NME1 (NME/NM23 nucleoside diphosphate kinase 1)

2013-02-01   Marie-Lise Lacombe , Mathieu Boissan 

INSERM UMRS_938, UPMC Univ Paris 06, 27 rue Chaligny, 75012 Paris, France

Identity

HGNC
LOCATION
17q21.33
LOCUSID
ALIAS
AWD,GAAD,NB,NBS,NDKA,NDPK-A,NDPKA,NM23,NM23-H1
FUSION GENES

DNA/RNA

Note

The NME1 gene was identified in 1988 as the first metastasis suppressor, due to its reduced expression in metastatic murine melanoma cell line (Steeg et al., 1988; reviewed in: Lee et al., 2009). The human gene, also named NM23-H1, was shown to be homologous to the Drosophila AWD gene, involved in larvae development, and to exhibit an expression inversely correlated to the metastatic spread in primary breast tumors (Rosengard et al., 1989). It is the first described member of a family of ten genes in human (Desvignes et al., 2009; reviewed in: Boissan et al., 2009).
Atlas Image
The NME1 gene viewed at three different levels of detail (highlighted between two red vertical boundary lines). 1) Overview within chromosome 17. 2) Partial regional view within chromosome 17q21.3. 3) Detailed view within chromosome 17q21.33 showing two of the transcription variants of NME1, which include NME1 (NM_000269.2) and NME1B (NM_198175.1). Abbreviations: M and K: mega- and kilobase pairs from pter; Kbp: kilobase pairs; Chr: chromosome; CDS: coding sequence.

Description

The gene is composed of 6 exons of which five are coding exons. Exon 2 skipping results in a shorter transcript.

Transcription

Two transcripts have been reported for this gene (Rosengard et al., 1989; Ni et al., 2003). A read-through variant, resulting of the co-transcription of NME1 and the neighboring NME2, generates a transcript, which encodes a fusion protein sharing identity with each individual gene products (Valentijn et al., 2006).

Pseudogene

A pseudogene of NME1 (NME1P1) is located on chromosome 13q12.11 (NC_000013.10, Gene ID: 100874501).

Proteins

Note

The NME1 gene encodes a nucleoside diphosphate kinase (NDPK) (Wallet et al., 1990). The two most abundantly expressed and the most studied genes are NM23-H1 and NM23-H2 (NME1 and NME2). They encode, respectively the A and B subunits of NDPK, 88% identical in their amino acid sequences (Gilles et al., 1991).
NME1 was demonstrated to be a metastasis suppressor 1) by its enforced expression in various metastatic cell lines which decreased motility and invasion (Lee et al., 2009), 2) in double transgenic mice invalidated for Nme1 and prone to develop hepatocarcinoma in which lack of Nme1 increased incidence of pulmonary metastases (Boissan et al., 2005) and 3) by its invalidation (SiRNA) in non-aggressive hepatoma and colon cancer cell lines which induced a "metastatic phenotype" (Boissan et al., 2010). The role of the homologous gene, NME2, in cancer progression is less documented (reviewed in: Thakur et al., 2011).
The mechanisms involved in the metastatic potential control are largely unknown. They could involve several known NM23 enzymatic activities (nucleoside diphosphate kinase, histidine kinase, and 3-5 exonuclease), protein-protein interactions and downstream gene regulation properties (for reviews: Marino et al., 2011; Marino et al., 2012). A Granzyme A activated DNAse (GAAD) activity involved in caspase-independent apoptosis was also reported for this gene (reviewed in: Lieberman, 2010).

Description

The main transcript encodes a protein of 152 amino acids with a Mr of 17 kDa (Rosengard et al., 1989). The longer transcript encodes a protein of 177 amino acids (Ni et al., 2003).

Expression

Ubiquitous.

Localisation

Mostly cytoplasmic but also reported in nucleus (Bosnar et al., 2009).

Function

Nucleoside diphosphate kinase activity responsible for the synthesis of most cellular (oxy- and deoxy-) nucleoside triphosphates (Parks and Agarwal, 1973). Other functions have been proposed, histidine protein kinase activity, 3-5 exonuclease activity (for review: Marino et al., 2011) and Granzyme A activated DNAse (GAAD) activity (Lieberman, 2010).

Homology

The human NME1 gene is conserved in amniota with a high percentage of identity in the pairwise alignment of protein vs. chimpanzee (99%), rat (95%), mouse (94%), dog (93%), cow (93%), opossum (89%) and chicken (84%). The paralogs of human NME1 include NME2, NME3, NME4, NME5, NME6, NME7, NME8 (TXNDC3), NME9 (TXL2) and RP2 (NME10) (Desvignes et al., 2009; Desvignes et al., 2010). These genes encode one (NME1 to NME6 and NME9) or several (NME7 and NME8) conserved NDPK domains, either full length or truncated. The NDPK domain occurs individually or associated with extra-domains (NME5, NME7, NME8, NME9 and RP2) (Boissan et al., 2009).

Mutations

Note

A S120G mutation was reported in aggressive neuroblastoma (Chang et al., 1994).

Implicated in

Entity name
Cancers
Note
NME1 plays a crucial role in cancer metastasis. Numerous clinical studies reported an inverse association between NME1 expression and the metastatic potential for human solid tumors of epithelial origin such as breast, liver, colorectal, ovarian and lung carcinomas and for melanoma (for review: Marino et al., 2012). A dual expression was reported with an increased expression of NME1 and often NME2 in the primary tumor as compared to the adjacent non-tumoral tissue (Lacombe et al., 1991; Flørenes et al., 1992; Martinez et al., 1995) and with a decreased expression of NME1 in the primary tumor correlated with metastatic spread. If, for liver, breast and lung carcinomas and for melanoma, the vast majority of studies reported an inverse correlation with metastasis and/or poor overall survival, this is less marked in colorectal, gastric and ovarian carcinomas for which more discrepant results are found. The conflicting data reported in the literature, might be due to the presence of the two closely related isoforms (NME1 and NME2) which are most often not discriminated by antibodies and probes, the heterogeneous expression in the primary tumors and the criteria to evaluate and grade NME1 expression in the clinical samples.
Remarkably, enforced NME1 expression induced by transfection in epithelial cancer derived cell lines and melanoma reverses their motility and invasive potential. This was observed with cell lines derived from melanoma (Leone et al., 1991) and from breast (Leone et al., 1993a), colon (Suzuki et al., 2004), lung (Nie et al., 2008), liver (She et al., 2010), ovarian (Li et al., 2006), prostate (Andolfo et al., 2011) and oral (Wang YF et al., 2008) carcinomas.
In other types of cancers such as neuroblastoma (Leone et al., 1993b; Garcia et al., 2012), hematopoietic malignancies (Yokoyama et al., 1998) and osteosarcoma (Liao et al., 2000), a high tumoral expression was noted which was most often correlated with poor clinical outcome.
Entity name
Breast cancer
Note
Most clinical studies reported an inverse correlation between NME1 expression in breast primary tumors and the metastatic dissemination and/or shorter patient survival (Bevilacqua et al., 1989; Hennessy et al., 1991; Tokunaga et al., 1993; Toulas et al., 1996; Charpin et al., 1997; Caligo et al., 1997; Yamaguchi et al., 1998; Yoshida et al., 1998; Bertheau et al., 1998; Heimann et al., 2000; Mao et al., 2001; Terasaki-Fukuzawa et al., 2002; Niu et al., 2002; Ding and Wu, 2004; Bal et al., 2008; Dong et al., 2011). In some cases, an increased NME1 expression in tumoral cells as compared to normal tissue was observed (Lacombe et al., 1991; Goodall et al., 1994; Caligo et al., 1997). However, some studies showed that NME1 expression was of no prognostic relevance (Russo et al., 1996; Russell et al., 1997; Belev et al., 2002; Göhring et al., 2002) or even positively associated with a poor overall survival (Galani et al., 2002). Yoshida et al. (Yoshida et al., 1998) noted a low NME1 expression at the invasive front. Forced expression of NME1 by transfection in breast cancer cell lines reduced cell motility in vitro and metastasis formation in xenograft mouse models (Kantor et al., 1993; Leone et al., 1993a; Russell et al., 1998; Bhujwalla et al., 1999).
Entity name
Hepatobiliary carcinoma
Note
Hepatobiliary carcinoma are among of the most aggressive cancers with a five year survival of less than 15%. Most studies reported an inverse association between NME1 expression and metastatic dissemination in hepatocellular carcinoma (reviews: Boissan and Lacombe, 2006 and An et al., 2010) and gallbladder carcinoma (Lee and Pirdas-Zivcic, 1994; Yang et al., 2008) but this is not always the case (Lin et al., 1998). Boissan et al. (2010) noted a low NME1 expression at the invasive front of hepatocellular carcinoma. Also, highly aggressive hepatocarcinoma cell lines exhibited a decrease level of NME1 as compared to less aggressive counterpart (Lin et al., 1995; Qin et al., 2007). NME1 overexpression, induced by transfection in the H7721 hepatocarcinoma cell line, inhibited cell migration and invasion (She et al., 2010). Conversely, NME1 silencing in non-aggressive hepatoma cell lines, HepG2 and PLC/PRF5 (Boissan et al., 2010), induced several parameters of a "metastatic phenotype" (loss of cell-cell contacts, increased motility and invasion).
Entity name
Lung carcinoma
Note
In lung carcinoma, an inverse association with metastatic spread was reported by several studies (Huwer et al., 1994; Lai et al., 1996; Kawakubo et al., 1997; Ohta et al., 2001; Graham et al., 2002; Katakura et al., 2002; Goncharuk et al., 2004; Tang et al., 2005; Chen et al., 2005; Liu et al., 2011) but was not found by others (Higashiyama et al., 1992; Gazzeri et al., 1996; MacKinnon et al., 1997; Tomita et al., 1999; Wang et al., 2010). Some studies noted an increased level of NME1 in tumors as compared to non-tumoral tissue (Huwer et al., 1994; Gazzeri et al., 1996). Few studies reported a positive association between NME1 expression and metastatic dissemination to lymph nodes (Tomita et al., 2001). NME1 determination in bronchial lavages was proposed as a diagnostic tool for lung cancer (Huwer et al., 1997). In lung carcinoma cell lines, increased NME1 expression (Nie et al., 2008) and NME1 silencing (Zhao et al., 2013) decreased invasion and increased TGFβ-induced epithelial mesenchymal transition, respectively.
Entity name
Melanoma
Note
An inverse correlation between NME1 mRNA levels and malignant potential of melanoma was reported in several studies (Flørenes et al., 1992; Xerri et al., 1994). This correlation was also found by immunohistochemical studies (Lee et al., 1996; Sarris et al., 2004; Ferrari et al., 2007), one including more than 100 patients (McDermott et al., 2000). However, other studies, including fewer cases, concluded to a lack of correlation (Easty et al., 1996; Saitoh et al., 1996; van den Oord et al., 1997).
In uveal melanoma, high NME1 expression was related to better survival rate (Bakalian et al., 2007) and, inversely, with prognostic factors of metastasis (Greco et al., 1997). Moreover, the high expression of NME1 mRNA and NME1 protein in derived-cell lines from human uveal melanomas is closely correlated with a reduced metastatic behavior in experimental animals (Ma et al., 1996). In accordance with its role as a metastasis suppressor, NME1 deficiency promotes metastasis in a UV radiation-induced mouse model of human melanoma (Jarrett et al., 2013). Enforced expression of NME1 in aggressive melanoma cell lines inhibited their metastatic potential (Leone et al., 1991; Zabrenetzky et al., 1994).
Entity name
Colorectal cancer
Note
Concerning colorectal cancers (CRC), data about NME1 expression are highly conflicting. An enhanced NME1 expression was noted in CRC as compared to normal adjacent tissues at the mRNA (Ayhan et al., 1993; Myeroff and Markowitz, 1993; Yamaguchi et al., 1993; Zeng et al., 1994; Martinez et al., 1995; Okuno et al., 2001) as well as at the protein (Haut et al., 1991; Ayhan et al., 1993; Martinez et al., 1995; Sarris and Lee, 2001; Kapitanovic et al., 2004; Lin et al., 2011; Alvarez-Chaver et al., 2011) levels. Several studies reported 1) an inverse correlation with tumor stages (Cheah et al., 1998) and metastatic spread (Ayhan et al., 1993; Yamaguchi et al., 1993; Royds et al., 1994a; Martinez et al., 1995; Tannapfel et al., 1997; Dursun et al., 2002; Bertucci et al., 2004; Su and Li, 2004; Kapitanovic et al., 2004; Liu et al., 2005; Elagoz et al., 2006; Chen et al., 2007; Lin et al., 2011) or 2) no correlation (Haut et al., 1991; Myeroff and Markowitz, 1993; Ichikawa, 1994; Heide et al., 1994; Lindmark, 1996; Heys et al., 1998; Tabuchi et al., 1999; Lee et al., 2001; Dusonchet et al., 2003; Soliani et al., 2004; Qian et al., 2012) and 3) even a positive correlation with aggressiveness (Berney et al., 1999; Brenner et al., 2003). Boissan et al. (2010) observed a low NME1 expression at the invasive front of CRC.
In contrast to other cancers, for which NME1 LOH was rarely reported, several studies reported LOH for NME1 gene in CRC (Lamb et al., 1996; Lenehan et al., 1997; Sugai et al., 2000; Tsai et al., 2002; Kapitanovic et al., 2004). Allelic loss was correlated with advanced stage of the disease (Kapitanovic et al., 2004), shorter disease free and overall patient survival (Campo et al., 1994) and with formation of distant metastases (Wang et al., 1993; Cohn et al., 1997; Yang et al., 2008) or not correlated (Lamb et al., 1996). In addition, few studies reported no allellic loss of NME1 in CRC (Heide et al., 1994; Cawkwell et al., 1994).
Enhanced expression of NME1 by transfection in colon cancer cell lines reduced their migratory ability and their metastatic potential to the liver (Suzuki et al., 2004). Conversely, silencing NME1 expression by SiRNA in the colon cancer cell line, HCT8/S11, induced a "metastatic phenotype" (Boissan et al., 2010).
Entity name
Gastric carcinoma
Note
In gastric carcinoma, many studies reported a negative correlation between NME1 expression in the primary tumors and advanced stage of the disease (Yang et al., 2008), metastatic dissemination (Kodera et al., 1994; Kim et al., 1995; Ura et al., 1996; Wang et al., 1999; Terada et al., 2002; Li et al., 2003; Chen et al., 2004; Liu et al., 2005; Guan-Zhen et al., 2007) and overall poor survival (Ura et al., 1996; Terada et al., 2002; Li et al., 2003). However, in some studies, NME1 expression was not correlated (Müller et al., 1998; Yoo et al., 1999; Lee et al., 2003; Mönig et al., 2007; Wang LB et al., 2008) or positively correlated (Wang et al., 1998; Nesi et al., 2001) with metastasis and poor survival.
Entity name
Ovarian carcinoma
Note
In ovarian cancers, conflicting results were obtained. If several studies observed an inverse correlation with metastatic dissemination and/or poor patient survival (Mandai et al., 1994; Kapitanovic et al., 1995; Okubo et al., 1995; Scambia et al., 1996; Ferrandina et al., 1996; Qian et al., 1997; Galani et al., 2002; Hua et al., 2008), other studies did not observed any correlation (Baekelandt et al., 1999) and others reported a positive correlation with advanced stages, lymph node invasion or shorter overall survival (Leary et al., 1995; Harlozinska et al., 1996; Schneider et al., 2000; Arik and Kulacoglu, 2011). NME1 overexpression induced by transfection inhibited the metastatic potential of aggressive ovarian cancer cells (Li et al., 2006).
Entity name
Neuroblastoma
Note
In neuroblastoma, all studies reported an enhanced expression of NME1 in tumors, correlated, when evaluated, with a poor prognosis (Hailat et al., 1991; Leone et al., 1993b; Chang et al., 1994; Hiyama et al., 2004; Garcia et al., 2012). In accordance with a metastatic promoting role, enhanced NME1 expression in the NB69 neuroblastoma cell line increased cell migration and metastatic potential (Almgren et al., 2004). A S120G mutation of Nme1 was found in aggressive cases (Chang et al., 1994).
Entity name
Leukemia
Note
In several hematopoietic malignancies, NME1 was overexpressed and this high expression was positively correlated with poor prognosis. This was the case for acute myeloid leukemia (Yokoyama et al., 1996; Okabe-Kado et al., 1998; Wakimoto et al., 1998; Yokoyama et al., 1998; Cui et al., 2004), for Hodgkin and non Hodgkin lymphoma (Aryee et al., 1996; Lee et al., 2006), for acute lymphoid leukemia (Koomägi et al., 1998; Ning et al., 2009), for peripheral T-cell lymphoma (Niitsu et al., 2003a; Huang et al., 2006; Niitsu et al., 2011) and for diffuse large B-cell lymphoma (Niitsu et al., 2004). Interestingly, the poor prognosis can be evaluated by ELISA test of the NME1 level in patient sera for Hodgkin lymphoma (Niitsu et al., 2008) and non-Hodgkin lymphoma (Niitsu et al., 2001a; Niitsu et al., 2001b), for acute myeloid leukemia (Niitsu et al., 2000), for myelodysplastic syndrome (Ito et al., 2002), for diffuse large B-cell lymphoma (Niitsu et al., 2004; Niitsu et al., 2006) and for extranodal NK/T-cell lymphoma (Niitsu et al., 2003b). However, Bircan et al. (Bircan et al., 2008) reported that the increased NME1 expression was of no prognostic value in a series of Hodgkin and non Hodgkin lymphoma. Pointing to a role of extracellular NME1, recombinant NME1 protein was shown to promote the survival of acute myeloid leukemia blast cells (Okabe-Kado et al., 2009a; Lilly et al., 2011) but to decrease the survival of primary cultured normal peripheral blood mononuclear cells (Okabe-Kado et al., 2009b).
Entity name
Other cancers
Note
NME1 has been evaluated as a prognostic marker in other types of cancer with various results, against pointing to a potential interest of NME1 as a metastasis suppressor specifically in carcinoma.
Controversial data have been obtained for prostate cancers (reviewed in: Myers and Grizzle, 1997). Several studies reported NME1 overexpression in tumor cells as compared to normal prostatic tissue (Myers et al., 1996; Jensen et al., 1996; Igawa et al., 1996; Luo et al., 2001; Prowatke et al., 2007). NME1 expression was shown to be inversely correlated with metastatic dissemination (Konishi et al., 1993; Stravodimos et al., 2000; Ding et al., 2006), of no prognostic interest (Borchers et al., 1996; Prowatke et al., 2007) or even related to advanced stage of the disease (Igawa et al., 1994) and poor prognosis (Andolfo et al., 2011). Interestingly, NME1 overexpression induced by transfection in PC3 prostate cancer cells, inhibited cell motility (Andolfo et al., 2011).
Few reports exist for pancreas cancers. Friess et al. (Friess et al., 2001) reported that early pancreatic cancer stages exhibited higher NME1 immunostaining than advanced tumor stages, while Nakamori et al. (Nakamori et al., 1993) observed that NME1 expression was positively associated with lymph node metastasis.
In thyroid cancers, several studies reported an increased expression in primary tumors (Zou et al., 1993; Ferenc et al., 2004; Al-Maghrabi and Asa, 2005) and a reduced expression in the metastatic lymph nodes (Arai et al., 1995; Shirahige et al., 1997), most often not correlated with patient survival (Luo et al., 1993; Farley et al., 1993; Zou et al., 1993; Royds et al., 1994b; Okubo et al., 1995; Al-Maghrabi and Asa, 2005; Tabriz et al., 2009). Zafon et al. (2001) observed a decreased expression in metastatic lymph nodes from papillary and follicular carcinomas, correlated with a decreased overall patient survival in follicular carcinoma. Bertheau et al. (1994) noted a nuclear NME1 labeling associated with a longer disease free survival.
For head and neck squamous cell carcinoma, several studies pointed to the absence of prognostic interest for NME1 (Takes et al., 2001; Tsuzuki et al., 2005; Sheikh et al., 2006; Mhawech-Fauceglia et al., 2007). However, some authors reported a lower NME1 level in lymph nodes as compared to the primary tumor (Takes et al., 2001; Wang YF et al., 2008) or an inverse correlation with lymph node invasion but not associated with better survival (Song et al., 2000). McDonald et al. (1996) have shown that a high NME1 expression in the primary tumor predicts a favorable outcome although the reverse was found by another study (Pavelic et al., 2000). Wang YF et al. (2008) have observed a low NME1 level in lymph node metastases of patient with oral squamous cell carcinoma and that induced NME1 overexpression in these cancer derived cell lines decreased their invasive potential.
In osteosarcoma, a positive immunoreactivity was detected in tumoral cells (Oda et al., 1995; Liao et al., 2000), but no correlation (Liao et al., 2000; Ozger et al., 2009) or a positive correlation (Oda et al., 2000) between NME1 expression and metastatic spread was observed.
Two studies reported that NME1 expression could possess a diagnostic interest by discriminating between benign and malignant pheochromocytoma (Ohta et al., 2005; Saffar et al., 2011) with a lower expression in malignant tumors. This observation should be confirmed by larger studies.

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155636742004nm23-H1 expression and loss of heterozygosity in colon adenocarcinoma.Kapitanović S et al
119962412002Clinical significance of nm23 expression in resected pathologic-stage I, non-small cell lung cancer.Katakura H et al
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89242241995Expression of p53 and NDP-K/nm23 in gastric carcinomas--association with metastasis and clinicopathologic parameters.Kim KM et al
82933861994Expression of nm23 H-1 RNA levels in human gastric cancer tissues. A negative correlation with nodal metastasis.Kodera Y et al
76936351993Expression of nm23-H1 and nm23-H2 proteins in prostate carcinoma.Konishi N et al
98914831998nm23-H1 protein expression in newly diagnosed and relapsed childhood acute lymphoblastic leukemia.Koomägi R et al
16598431991Overexpression of nucleoside diphosphate kinase (Nm23) in solid tumours.Lacombe ML et al
88935911996Immunohistochemical analysis of nm23-H1 in stage I non-small cell lung cancer: a useful marker in prediction of metastases.Lai WW et al
86310331996Allelic imbalance at NME1 in microdissected primary and metastatic human colorectal carcinomas is frequent but not associated with metastasis to lymph nodes or liver.Lamb RF et al
76223071995Increased expression of the NME1 gene is associated with metastasis in epithelial ovarian cancer.Leary JA et al
89123481996Immunohistochemical demonstration of the nm23-H1 gene product in human malignant melanoma and Spitz nevi.Lee CS et al
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161799302006Inhibition of ovarian cancer metastasis by adeno-associated virus-mediated gene transfer of nm23H1 in an orthotopic implantation model.Li J et al
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85292111995Increased invasive activity of human hepatocellular carcinoma cells is associated with an overexpression of thyroid hormone beta 1 nuclear receptor and low expression of the anti-metastatic nm23 gene.Lin KH et al
95681751998Significance of nm23 mRNA expression in human hepatocellular carcinoma.Lin LI et al
220240622011Tissue microarrays in Chinese human rectal cancer: study of expressions of the tumor-associated genes.Lin MS et al
89125371996NM-23 H1 immunohistochemistry is not useful as predictor of metastatic potential of colorectal cancer.Lindmark G et al
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88439131996Association between NM23-H1 gene expression and metastasis of human uveal melanoma in an animal model.Ma D et al
91962971997p53, c-erbB-2 and nm23 expression have no prognostic significance in primary pulmonary adenocarcinoma.MacKinnon M et al
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111794912001Loss of nm23 expression predicts distal metastases and poorer survival for breast cancer.Mao H et al
217133832011Protein-protein interactions: a mechanism regulating the anti-metastatic properties of Nm23-H1.Marino N et al
227067792012Insights into the biology and prevention of tumor metastasis provided by the Nm23 metastasis suppressor gene.Marino N et al
85499511995Overexpression of nm23-H1 and nm23-H2 genes in colorectal carcinomas and loss of nm23-H1 expression in advanced tumour stages.Martinez JA et al
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111735801996nm23-H1 Expression in Squamous Cell Carcinoma of the Head and Neck.McDonald JS et al
166989502007Value of ezrin, maspin and nm23-H1 protein expressions in predicting outcome of patients with head and neck squamous-cell carcinoma treated with radical radiotherapy.Mhawech-Fauceglia P et al
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98744521998Expression of nm23 in gastric carcinoma: association with tumor progression and poor prognosis.Müller W et al
84183041993Increased nm23-H1 and nm23-H2 messenger RNA expression and absence of mutations in colon carcinomas of low and high metastatic potential.Myeroff LL et al
91525211997Changes in biomarker expression in the development of prostatic adenocarcinoma.Myers RB et al
88925851996Expression of nm23-H1 in prostatic intraepithelial neoplasia and adenocarcinoma.Myers RB et al
83830291993Expression of nucleoside diphosphate kinase/nm23 gene product in human pancreatic cancer: an association with lymph node metastasis and tumor invasion.Nakamori S et al
118485372001Expression of nm23 gene in gastric cancer is associated with a poor 5-year survival.Nesi G et al
126015552003Isolation and characterization of a novel human NM23-H1B gene, a different transcript of NM23-H1.Ni X et al
207319322008[The mechanism and influence on the biological behavior of human high-metastatic large cell lung cancer cell lines with transfection of nm23-H1 gene.].Nie Q et al
168058252006Phase II study of the CPT-11, mitoxantrone and dexamethasone regimen in combination with rituximab in elderly patients with relapsed diffuse large B-cell lymphoma.Niitsu N et al
214783362011Expression of nm23-H1 is associated with poor prognosis in peripheral T-cell lymphoma, not otherwise specified.Niitsu N et al
127507202003Serum levels of the nm23-H1 protein and their clinical implication in extranodal NK/T-cell lymphoma.Niitsu N et al
201136512009[Expression of nm23 H(1) gene in childhood acute lymphoblastic leukemia and the relationship between nm23 H(1) expression and immunophenotype].Ning F et al
119206472002Potential markers predicting distant metastasis in axillary node-negative breast carcinoma.Niu Y et al
108726652000Comparison of histological changes and changes in nm23 and c-MET expression between primary and metastatic sites in osteosarcoma: a clinicopathologic and immunohistochemical study.Oda Y et al
75931311995Immunohistochemical analysis of nm23 protein expression in malignant bone tumors.Oda Y et al
155236992005Downregulation of metastasis suppressor genes in malignant pheochromocytoma.Ohta S et al
112679482001The predictive value of vascular endothelial growth factor and nm23 for the diagnosis of occult metastasis in non-small cell lung cancer.Ohta Y et al
196552212009Extracellular NM23-H1 protein inhibits the survival of primary cultured normal human peripheral blood mononuclear cells and activates the cytokine production.Okabe-Kado J et al
85214521995Expression of nm23-H1 gene product in thyroid, ovary, and breast cancers.Okubo T et al
112279512001Gene expression analysis in colorectal cancer using practical DNA array filter.Okuno K et al
192936132009[The effect of resistance-related proteins on the prognosis and survival of patients with osteosarcoma: an immunohistochemical analysis].Ozger H et al
107945472000Increased activity of nm23-H1 gene in squamous cell carcinoma of the head and neck is associated with advanced disease and poor prognosis.Pavelić K et al
171464772007Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays.Prowatke I et al
230985012012Multivariate analysis of molecular indicators for postoperative liver metastasis in colorectal cancer cases.Qian LY et al
95942871997Expression of antimetastatic gene nm23-H1 in epithelial ovarian cancer.Qian M et al
179645172007Proliferation and migration mediated by Dkk-1/Wnt/beta-catenin cascade in a model of hepatocellular carcinoma cells.Qin X et al
196620922009Genome-wide profile of pleural mesothelioma versus parietal and visceral pleura: the emerging gene portrait of the mesothelioma phenotype.Røe OD et al
25099411989Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development.Rosengard AM et al
81959291994Nm23 'anti-metastatic' gene product expression in colorectal carcinoma.Royds JA et al
78087921994Nm23 protein expression in thyroid neoplasms.Royds JA et al
97432881998Relationship of nm23 to proteolytic factors, proliferation and motility in breast cancer tissues and cell lines.Russell RL et al
215943411996nm23-H1 protein immunohistochemical expression in human breast cancer.Russo A et al
213501022011Expression of galectin-3, nm-23, and cyclooxygenase-2 could potentially discriminate between benign and malignant pheochromocytoma.Saffar H et al
89715561996Expression of metastasis suppressor gene product, nm23 protein, is not inversely correlated with the tumour progression in human malignant melanomas.Saitoh K et al
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150911902004Cytoplasmic expression of nm23 predicts the potential for cerebral metastasis in patients with primary cutaneous melanoma.Sarris M et al
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108175012000nm23-H1 expression defines a high-risk subpopulation of patients with early-stage epithelial ovarian carcinoma.Schneider J et al
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Other Information

Locus ID:

NCBI: 4830
MIM: 156490
HGNC: 7849
Ensembl: ENSG00000239672

Variants:

dbSNP: 4830
ClinVar: 4830
TCGA: ENSG00000239672
COSMIC: NME1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000239672ENST00000013034P15531
ENSG00000239672ENST00000336097P15531
ENSG00000239672ENST00000393196P15531
ENSG00000239672ENST00000393196A0A384MTW7
ENSG00000239672ENST00000456492C9K028
ENSG00000239672ENST00000475573E5RHP0
ENSG00000239672ENST00000480143E7ERL0
ENSG00000239672ENST00000511355E5RHP0

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Purine metabolismKEGGko00230
Pyrimidine metabolismKEGGko00240
Purine metabolismKEGGhsa00230
Pyrimidine metabolismKEGGhsa00240
Metabolic pathwaysKEGGhsa01100
Pyrimidine ribonucleotide biosynthesis, UMP => UDP/UTP,CDP/CTPKEGGhsa_M00052
Adenine ribonucleotide biosynthesis, IMP => ADP,ATPKEGGM00049
Guanine ribonucleotide biosynthesis IMP => GDP,GTPKEGGM00050
Pyrimidine ribonucleotide biosynthesis, UMP => UDP/UTP,CDP/CTPKEGGM00052
Adenine ribonucleotide biosynthesis, IMP => ADP,ATPKEGGhsa_M00049
Guanine ribonucleotide biosynthesis IMP => GDP,GTPKEGGhsa_M00050
MetabolismREACTOMER-HSA-1430728
Metabolism of nucleotidesREACTOMER-HSA-15869
Synthesis and interconversion of nucleotide di- and triphosphatesREACTOMER-HSA-499943

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10005adefovir dipivoxilChemicalPathwayassociated
PA10204tenofovirChemicalPathwayassociated
PA450163lamivudineChemicalPathwayassociated
PA451954zidovudineChemicalPathwayassociated22960662

References

Pubmed IDYearTitleCitations
121052132002Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway.55
155926842005Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases.46
208414692010Implication of metastasis suppressor NM23-H1 in maintaining adherens junctions and limiting the invasive potential of human cancer cells.46
158704342005Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer.43
249700862014Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling.42
180898052007Nm23-H1 suppresses metastasis by inhibiting expression of the lysophosphatidic acid receptor EDG2.34
149605672004The metastasis suppressor NM23-H1 possesses 3'-5' exonuclease activity.32
187007472008Human metastasis regulator protein H-prune is a short-chain exopolyphosphatase.32
121635902002The metastatic suppressor Nm23-H1 interacts with EBNA3C at sequences located between the glutamine- and proline-rich domains and can cooperate in activation of transcription.31
197248522009CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer.28

Citation

Marie-Lise Lacombe ; Mathieu Boissan

NME1 (NME/NM23 nucleoside diphosphate kinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-02-01

Online version: http://atlasgeneticsoncology.org/gene/445/nme1