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Regulatory functions of Nm23-H2 in tumorigenesis: insights from biochemical to clinical perspectives

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Abstract

Substantial effort has been directed at elucidating the functions of the products of the Nm23 tumor metastasis suppressor genes over the past two decades, with the ultimate goal of exploring their translational potentials in changing cancer patients’ outcomes. Much attention has been focused on the better-known Nm23-H1, but despite having high sequence similarity, Nm23-H2 functions differently in many aspects. Besides acting as a metastasis suppressor, compelling data suggest that Nm23-H2 may modulate various tumor-associated biological events to enhance tumorigenesis in human solid tumors and hematological malignancies. Linkage to tumorigenesis may occur through the ability of Nm23-H2 to regulate transcription, cell proliferation, apoptosis, differentiation, and telomerase activity. In this review, we examine the linkages of Nm23-H2 to tumorigenesis in terms of its biochemical and structural properties and discuss its potential role in various tumor-associated events.

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References

  • Aktary Z, Chapman K, Lam L et al (2010) Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1. Oncogene 29:2118–2129

    CAS  PubMed  Google Scholar 

  • Anzinger J, Malmquist NA, Gould J, Buxton IL (2001) Secretion of a nucleoside diphosphate kinase (Nm23-H2) by cells from human breast, colon, pancreas and lung tumors. Proc West Pharmacol Soc 44:61–63

    CAS  PubMed  Google Scholar 

  • Arnaud-Dabernat S, Bourbon PM, Dierich A, Le Meur M, Daniel JY (2003) Knockout mice as model systems for studying nm23/NDP kinase gene functions. Application to the nm23-M1 gene. J Bioenerg Biomembr 35:19–30

    CAS  PubMed  Google Scholar 

  • Baba H, Urano T, Okada K et al (1995) Two isotypes of murine nm23/nucleoside diphosphate kinase, nm23-M1 and nm23-M2, are involved in metastatic suppression of a murine melanoma line. Cancer Res 55:1977–1981

    CAS  PubMed  Google Scholar 

  • Bai F, Feng J, Cheng Y, Shi J, Yang R, Cui H (2006) Analysis of gene expression patterns of ovarian cancer cell lines with different metastatic potentials. Int J GynecolCancer16:202–209

  • Bal A, Joshi K, Logasundaram R, Radotra BD, Singh R (2008) Expression of nm23 in the spectrum of pre-invasive, invasive and metastatic breast lesions. Diagn Pathol 3:23

    PubMed Central  PubMed  Google Scholar 

  • Berberich SJ, Postel EH (1995) PuF/NM23-H2/NDPK-B transactivates a human c-myc promoter-CAT gene via a functional nuclease hypersensitive element. Oncogene 10:2343–2347

    CAS  PubMed  Google Scholar 

  • Boissan M, Dabernat S, Peuchant E, Schlattner U, Lascu I, Lacombe ML (2009) The mammalian Nm23/NDPK family: from metastasis control to cilia movement. Mol Cell Biochem 329:51–62

    CAS  PubMed  Google Scholar 

  • Caligo MA, Cipollini G, Petrinit M, Valentini P, Bevilacqua G (1996) Down regulation of NM23.H1, NM23.H2 and c-myc genes during differentiation induced by 1,25 dihydroxyvitamin D3. Leuk Res 20:161–167

    CAS  PubMed  Google Scholar 

  • Chang CL, Zhu XX, Thoraval DH et al (1994) Nm23-H1 mutation in neuroblastoma. Nature 370:335–336

    CAS  PubMed  Google Scholar 

  • Chen HY, Hsu CT, Lin WC, Tsai HD, Chang WC (2001) Prognostic valueof nm23 expression in stage IB1 cervical carcinoma. Jpn J Clin Oncol 31:327–332

    CAS  PubMed  Google Scholar 

  • Chen S, Su L, Qiu J et al (2013) Mechanistic studies for the role of cellular nucleic-acid-binding protein (CNBP) in regulation of c-myc transcription. Biochim Biophys Acta 1830:4769–4777

    CAS  PubMed  Google Scholar 

  • Chen Y, Gallois-Montbrun S, Schneider B et al (2003) Nucleotide binding to nucleoside diphosphate kinases: X-ray structure of human NDPK-A in complex with ADP and comparison to protein kinases. J Mol Biol 332:915–926

    CAS  PubMed  Google Scholar 

  • Cubukcu E, Kanat O, Fatih Olmez O et al (2013) Prognostic significance of estrogen receptor, progesterone receptor, HER2/neu, Ki-67, and nm23 expression in patients with invasive breast cancer. J BUON 18:359–365

    CAS  PubMed  Google Scholar 

  • Dexheimer TS, Carey SS, Song ZH et al (2009) While NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression, it does not cleave the NHE III1 element. Mol Cancer Ther 8:14

    Google Scholar 

  • Donate LE, Blasco MA (2011) Telomeres in cancer and ageing. Philos Trans R Soc Lond B Biol Sci 366:76–84

    CAS  PubMed Central  PubMed  Google Scholar 

  • D'Souza RJ, Sheikh ZA, Busund LT, Russell PJ, Crowe PJ, Yang JL (2003) Expression of nm23 protein in adult soft tissue sarcoma is correlated with histological grade. Anticancer Res 23:3289–3294

    PubMed  Google Scholar 

  • Egistelli L, Chichiarelli S, Gaucci E et al (2009) IFI16 and NM23 bind to a common DNA fragment both in the P53 and the cMYC gene promoters. J Cell Biochem 106:666–672

    CAS  PubMed  Google Scholar 

  • Engel M, Theisinger B, Seib T et al (1993) 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 55:375–379

    CAS  PubMed  Google Scholar 

  • Fernandez PC, Frank SR, Wang L et al (2003) Genomic targets of the human c-Myc protein. Genes Dev 17:1115–1129

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fournier HN, Dupe-Manet S, Bouvard D et al (2002) Integrin cytoplasmic domain-associated protein 1α (ICAP-α) interacts directly with the metastasis suppressor nm23-H2, and both proteins are targeted to newly formed cell adhesion sites upon integrin engagement. J Biol Chem 277:20895–20902

    CAS  PubMed  Google Scholar 

  • Fournier HN, Dupe-Manet S, Bouvard D et al (2005) Nuclear translocation of integrin cytoplasmic domain-associated protein 1 stimulates cellular proliferation. Mol Biol Cell 16:1859–1871

    CAS  PubMed Central  PubMed  Google Scholar 

  • Francois-Moutal L, Marcillat O, Granjon T (2014) Structural comparison of highly similar nucleoside-diphosphate kinases: molecular explanation of distinct membrane-binding behavior. Biochimie 105:110–118

    CAS  PubMed  Google Scholar 

  • Freije JM, Blay P, MacDonald NJ, Manrow RE, Steeg PS (1997) Site-directed mutation of Nm23-H1 mutations lacking motility suppressive capacity upon transfection are deficient in histidine-dependent protein phosphotransferase pathways in vitro. J Biol Chem 272:5525–5532

    CAS  PubMed  Google Scholar 

  • Fukuda M, Ishii A, Yasutomo Y et al (1996) Decreased expression of nucleoside diphosphate kinase alpha isoform, an nm23-H2 gene homolog, is associated with metastatic potential of rat mammary-adenocarcinoma cells. Int J Cancer 65:531–537

    CAS  PubMed  Google Scholar 

  • Garcia I, Mayol G, Rios J et al (2012) A three-gene expression signature model for risk stratification of patients with neuroblastoma. Clin Cancer Res 18:2012–2023

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gervasi F, D’Agnano I, Vossio S, Zupi G, Sacchi A, Lombardi D (1996) Nm23 influences proliferation and differentiation of PC12 cells in response to nerve growth factor. Cell Growth Differ 7:1689–1695

    CAS  PubMed  Google Scholar 

  • Gilles AM, Presecan E, Vonica A, Lascu I (1991) Nucleoside diphosphate kinase from human erythrocytes structural characterization of the two polypeptide chains responsible for heterogeneity of the hexameric enzyme. J Biol Chem 266:8784–8789

    CAS  PubMed  Google Scholar 

  • Gordon GJ, Rockwell GN, Jensen RV et al (2005) Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling. Am J Pathol 166:1827–1840

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goueli BS, Janknecht R (2004) Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol 24:25–35

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hailat N, Keim DR, Melhem RF et al (1991) High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification. J Clin Invest 88:341–345

    CAS  PubMed Central  PubMed  Google Scholar 

  • Haitel A, Wiener HG, Baethge U, Marberger M, Susani M (2000) Mdm2 expression as a prognostic indicator in clear cell renal cell carcinoma: comparison with p53 overexpression and clinicopathological parameters. Clin Cancer Res 6:1840–1844

    CAS  PubMed  Google Scholar 

  • Hamby CV, Abbi R, Prasad N et al (2000) Expression of a catalytically inactive H118Y mutant of nm23-H2 suppresses the metastatic potential of line IV Cl 1 human melanoma cells. Int J Cancer 88:547–553

    CAS  PubMed  Google Scholar 

  • Haring J, Schuler S, Lattrich C, Ortmann O, Treeck O (2012) Role of estrogen receptor beta in gynecological cancer. Gynecol Oncol 127:673–676

    PubMed  Google Scholar 

  • Hartsough MT, Morrison DK, Salemo M et al (2002) Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J Biol Chem 277:32389–32399

    CAS  PubMed  Google Scholar 

  • Herak Bosnar M, Bago R, Konjevoda P, Pavelic J (2008) Gene expression profiling of Nm23-H2 overexpressing CAL 27 cells using DNA microarray. Neoplasma 55:447–454

    CAS  PubMed  Google Scholar 

  • Hikita ST, Kosik KS, Clegg DO, Bamdad C (2008) MUC1* mediates the growth of human pluripotent stem cells. PLoS One 3:e3312

    PubMed Central  PubMed  Google Scholar 

  • Hippe HJ, Wolf NM, Abu-Taha HI et al (2011) Nucleoside diphosphate kinase B is required for the formation of heterotrimeric G protein containing caveolae. Naunyn Schmiedebergs Arch Pharmacol 384:461–472

    CAS  PubMed  Google Scholar 

  • Hudelist G, Czerwenka K, Singer C, Pischinger K, Kubista E, Manavi M (2005) cDNA array analysis of cytobrush-collected normal and malignant cervical epithelial cells: a feasibility study. Cancer Genet Cytogenet 158:35–42

    CAS  PubMed  Google Scholar 

  • Huwer H, Kalweit G, Engel M, Welter C, Dooley S, Gams E (1997) Expression of the candidate tumor suppressor gene nm23 in the bronchial system of patients with squamous cell lung cancer. Eur J Cardiothorac Surg 11:206–209

    CAS  PubMed  Google Scholar 

  • Iizuka N, Mori N, Tamesa T, Tangoku A, Oka M (2003) Telomerase activity and Nm23-H2 protein expression in hepatocellular carcinoma. Anticancer Res 23:43–47

    CAS  PubMed  Google Scholar 

  • Iizuka N, Tsunedomi R, Tamesa T et al (2006) Involvement of c-myc-regulated genes in hepatocellular carcinoma related to genotype-C hepatitis B virus. J Cancer Res Clin Oncol 132:473–481

    CAS  PubMed  Google Scholar 

  • Iwashita S, Fujii M, Mukai H, Ono Y, Miyamoto M (2004) Lbc proto-oncogene product binds to and could be negatively regulated by metastasis suppressor nm23-H2. Biochem Biophys Res Commun 320:1063–1068

    CAS  PubMed  Google Scholar 

  • Joosten M, Blazquez-Domingo M, Lindeboom F et al (2004) Translational control of putative protooncogene Nm23-M2 by cytokines via phosphoinositide 3-kinase signaling. J Biol Chem 279:38169–38176

    CAS  PubMed  Google Scholar 

  • Kang Y, Lee DC, Han J et al (2007) NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling. Biochem Biophys Res Commun 359:76–82

    CAS  PubMed  Google Scholar 

  • Kar A, Saha D, Purohit G et al (2012) Metastases suppressor NME2 associates with telomere ends and telomerase and reduces telomerase activity within cells. Nucleic Acids Res 40:2554–2565

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lacombe ML, Milon L, Munier A, Mehus JG, Lambeth DO (2000) The human Nm23/nucleoside diphosphate kinases. J Bioenerg Biomembr 32:247–258

    CAS  PubMed  Google Scholar 

  • Lee MJ, Xu DY, Li H et al (2012) Pro-oncogenic potential of NM23-H2 in hepatocellular carcinoma. Exp Mol Med 44:214–224

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee MY, Jeong WJ, Oh JW, Choi KY (2009) NM23H2 inhibits EGF- and Ras-induced proliferation of NIH3T3 cells by blocking the ERK pathway. Cancer Lett 275:221–226

    CAS  PubMed  Google Scholar 

  • Lim JQ, Lu J, He BP (2012) Diva/BclB regulates differentiation by inhibiting NDPKB/Nm23H2-mediated neuronal differentiation in PC-12 cells. BMC Neurosci 13:123

    CAS  PubMed Central  PubMed  Google Scholar 

  • MacDonald NJ, De la Rosa A, Benedict MA, Freije JM, Krutsch H, Steeg PS (1993) A serine phosphorylation of Nm23, and not its nucleoside diphosphate kinase activity, correlates with suppression of tumor metastatic potential. J Biol Chem 268:25780–25789

    CAS  PubMed  Google Scholar 

  • Mahanta S, Fessler SP, Park J, Bamdad C (2008) A minimal fragment of MUC1 mediates growth of cancer cells. PLoS One 3:e2054

    PubMed Central  PubMed  Google Scholar 

  • Maida Y, Kyo S, Kanaya T et al (2002) Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway. Oncogene 21:4071–4079

    CAS  PubMed  Google Scholar 

  • Manavi M, Hudelist G, Fink-Retter A, Gschwandtler-Kaulich D, Pischinger K, Czerwenka K (2007) Gene profiling in Pap-cell smears of high-risk human papillomavirus-positive squamous cervical carcinoma. Gynecol Oncol 105:418–426

    CAS  PubMed  Google Scholar 

  • Mandai M, Konishi I, Komatsu T et al (1995) Mutation of the nm23 gene, loss of heterozygosity at the nm23 locus and K-ras mutation in ovarian carcinoma: correlation with tumour progression and nm23 gene expression. Br J Cancer 72:691–695

    CAS  PubMed Central  PubMed  Google Scholar 

  • Marone M, Scambia G, Ferrandina G et al (1996) Nm23 expression in endometrial and cervical cancer: inverse correlation with lymph node involvement and myometrial invasion. Br J Cancer 74:1063–1068

    CAS  PubMed Central  PubMed  Google Scholar 

  • Martinez JA, Prevot S, Nordlinger B et al (1995) Overexpression of nm23-H1 and nm23-H2 genes in colorectal carcinomas and loss of nm23-H1 expression in advanced tumour stages. Gut 37:712–720

    CAS  PubMed Central  PubMed  Google Scholar 

  • Masoudi N, Fancsalszky L, Pourkarimi E et al (2013) The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans. Development 140:3486–3495

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mileo AM, Piombino E, Severino A, Tritarelli A, Paggi MG, Lombardi D (2006) Multiple interference of the human papillomavirus-16 E7 oncoprotein with the functional role of the metastasis suppressor Nm23-H1 protein. J Bioenerg Biomembr 38:215–225

    CAS  PubMed  Google Scholar 

  • Miyamoto M, Iwashita S, Yamaguchi S, Ono Y (2009) Role of nm23 in the regulation of cell shape and migration via Rho family GTPase signals. Mol Cell Biochem 329:175–179

    CAS  PubMed  Google Scholar 

  • Miyazaki H, Fukuda M, Ishijima Y et al (1999) Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. Clin Cancer Res 5:4301–4307

    CAS  PubMed  Google Scholar 

  • Monig SP, Nolden B, Lubke T et al (2007) Clinical significance of nm23 gene expression in gastric cancer. Anticancer Res 27:3029–3033

    PubMed  Google Scholar 

  • Murakami H, Sanderson ND, Nagy P, Marino PA, Merlino G, Thorgeirsson SS (1993) Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res 53:1719–1723

    CAS  PubMed  Google Scholar 

  • Neidle S (2010) Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer. FEBS J 277:1118–1125

    CAS  PubMed  Google Scholar 

  • New DC, Wong YH (2007) Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression. J Mol Signal 2:2. doi:10.1186/1750-2187-2-2

    PubMed Central  PubMed  Google Scholar 

  • Niitsu N, Okabe-Kado J, Nakayama M et al (2000) Plasma levels of the differentiation inhibitory factor nm23–H1 protein and their clinical implications in acute myelogenous leukemia. Blood 96:1080–1086

    CAS  PubMed  Google Scholar 

  • Niitsu N, Okabe-Kado J, Okamoto M et al (2001) Serum nm23-H1 protein as a prognostic factor in aggressive non-Hodgkin lymphoma. Blood 97:1202–1210

    CAS  PubMed  Google Scholar 

  • Nosaka K, Kawahara M, Masuda M, Satomi Y, Nishino H (1998) Association of nucleoside diphosphate kinase nm23-H2 with human telomeres. Biochem Biophys Res Commun 243:342–348

    CAS  PubMed  Google Scholar 

  • Ohya S, Fukuyo Y, Kito H et al (2014) Upregulation of KCa3.1 K+ channel in mesenteric lymph node CD4+ T lymphocytes from a mouse model of dextran sodium sulfate-induced inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 306:G873–G885

    CAS  PubMed  Google Scholar 

  • Okabe-Kado J, Kasukabe T, Honma Y, Hayashi M, Henzel WJ, Hozumi M (1992) Identity of a differentiation inhibiting factor for mouse myeloid leukemia cells with NM23/nucleoside diphosphate kinase. Biochem Biophys Res Commun 182:987–994

    CAS  PubMed  Google Scholar 

  • Okabe-Kado J, Kasukabe T, Baba H, Urano T, Shiku H, Honma Y (1995a) Inhibitory action of nm23 proteins on induction of erythroid differentiation of human leukemia cells. Biochim Biophys Acta 1267:101–106

    PubMed  Google Scholar 

  • Okabe-Kado J, Kasukabe T, Hozumi M et al (1995b) A new function of Nm23/NDP kinase as a differentiation inhibitory factor, which does not require its kinase activity. FEBS Lett 363:311–315

    CAS  PubMed  Google Scholar 

  • Okabe-Kado J, Kasukabe T, Honma Y (1998) Differentiation inhibitory factor Nm23 as a prognostic factor for acute myeloid leukemia. Leuk Lymphoma 32:19–28

    CAS  PubMed  Google Scholar 

  • Okabe-Kado J, Kasukabe T, Honma Y (2002) Expression of cell surface NM23 proteins of human leukemia cell lines of various cellular lineage and differentiation stages. Leuk Res 26:569–576

    CAS  PubMed  Google Scholar 

  • Okabe-Kado J, Kasukabe T (2003) Physiological and pathological relevance of extracellular NM23/NDP kinases. J Bioenerg Biomembr 35:89–93

    CAS  PubMed  Google Scholar 

  • Paravicini G, Steinmayr M, Andre E, Becker-Andre M (1996) The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem Biophys Res Commun 227:82–87

    CAS  PubMed  Google Scholar 

  • Polanski R, Maguire M, Nield PC et al (2011) MDM2 interacts with NME2 (non-metastatic cells 2, protein) and suppresses the ability of NME2 to negatively regulate cell motility. Carcinogenesis 32:1133–1142

    CAS  PubMed  Google Scholar 

  • Postel EH, Berberich SJ, Flint SJ, Ferrone CA (1993) Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261:478–480

    CAS  PubMed  Google Scholar 

  • Postel EH, Weiss VH, Beneken J, Kirtane A (1996) Mutational analysis of NM23-H2/NDP kinase identifies the structural domains critical to recognition of a c-myc regulatory element. Proc Natl Acad Sci U S A 93:6892–6897

    CAS  PubMed Central  PubMed  Google Scholar 

  • Postel EH, Abramczyk BM, Levit MN, Kyin S (2000) Catalysis of DNA cleavage and nucleoside triphosphate synthesis by NM23-H2/NDP kinase share an active site that implies a DNA repair function. Proc Natl Acad Sci U S A 97:14194–14199

    CAS  PubMed Central  PubMed  Google Scholar 

  • Postel EH, Abramczyk BA, Gursky SK, Xu Y (2002) Structure-based mutational and functional analysis identify human NM23-H2 as a multifunctional enzyme. Biochemistry 41:6330–6337

    CAS  PubMed  Google Scholar 

  • Postel EH, Zou X, Notterman DA, La Perle KMD (2009) Double knockout Nme1/Nme2 mouse model suggests a critical role for NDP kinases in erythroid development. Mol Cell Biochem 329:45–50

    CAS  PubMed  Google Scholar 

  • Radovic S, Doric M, Hukic A, Babic M, Kuskunovic S, Spahovic N (2013) Immunohistochemical expression and significance of NM23 suppressor protein in primary gastric adenocarcinoma. Bosn J Basic Med Sci 13:72–77

    CAS  PubMed  Google Scholar 

  • Rayner K, Chen YX, Hibbert B et al (2007) NM23-H2, an estrogen receptor β-associated protein, shows diminished expression with progression of atherosclerosis. Am J Physiol Regul Integr Comp Physiol 292:R743–R750

    CAS  PubMed  Google Scholar 

  • Rayner K, Chen YX, Hibbert B et al (2008) Discovery of NM23-H2 as an estrogen receptor beta-associated protein: role in estrogen-induced gene transcription and cell migration. J Steroid Biochem Mol Biol 108:72–81

    CAS  PubMed  Google Scholar 

  • Rochdi MD, Laroche G, Dupre E et al (2004) Nm23-H2 interacts with a G protein-coupled receptor to regulate its endocytosis through an Rac1-dependent mechanism. J Biol Chem 279:18981–18989

    CAS  PubMed  Google Scholar 

  • Rumjahn SM, Javed MA, Wong N, Law WE, Buxton IL (2007) Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase. Br J Cancer 97:1372–1380

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sarris M, Lee CS (2001) nm23 protein expression in colorectal carcinoma metastasis in regional lymph nodes and the liver. Eur J Surg Oncol 27:170–174

    CAS  PubMed  Google Scholar 

  • Sato Y, Tsuchiya B, Urao T, Baba H, Shiku H, Kodama T, Kameya T (2000) Semiquantitative immunoblot analysis of nm23-H1 and -H2 isoforms in adenocarcinomas of the lung: prognostic significance. Pathol Int 50:200–205

    CAS  PubMed  Google Scholar 

  • Shaul YD, Seger R (2007) The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 1773:1213–1226

    CAS  PubMed  Google Scholar 

  • Smagghe BJ, Stewart AK, Carter MG et al (2013) MUC1* ligand, NM23-H1, is a novel growth factor that maintains human stem cells in a more naive state. PLoS One 8:e58601

    CAS  PubMed Central  PubMed  Google Scholar 

  • Srivastava S, Li Z, Ko K et al (2006) Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Mol Cell 24:665–675

    CAS  PubMed  Google Scholar 

  • Steeg PS (1991) Genetic control of the metastatic phenotype. Semin Cancer Biol 2:105–110

    CAS  PubMed  Google Scholar 

  • Steeg PS, Bevilacqua G, Kopper L et al (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80:200–204

    CAS  PubMed  Google Scholar 

  • Steeg PS, de la Rosa A, Flatow U, MacDonald NJ, Benedict M, Leone A (1993) Nm23 and breast cancer metastasis. Breast Cancer Res Treat 25:175–187

    CAS  PubMed  Google Scholar 

  • Steeg PS, Zollo M, Wieland T (2011) A critical evaluation of biochemical activities reported for the nucleoside diphosphate kinase/Nm23/Awd family proteins: opportunities and missteps in understanding their biological functions. Naunyn Schmiedebergs Arch Pharmacol 384:331–339

    CAS  PubMed  Google Scholar 

  • Syed V, Mukherjee K, Lyons-Weiler J et al (2005) Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. Oncogene 24:1774–1787

    CAS  PubMed  Google Scholar 

  • Tagashira H, Hamazaki K, Tanaka N, Gao C, Namba M (1998) Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2/rat nucleoside diphosphate kinase alpha isoform. Int J Mol Med 2:65–68

    CAS  PubMed  Google Scholar 

  • Tannapfel A, Anhalt K, Hausermann P et al (2003) Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol 201:238–249

    CAS  PubMed  Google Scholar 

  • Tas F, Tuzlali S, Aydiner A et al (2002) Prognostic role of nm23 gene expression in patients with ovarian cancer. Am J Clin Oncol 25:164–167

    PubMed  Google Scholar 

  • Toksoz D, Williams DA (1994) Novel human oncogene lbc detected by transfection with distinct homology regions to signal transduction products. Oncogene 9:621–628

    CAS  PubMed  Google Scholar 

  • Tschiedel S, Gentilini C, Lange T et al (2008) Identification of NM23-H2 as a tumour-associated antigen in chronic myeloid leukaemia. Leukemia 22:1542–1550

    CAS  PubMed  Google Scholar 

  • Tschiedel S, Bach E, Jilo A et al (2012) Bcr-Abl dependent post-transcriptional activation of NME2 expression is a specific and common feature of chronic myeloid leukemia. Leuk Lymphoma 53:1569–1576

    CAS  PubMed  Google Scholar 

  • Tso PH, Wang YC, Yung LY, Tong Y, Lee MMK, Wong YH (2013) RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras. Cell Signal 25:1064–1074

    CAS  PubMed  Google Scholar 

  • Urano T, Takamiya K, Furukawa K, Shiku H (1992) Molecular cloning and functional expression of the second mouse nm23/NDP kinase gene, nm23-M2. FEBS Lett 309:358–362

    CAS  PubMed  Google Scholar 

  • Valentijn LJ, Koppen A, van Asperen R et al (2005) Inhibition of a new differentiation pathway in neuroblastoma by copy number defects of N-myc, Cdc42, and nm23 genes. Cancer Res 65:3136–3145

    CAS  PubMed  Google Scholar 

  • van Steensel B, de Lange T (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385:740–743

    PubMed  Google Scholar 

  • Webb PA, Perisic O, Mendola CE, Backer JM, Williams RL (1995) The crystal structure of a human nucleoside diphosphate kinase, NM23-H2. J Mol Biol 251:574–587

    CAS  PubMed  Google Scholar 

  • Wei SJ, Trempus CS, Ali RC, Hansen LA, Tennant RW (2004) 12-O-tetradecanoylphorbol-13-acetate and UV radiation-induced nucleoside diphosphate protein kinase B mediates neoplastic transformation of epidermal cells. J Biol Chem 279:5993–6004

    CAS  PubMed  Google Scholar 

  • Wieland T (2007) Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein betagamma dimers: consequences on G protein activation and stability. Naunyn Schmiedebergs Arch Pharmacol 374:373–383

    CAS  PubMed  Google Scholar 

  • Willems R, Van Bockstaele DR, Lardon F et al (1998) Decrease in nucleoside diphosphate kinase (NDPK/nm23) expression during hematopoietic maturation. J Biol Chem 273:13663–13668

    CAS  PubMed  Google Scholar 

  • Willems R, Slegers H, Rodrigus I et al (2002) Extracellular nucleoside diphosphate kinase NM23/NDPK modulates normal hematopoietic differentiation. Expt Hematol 30:640–648

    CAS  Google Scholar 

  • Wuelling M, Delling G, Kaiser E (2004) Differential gene expression in stromal cells of human giant cell tumor of bone. Virchows Arch 445:621–630

    CAS  PubMed  Google Scholar 

  • Xu JD, Cao XX, Long ZW et al (2011) BCL2L10 protein regulates apoptosis/proliferation through differential pathways in gastric cancer cells. J Pathol 223:400–409

    CAS  PubMed  Google Scholar 

  • Yamashiro S, Urano T, Shiku H, Furukawa K (1994) Alteration of nm23 gene expression during the induced differentiation of human leukemia cell lines. Oncogene 9:2461–2468

    CAS  PubMed  Google Scholar 

  • Yao Y, Li C, Zhou X et al. (2014) PIWIL2 induces c-Myc expression by interacting with NME2 and regulates c-Myc-mediated tumor cell proliferation. Oncotarget 5:8466–8477

    PubMed Central  PubMed  Google Scholar 

  • Yokoyama A, Okabe-Kado J, Sakashita A et al (1996) Differentiation inhibitory factor nm23 as a new prognostic factor in acute monocytic leukemia. Blood 88:3555–3561

    CAS  PubMed  Google Scholar 

  • Yung LY, Lam WS, Ho MK et al (2012) Astragaloside IV and cycloastragenol stimulate the phosphorylation of extracellular signal-regulated protein kinase in multiple cell types. Planta Medica 78:115–121

    CAS  PubMed  Google Scholar 

  • Zhu S, Wurdak H, Wang J et al (2009) A small molecule primes embryonic stem cells for differentiation. Cell Stem Cell 4:416–426

    CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by the National Key Basic Research Program of China (2013CB530900), Hong Kong RGC (663110 and 663412), UGC (T13-607/12R), and the Hong Kong Jockey Club.

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The authors declare no conflict of interest.

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Correspondence to Yung H. Wong.

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Li, Y., Tong, Y. & Wong, Y.H. Regulatory functions of Nm23-H2 in tumorigenesis: insights from biochemical to clinical perspectives. Naunyn-Schmiedeberg's Arch Pharmacol 388, 243–256 (2015). https://doi.org/10.1007/s00210-014-1066-1

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  • DOI: https://doi.org/10.1007/s00210-014-1066-1

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