2017;42:81–90.
Cheung NK, Dyer MA . Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer 2013;13:397–411.
Brodeur GM, Seeger RC, Barrett A et al. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 1988;6:1874–1881.
Leone A, Seeger RC, Hong CM et al. Evidence for nm23 RNA overexpression, DNA amplification and mutation in aggressive childhood neuroblastomas. Oncogene 1993;8:855–865.
Takeda O, Handa M, Uehara T et al. An increased NM23H1 copy number may be a poor prognostic factor independent of LOH on 1p in neuroblastomas. Br J Cancer 1996;74:1620–1626.
Lascu I, Deville-Bonne D, Glaser P et al. Equilibrium dissociation and unfolding of nucleoside diphosphate kinase from Dictyostelium discoideum. Role of proline 100 in the stability of the hexameric enzyme. J Biol Chem 1993;268:20268–20275.
Lastowska M, Van Roy N, Bown N et al. Molecular cytogenetic delineation of 17q translocation breakpoints in neuroblastoma cell lines. Genes Chromosomes Cancer 1998;23:116–122.
Abel F, Ejeskar K, Kogner P et al. Gain of chromosome arm 17q is associated with unfavourable prognosis in neuroblastoma, but does not involve mutations in the somatostatin receptor 2(SSTR2) gene at 17q24. Br J Cancer 1999;81:1402–1409.
Bown N, Cotterill S, Lastowska M et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 1999;340:1954–1961.
Hailat N, Keim DR, Melhem RF et al. High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification. J Clin Invest 1991;88:341–345.
Caron H . Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma. Med Pediatr Oncol 1995;24:215–221.
Ohira M, Morohashi A, Inuzuka H et al. Expression profiling and characterization of 4200 genes cloned from primary neuroblastomas: identification of 305 genes differentially expressed between favorable and unfavorable subsets. Oncogene 2003;22:5525–5536.
Godfried MB, Veenstra M, v Sluis P et al. The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. Oncogene 2002;21:2097–2101.
Okabe-Kado J, Kasukabe T, Honma Y et al. Clinical significance of serum NM23-H1 protein in neuroblastoma. Cancer Sci 2005;96:653–660.
Okabe-Kado J, Kasukabe T, Honma Y et al. Identity of a differentiation inhibiting factor for mouse myeloid leukemia cells with NM23/nucleoside diphosphate kinase. Biochem Biophys Res Commun 1992;182:987–994.
Chang CL, Zhu XX, Thoraval DH et al. Nm23-H1 mutation in neuroblastoma. Nature 1994;370:335–336.
Garcia I, Mayol G, Rios J et al. A three-gene expression signature model for risk stratification of patients with neuroblastoma. Clin Cancer Res 2012;18:2012–2023.
Almgren MA, Henriksson KC, Fujimoto J et al. Nucleoside diphosphate kinase A/nm23-H1 promotes metastasis of NB69-derived human neuroblastoma. Mol Cancer Res 2004;2:387–394.
Chang CL, Strahler JR, Thoraval DH et al. A nucleoside diphosphate kinase A (nm23-H1) serine 120—>glycine substitution in advanced stage neuroblastoma affects enzyme stability and alters protein-protein interaction. Oncogene 1996;12:659–667.
MacDonald NJ, Freije JM, Stracke ML et al. Site-directed mutagenesis of nm23-H1. Mutation of proline 96 or serine 120 abrogates its motility inhibitory activity upon transfection into human breast carcinoma cells. J Biol Chem 1996;271:25107–25116.
Kim YI, Park S, Jeoung DI et al. Point mutations affecting the oligomeric structure of Nm23-H1 abrogates its inhibitory activity on colonization and invasion of prostate cancer cells. Biochem Biophys Res Commun 2003;307:281–289.
Brodeur GMS T, Tsuchida Y, Voute PA . Neuroblastoma. Elsevier Science BV: Amsterdam, the Netherlands, 2000.
Henriksson KC, Almgren MA, Thurlow R et al. A fluorescent orthotopic mouse model for reliable measurement and genetic modulation of human neuroblastoma metastasis. Clin Exp Metastasis 2004;21:563–570.
Parks RE Jr, Agarwal RP. Nucleosdie diphosphokinase. In: Boyer PD ed. The Enzymes; vol 8. Acadmic Press: New York, 1973; 307–334.
Lascu I, Gonin P . The catalytic mechanism of nucleoside diphosphate kinases. J Bioenerg Biomembr 2000;32:237–246.
Tepper AD, Dammann H, Bominaar AA et al. Investigation of the active site and the conformational stability of nucleoside diphosphate kinase by site-directed mutagenesis. J Biol Chem 1994;269:32175–32180.
Stahl JA, Leone A, Rosengard AM et al. Identification of a second human nm23 gene, nm23-H2. Cancer Res 1991;51:445–449.
Lascu L, Giartosio A, Ransac S et al. Quaternary structure of nucleoside diphosphate kinases. J Bioenerg Biomembr 2000;32:227–236.
Lascu I, Schaertl S, Wang C et al. A point mutation of human nucleoside diphosphate kinase A found in aggressive neuroblastoma affects protein folding. J Biol Chem 1997;272:15599–15602.
Mocan I, Georgescauld F, Gonin P et al. Protein phosphorylation corrects the folding defect of the neuroblastoma (S120G) mutant of human nucleoside diphosphate kinase A/Nm23-H1. Biochem J 2007;403:149–156.
Giraud MF, Georgescauld F, Lascu I et al. Crystal structures of S120G mutant and wild type of human nucleoside diphosphate kinase A in complex with ADP. J Bioenerg Biomembr 2006;38:261–264.
Reymond A, Volorio S, Merla G et al. Evidence for interaction between human PRUNE and nm23-H1 NDPKinase. Oncogene 1999;18:7244–7252.
Otero AS, Doyle MB, Hartsough MT et al. Wild-type NM23-H1, but not its S120 mutants, suppresses desensitization of muscarinic potassium current. Biochim Biophys Acta 1999;1449:157–168.
Hikita ST, Kosik KS, Clegg DO et al. MUC1* mediates the growth of human pluripotent stem cells. PLoS One 2008;3:e3312.
Vlatkovic N, Chang SH, Boyd MT . Janus-faces of NME-oncoprotein interactions. Naunyn Schmiedebergs Arch Pharmacol 2015;388:175–187.
Lasorsa VA, Formicola D, Pignataro P et al. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression. Oncotarget 2016;7:21840–21852.
Eleveld TF, Oldridge DA, Bernard V et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 2015;47:864–871.
Schramm A, Koster J, Assenov Y et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 2015;47:872–877.
Hodge RG, Ridley AJ . Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol 2016;17:496–510.
Pugh TJ, Morozova O, Attiyeh EF et al. The genetic landscape of high-risk neuroblastoma. Nat Genet 2013;45:279–284.
Otsuki Y, Tanaka M, Yoshii S et al. Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc Natl Acad Sci USA 2001;98:4385–4390.
Habets GG, Scholtes EH, Zuydgeest D et al. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 1994;77:537–549.
Bollag G, Crompton AM, Peverly-Mitchell D et al. Activation of Rac1 by human Tiam1. Methods Enzymol 2000;325:51–61.
Minard ME, Kim LS, Price JE et al. The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Res Treat 2004;84:21–32.
Murakami M, Meneses PI, Lan K et al. The suppressor of metastasis Nm23-H1 interacts with the Cdc42 Rho family member and the pleckstrin homology domain of oncoprotein Dbl-1 to suppress cell migration. Cancer Biol Ther 2008;7:677–688.
Valentijn LJ, Koppen A, van Asperen R et al. Inhibition of a new differentiation pathway in neuroblastoma by copy number defects of N-myc, Cdc42, and nm23 genes. Cancer Res 2005;65:3136–3145.
Mayor R, Theveneau E . The neural crest. Development 2013;140:2247–2251.
Maguire LH, Thomas AR, Goldstein AM . Tumors of the neural crest: common themes in development and cancer. Dev Dyn 2015;244:311–322.
Okamoto T, Iwase K, Niu R . Expression and localization of nm23-H1 in the human placenta. Arch Gynecol Obstet 2002;266:1–4.
Bellmeyer A, Krase J, Lindgren J et al. The protooncogene c-myc is an essential regulator of neural crest formation in xenopus. Dev Cell 2003;4:827–839.
Sauka-Spengler T, Bronner-Fraser M . A gene regulatory network orchestrates neural crest formation. Nat Rev Mol Cell Biol 2008;9:557–568.
Liu H, Radisky DC, Yang D et al. MYC suppresses cancer metastasis by direct transcriptional silencing of alphav and beta3 integrin subunits. Nat Cell Biol 2012;14:567–574.
Kanayama H, Takigawa H, Kagawa S . Analysis of nm23 gene expressions in human bladder and renal cancers. Int J Urol 1994;1:324–331.
Nasser JA, Falavigna A, Ferraz F et al. Transcription analysis of TIMP-1 and NM23-H1 genes in glioma cell invasion. Arq Neuropsiquiatr 2006;64:774–780.
Bevilacqua G, Sobel ME, Liotta LA et al. Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. Cancer Res 1989;49:5185–5190.
Hennessy C, Henry JA, May FE et al. Expression of the antimetastatic gene nm23 in human breast cancer: an association with good prognosis. J Natl Cancer Inst 1991;83:281–285.
Goodall RJ, Dawkins HJ, Robbins PD et al. Evaluation of the expression levels of nm23-H1 mRNA in primary breast cancer, benign breast disease, axillary lymph nodes and normal breast tissue. Pathology 1994;26:423–428.
Marone M, Scambia G, Ferrandina G et al. Nm23 expression in endometrial and cervical cancer: inverse correlation with lymph node involvement and myometrial invasion. Br J Cancer 1996;74:1063–1068.
Yamaguchi A, Urano T, Fushida S et al. Inverse association of nm23-H1 expression by colorectal cancer with liver metastasis. Br J Cancer 1993;68:1020–1024.
Garinis GA, Manolis EN, Spanakis NE et al. High frequency of concomitant nm23-H1 and E-cadherin transcriptional inactivation in primary non-inheriting colorectal carcinomas. J Mol Med (Berl) 2003;81:256–263.
Haut M, Steeg PS, Willson JK et al. Induction of nm23 gene expression in human colonic neoplasms and equal expression in colon tumors of high and low metastatic potential. J Natl Cancer Inst 1991;83:712–716.
Zeng ZS, Hsu S, Zhang ZF et al. High level of Nm23-H1 gene expression is associated with local colorectal cancer progression not with metastases. Br J Cancer 1994;70:1025–1030.
Myeroff LL, Markowitz SD . Increased nm23-H1 and nm23-H2 messenger RNA expression and absence of mutations in colon carcinomas of low and high metastatic potential. J Natl Cancer Inst 1993;85:147–152.
Heide I, Thiede C, Poppe K et al. Expression and mutational analysis of Nm23-H1 in liver metastases of colorectal cancer. Br J Cancer 1994;70:1267–1271.
Muta H, Iguchi H, Kono A et al. Nm23 expression in human gastric cancers - possible correlation of nm23 with lymph-node metastasis. Int J Oncol 1994;5:93–96.
Kodera Y, Isobe K, Yamauchi M et al. Expression of nm23 H-1 RNA levels in human gastric cancer tissues. A negative correlation with nodal metastasis. Cancer 1994;73:259–265.
Hwang BG, Park IC, Park MJ et al. Role of the nm23-H1 gene in the metastasis of gastric cancer. J Korean Med Sci 1997;12:514–518.
Guo X, Min HQ, Zeng MS et al. nm23-H1 expression in nasopharyngeal carcinoma: correlation with clinical outcome. Int J Cancer 1998;79:596–600.
Liu SJ, Sun YM, Tian DF et al. Downregulated NM23-H1 expression is associated with intracranial invasion of nasopharyngeal carcinoma. Br J Cancer 2008;98:363–369.
Yokoyama A, Okabe-Kado J, Sakashita A et al. Differentiation inhibitory factor nm23 as a new prognostic factor in acute monocytic leukemia. Blood 1996;88:3555–3561.
Boix L, Bruix J, Campo E et al. nm23-H1 expression and disease recurrence after surgical resection of small hepatocellular carcinoma. Gastroenterology 1994;107:486–491.
Iizuka N, Oka M, Noma T et al. NM23-H1 and NM23-H2 messenger RNA abundance in human hepatocellular carcinoma. Cancer Res 1995;55:652–657.
Zheng XY, Ling ZY, Tang ZY et al. The abundance of NM23-H1 mRNA is related with in situ microenvironment and intrahepatic metastasis in hepato-cellular carcinoma. J Exp Clin Cancer Res 1998;17:337–341.
Lin LI, Lee PH, Wu CM et al. Significance of nm23 mRNA expression in human hepatocellular carcinoma. Anticancer Res 1998;18:541–546.
Engel M, Theisinger B, Seib T et al. High levels of nm23-H1 and nm23-H2 messenger RNA in human squamous-cell lung carcinoma are associated with poor differentiation and advanced tumor stages. Int J Cancer 1993;55:375–379.
Ayabe T, Tomita M, Matsuzaki Y et al. Micrometastasis and expression of nm23 messenger RNA of lymph nodes from lung cancer and the postoperative clinical outcome. Ann Thorac Cardiovasc Surg 2004;10:152–159.
Aryee DN, Simonitsch I, Mosberger I et al. Variability of nm23-H1/NDPK-A expression in human lymphomas and its relation to tumour aggressiveness. Br J Cancer 1996;74:1693–1698.
Florenes VA, Aamdal S, Myklebost O et al. Levels of nm23 messenger RNA in metastatic malignant melanomas: inverse correlation to disease progression. Cancer Res 1992;52:6088–6091.
Xerri L, Grob JJ, Battyani Z et al. NM23 expression in metastasis of malignant melanoma is a predictive prognostic parameter correlated with survival. Br J Cancer 1994;70:1224–1228.
Mandai M, Konishi I, Koshiyama M et al. Expression of metastasis-related nm23-H1 and nm23-H2 genes in ovarian carcinomas: correlation with clinicopathology, EGFR, c-erbB-2, and c-erbB-3 genes, and sex steroid receptor expression. Cancer Res 1994;54:1825–1830.
Viel A, Dall'Agnese L, Canzonieri V et al. Suppressive role of the metastasis-related nm23-H1 gene in human ovarian carcinomas: association of high messenger RNA expression with lack of lymph node metastasis. Cancer Res 1995;55:2645–2650.
Kapitanovic S, Spaventi R, Vujsic S et al. nm23-H1 gene expression in ovarian tumors—a potential tumor marker. Anticancer Res 1995;15:587–590.
Yi S, Guangqi H, Guoli H . The association of the expression of MTA1, nm23H1 with the invasion, metastasis of ovarian carcinoma. Chin Med Sci J 2003;18:87–92.
Leary JA, Kerr J, Chenevix-Trench G et al. Increased expression of the NME1 gene is associated with metastasis in epithelial ovarian cancer. Int J Cancer 1995;64:189–195.
Adamek HE, Riemann JF . Differential expression of metastasis-associated genes in papilla of Vater and pancreatic cancer correlates with disease stage. Z Gastroenterol 2001;39:909–910.
Golouh R, Stanta G, Bracko M et al. Correlation of MTS1/p16 and nm23 mRNA expression with survival in patients with peripheral synovial sarcoma. J Surg Oncol 2001;76:83–88.
Jensen SL, Wood DP Jr, Banks ER et al. Increased levels of nm23 H1/nucleoside diphosphate kinase A mRNA associated with adenocarcinoma of the prostate. World J Urol 1996;14:S21–S25.
Arai TWM, Onodera M, Yamashita T et al. Reduced nm 23-H1 messenger RNA expression in metastatic lymph nodes from patients with papillary carcinoma of the thyroid. Am J Pathol 1993;142:1938–1944.
Zou M, Shi Y, al-Sedairy S et al. High levels of Nm23 gene expression in advanced stage of thyroid carcinomas. Br J Cancer 1993;68:385–388.
Indinnimeo M, Cicchini C, Stazi A et al. Correlation between nm23-H1 overexpression and clinicopathological variables in human anal canal carcinoma. Oncol Rep 1999;6:1353–1356.
Chow NH, Liu HS, Chan SH . The role of nm23-H1 in the progression of transitional cell bladder cancer. Clin Cancer Res 2000;6:3595–3599.
Cheng HL, Tong YC, Tzai TS et al. Expression of nm23-H1 in transitional cell carcinoma of the upper urinary tract. Oncol Rep 2001;8:193–196.
Shiina H, Igawa M, Urakami S et al. Immunohistochemical analysis of nm23 protein in transitional cell carcinoma of the bladder. Br J Urol 1995;76:708–713.
Kuo JY, Chiang H, Chen KK et al. Immunohistochemical analysis of nm23-H1 protein in bladder cancer. Zhonghua Yi Xue Za Zhi (Taipei) 1999;62:411–417.
Oda Y, Walter H, Radig K et al. Immunohistochemical analysis of nm23 protein expression in malignant bone tumors. J Cancer Res Clin Oncol 1995;121:667–673.
Nawashiro H, Ozeki Y, Takishima K et al. Immunohistochemical analysis of the nm23 gene product (NDP kinase) expression in astrocytic neoplasms. Acta Neurochir (Wien) 1996;138:445–450.
Tokunaga Y, Urano T, Furukawa K et al. Reduced expression of nm23-H1, but not of nm23-H2, is concordant with the frequency of lymph-node metastasis of human breast cancer. Int J Cancer 1993;55:66–71.
Royds JA, Stephenson TJ, Rees RC et al. Nm23 protein expression in ductal in situ and invasive human breast carcinoma. J Natl Cancer Inst 1993;85:727–731.
Okubo T, Inokuma S, Takeda S et al. Expression of nm23-H1 gene product in thyroid, ovary, and breast cancers. Cell Biophys 1995;26:205–213.
Charpin C, Bouvier C, Garcia S et al. Automated and quantitative immunocytochemical assays of Nm23/NDPK protein in breast carcinomas. Int J Cancer 1997;74:416–420.
Kapranos N, Karaiossifidi H, Kouri E et al. Nm23 expression in breast ductal carcinomas: a ten year follow-up study in a uniform group of node-negative breast cancer patients. Anticancer Res 1996;16:3987–3990.
Mandai M, Konishi I, Koshiyama M et al. Altered expression of nm23-H1 and c-erbB-2 proteins have prognostic significance in adenocarcinoma but not in squamous cell carcinoma of the uterine cervix. Cancer 1995;75:2523–2529.
Lee CS, Gad J . nm23-H1 protein immunoreactivity in intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix. Pathol Int 1998;48:806–811.
Branca M, Giorgi C, Ciotti M et al. Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer. J Clin Pathol 2006;59:1044–1051.
Chen HY, Hsu CT, Lin WC et al. Prognostic value of nm23 expression in stage IB1 cervical carcinoma. Jpn J Clin Oncol 2001;31:327–332.
Kristensen GB, Holm R, Abeler VM et al. Evaluation of the prognostic significance of nm23/NDP kinase protein expression in cervical carcinoma: an immunohistochemical study. Gynecol Oncol 1996;61:378–383.
Wang PH, Chang H, Ko JL et al. Nm23-H1 immunohistochemical expression in multisteps of cervical carcinogenesis. Int J Gynecol Cancer 2003;13:325–330.
Ayhan A, Yasui W, Yokozaki H et al. Reduced expression of nm23 protein is associated with advanced tumor stage and distant metastases in human colorectal carcinomas. Virchows Arch B Cell Pathol Incl Mol Pathol 1993;63:213–218.
Wang C, Zhang X, Yang F . nm23 gene product/NDPK expression and its clinical significance in human colorectal carcinoma. Zhonghua Bing Li Xue Za Zhi 1995;24:356–358.
Cheah PY, Cao X, Eu KW et al. NM23-H1 immunostaining is inversely associated with tumour staging but not overall survival or disease recurrence in colorectal carcinomas. Br J Cancer 1998;77:1164–1168.
Dursun A, Akyurek N, Gunel N et al. Prognostic implication of nm23-H1 expression in colorectal carcinomas. Pathology 2002;34:427–432.
Lin MS, Chen WC, Huang JX et al. Tissue microarrays in Chinese human rectal cancer: study of expressions of the tumor-associated genes. Hepatogastroenterology 2011;58:1937–1942.
Tabuchi Y, Nakamura T, Kuniyasu T et al. Expression of nm23-H1 in colorectal cancer: no association with metastases, histological stage, or survival. Surg Today 1999;29:116–120.
Sarris M, Lee CS . nm23 protein expression in colorectal carcinoma metastasis in regional lymph nodes and the liver. Eur J Surg Oncol 2001;27:170–174.
Oliveira LA, Artigiani-Neto R, Waisberg DR et al. NM23 protein expression in colorectal carcinoma using TMA (tissue microarray): association with metastases and survival. Arq Gastroenterol 2010;47:361–367.
Yalcinkaya U, Ozuysal S, Bilgin T et al. Nm23 expression in node-positive and node-negative endometrial cancer. Int J Gynaecol Obstet 2006;95:35–39.
Watanabe J, Sato Y, Kuramoto H et al. Expression of nm23-H1 and nm23-H2 protein in endometrial carcinoma. Br J Cancer 1995;72:1469–1473.
Iizuka NTA, Hayashi H, Yosino S et al. The association between nm23-H1 expression and survival in patients with esophageal squamous cell carcinoma. Cancer Lett 1999;138:139–144.
Tomita M, Ayabe T, Matsuzaki Y et al. Expression of nm23-H1 gene product in esophageal squamous cell carcinoma and its association with vessel invasion and survival. BMC Cancer 2001;1:3.
Szumilo J, Skomra D, Chibowski D et al. Immunoexpression of nm23 in advanced esophageal squamous cell carcinoma. Folia Histochem Cytobiol 2002;40:377–380.
Fujii K, Yasui W, Shimamoto F et al. Immunohistochemical analysis of nm23 gene product in human gallbladder carcinomas. Virchows Arch 1995;426:355–359.
Nakayama H, Yasui W, Yokozaki H et al. Reduced expression of nm23 is associated with metastasis of human gastric carcinomas. Jpn J Cancer Res 1993;84:184–190.
Kim KM, Lee A, Chae HS et al. Expression of p53 and NDP-K/nm23 in gastric carcinomas—association with metastasis and clinicopathologic parameters. J Korean Med Sci 1995;10:406–413.
Muller W, Schneiders A, Hommel G et al. Expression of nm23 in gastric carcinoma: association with tumor progression and poor prognosis. Cancer 1998;83:2481–2487.
Nesi G, Palli D, Pernice LM et al. Expression of nm23 gene in gastric cancer is associated with a poor 5-year survival. Anticancer Res 2001;21:3643–3649.
Yeung P, Lee CS, Marr P et al. Nm23 gene expression in gastric carcinoma: an immunohistochemical study. Aust N Z J Surg 1998;68:180–182.
Monig SP, Nolden B, Lubke T et al. Clinical significance of nm23 gene expression in gastric cancer. Anticancer Res 2007;27:3029–3033.
Wang LB, Jiang ZN, Fan MY et al. Changes of histology and expression of MMP-2 and nm23-H1 in primary and metastatic gastric cancer. World J Gastroenterol 2008;14:1612–1616.
Song AU, Mais DD, Groo S et al. Expression of nm23 antimetastatic gene product in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 2000;122:96–99.
Ogawa I, Takata T, Miyauchi M et al. nm23-H1 expression in salivary adenoid cystic carcinoma in relation to metastasis and survival. Oncol Rep 1997;4:707–711.
Lee CS, Redshaw A, Boag G . nm23-H1 protein immunoreactivity in laryngeal carcinoma. Cancer 1996;77:2246–2250.
Gunduz M, Ayhan A, Gullu I et al. nm23 Protein expression in larynx cancer and the relationship with metastasis. Eur J Cancer 1997;33:2338–2341.
Huang GW, Mo WN, Kuang GQ et al. Expression of p16, nm23-H1, E-cadherin, and CD44 gene products and their significance in nasopharyngeal carcinoma. Laryngoscope 2001;111:1465–1471.
Ohtsuki K, Shintani S, Kimura N et al. Immunohistochemical study on the nm23 gene produce (NDP kinase) in oral squamous cell carcinoma. Oral Oncol 1997;33:237–239.
Lo Muzio L, Mignogna MD, Pannone G et al. The NM23 gene and its expression in oral squamous cell carcinoma. Oncol Rep 1999;6:747–751.
Wang YF, Chow KC, Chang SY et al. Prognostic significance of nm23-H1 expression in oral squamous cell carcinoma. Br J Cancer 2004;90:2186–2193.
Korabiowska M, Honig JF, Jawien J et al. Relationship of nm23 expression to proliferation and prognosis in malignant melanomas of the oral cavity. In Vivo 2005;19:1093–1096.
Aquino AR, de Carvalho CH, Nonaka CF et al. Immunoexpression of claudin-1 and Nm23-H1 in metastatic and nonmetastatic lower lip squamous-cell carcinoma. Appl Immunohistochem Mol Morphol 2012;20:595–601.
Hadice Elif P, Gulay O, Ozlem E et al. Nm23 and cathepsin D expression in laryngeal carcinomas. Adv Clin Path 2000;4:121–125.
Park DS, Cho NH, Lee YT et al. Analysis of nm23 expression as a prognostic parameter in renal cell carcinoma. J Korean Med Sci 1995;10:258–262.
Nakagawa Y, Tsumatani K, Kurumatani N et al. Prognostic value of nm23 protein expression in renal cell carcinomas. Oncology 1998;55:370–376.
Nakayama T, Ohtsuru A, Nakao K et al. Expression in human hepatocellular carcinoma of nucleoside diphosphate kinase, a homologue of the nm23 gene product. J Natl Cancer Inst 1992;84:1349–1354.
Yamaguchi A, Urano T, Goi T et al. Expression of human nm23-H1 and nm23-H2 proteins in hepatocellular carcinoma. Cancer 1994;73:2280–2284.
Fujimoto Y, Ohtake T, Nishimori H et al. Reduced expression and rare genomic alteration of nm23-H1 in human hepatocellular carcinoma and hepatoma cell lines. J Gastroenterol 1998;33:368–375.
Nanashima A, Yano H, Yamaguchi H et al. Immunohistochemical analysis of tumor biological factors in hepatocellular carcinoma: relationship to clinicopathological factors and prognosis after hepatic resection. J Gastroenterol 2004;39:148–154.
An R, Meng J, Shi Q et al. Expressions of nucleoside diphosphate kinase (nm23) in tumor tissues are related with metastasis and length of survival of patients with hepatocellular carcinoma. Biomed Environ Sci 2010;23:267–272.
Shimada M, Taguchi K, Hasegawa H et al. Nm23-H1 expression in intrahepatic or extrahepatic metastases of hepatocellular carcinoma. Liver 1998;18:337–342.
Liu YB, Gao SL, Chen XP et al. Expression and significance of heparanase and nm23-H1 in hepatocellular carcinoma. World J Gastroenterol 2005;11:1378–1381.
Cui J, Dong BW, Liang P et al. Construction and clinical significance of a predictive system for prognosis of hepatocellular carcinoma. World J Gastroenterol 2005;11:3027–3033.
Lai WW, Wu MH, Yan JJ et al. Immunohistochemical analysis of nm23-H1 in stage I non-small cell lung cancer: a useful marker in prediction of metastases. Ann Thorac Surg 1996;62:1500–1504.
Kawakubo Y, Sato Y, Koh T et al. Expression of nm23 protein in pulmonary adenocarcinomas: inverse 1orrelation to tumor progression. Lung Cancer 1997;17:103–113.
Graham AN, Maxwell P, Mulholland K et al. Increased nm23 immunoreactivity is associated with selective inhibition of systemic tumour cell dissemination. J Clin Pathol 2002;55:184–189.
Gazzeri S, Brambilla E, Negoescu A et al. Overexpression of nucleoside diphosphate/kinase A/nm23-H1 protein in human lung tumors: association with tumor progression in squamous carcinoma. Lab Invest 1996;74:158–167.
Tomita M, Ayabe T, Matsuzaki Y et al. Expression of nm23-H1 gene product in mediastinal lymph nodes from lung cancer patients. Eur J Cardiothorac Surg 2001;19:904–907.
Higashiyama M, Doi O, Yokouchi H et al. Immunohistochemical analysis of nm23 gene product/NDP kinase expression in pulmonary adenocarcinoma: lack of prognostic value. Br J Cancer 1992;66:533–536.
Tomita M, Ayabe T, Matsuzaki Y et al. Immunohistochemical analysis of nm23-H1 gene product in node-positive lung cancer and lymph nodes. Lung Cancer 1999;24:11–16.
Sato Y, Tsuchiya B, Urao T et al. Semiquantitative immunoblot analysis of nm23-H1 and -H2 isoforms in adenocarcinomas of the lung: prognostic significance. Pathol Int 2000;50:200–205.
Niitsu N, Okabe-Kado J, Kasukabe T et al. Prognostic implications of the differentiation inhibitory factor nm23-H1 protein in the plasma of aggressive non-Hodgkin's lymphoma. Blood 1999;94:3541–3550.
Niitsu N, Honma Y, Iijima K et al. Clinical significance of nm23-H1 proteins expressed on cell surface in non-Hodgkin's lymphoma. Leukemia 2003;17:196–202.
Niitsu N, Nakamine H, Okamoto M et al. Clinical significance of intracytoplasmic nm23-H1 expression in diffuse large B-cell lymphoma. Clin Cancer Res 2004;10:2482–2490.
Lee CS, Pirdas A, Lee MW . Immunohistochemical demonstration of the nm23-H1 gene product in human malignant melanoma and Spitz nevi. Pathology 1996;28:220–224.
Dome B, Somlai B, Timar J . The loss of NM23 protein in malignant melanoma predicts lymphatic spread without affecting survival. Anticancer Res 2000;20:3971–3974.
Easty DJ, Maung K, Lascu I et al. Expression of NM23 in human melanoma progression and metastasis. Br J Cancer 1996;74:109–114.
Reichrath JSP, Braun R, Müller SM et al. Expression of NM23 protein in acquired melanocytic nevi, malignant melanoma and metastases of malignant melanoma: an immunohistological assessment in human skin. Dermatology 1997;194:136–139.
Scambia G, Ferrandina G, Marone M et al. nm23 in ovarian cancer: correlation with clinical outcome and other clinicopathologic and biochemical prognostic parameters. J Clin Oncol 1996;14:334–342.
Qian M, Feng Y, Xu L et al. Expression of antimetastatic gene nm23-H1 in epithelial ovarian cancer. Chin Med J (Engl) 1997;110:142–144.
Srivatsa PJ, Cliby WA, Keeney GL et al. Elevated nm23 protein expression is correlated with diminished progression-free survival in patients with epithelial ovarian carcinoma. Gynecol Oncol 1996;60:363–372.
Nakamori S, Ishikawa O, Ohigashi H et al. Clinicopathological features and prognostic significance of nucleoside diphosphate kinase/nm23 gene product in human pancreatic exocrine neoplasms. Int J Pancreatol 1993;14:125–133.
Nakamori S, Ishikawa O, Ohhigashi H et al. Expression of nucleoside diphosphate kinase/nm23 gene product in human pancreatic cancer: an association with lymph node metastasis and tumor invasion. Clin Exp Metastasis 1993;11:151–158.
Ohshio G, Imamura T, Okada N et al. Immunohistochemical expression of nm23 gene product, nucleotide diphosphate kinase, in pancreatic neoplasms. Int J Pancreatol 1997;22:59–66.
Konishi N, Nakaoka S, Tsuzuki T et al. Expression of nm23-H1 and nm23-H2 proteins in prostate carcinoma. Jpn J Cancer Res 1993;84:1050–1054.
Stravodimos K, Constantinides C, Manousakas T et al. Immunohistochemical expression of transforming growth factor beta 1 and nm-23 H1 antioncogene in prostate cancer: divergent correlation with clinicopathological parameters. Anticancer Res 2000;20:3823–3828.
Krishnakumar S, Lakshmi A, Shanmugam MP et al. Nm23 expression in retinoblastoma. Ocul Immunol Inflamm 2004;12:127–135.
Stephenson TJ, Royds JA, Bleehen SS et al. 'Anti-metastatic' nm23 gene product expression in keratoacanthoma and squamous cell carcinoma. Dermatology 1993;187:95–99.
Ro YS, Jeong SJ . Expression of the nucleoside diphosphate kinase in human skin cancers: an immunohistochemical study. J Korean Med Sci 1995;10:97–102.
Hantschmann P, Beysiegel S, Assemi C et al. Immunohistologic detection of nm23-H1 protein in squamous cell carcinoma of the vulva. J Reprod Med 2004;49:787–795.
Arai T, Yamashita T, Urano T et al. Preferential reduction of nm23-H1 gene product in metastatic tissues from papillary and follicular carcinomas of the thyroid. Mod Pathol 1995;8:252–256.
Shirahige Y, Irie J, Ashizawa K et al. Immunohistochemical detection of nm23-H1/NDP kinase in childhood thyroid carcinoma. Oncol Rep 1997;4:285–288.
Zafon C, Obiols G, Castellvi J et al. nm23-H1 immunoreactivity as a prognostic factor in differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:3975–3980.
Luo W, Matsuo K, Nagayama Y et al. Immunohistochemical analysis of expression of nm23-H1/nucleoside diphosphate kinase in human thyroid carcinomas: lack of correlation between its expression and lymph node metastasis. Thyroid 1993;3:105–109.
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The authors thank Larry P Paris for editing the manuscript. This work was supported by the Hung-Hwa Memorial Fund in Taiwan.
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This review focuses on the metastasis-promoting role of NDPK-A in neuroblastoma, and summarizes the relationships between NDPK-A levels and the metastasis potential in a variety of human cancers. Because of NDPK-A can act as a metastasis suppressor or promoter depending on tumor type, identification of molecular drivers of metastasis in the NDPK-A network is warranted for the development of tumor-specific therapies.
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Tan, CY., Chang, C. NDPKA is not just a metastasis suppressor – be aware of its metastasis-promoting role in neuroblastoma. Lab Invest 98, 219–227 (2018). https://doi.org/10.1038/labinvest.2017.105
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DOI: https://doi.org/10.1038/labinvest.2017.105
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