NME1

Gene Summary

Gene:NME1; NME/NM23 nucleoside diphosphate kinase 1
Aliases: NB, AWD, NBS, GAAD, NDKA, NM23, NDPKA, NDPK-A, NM23-H1
Location:17q21.33
Summary:This gene (NME1) was identified because of its reduced mRNA transcript levels in highly metastatic cells. Nucleoside diphosphate kinase (NDK) exists as a hexamer composed of 'A' (encoded by this gene) and 'B' (encoded by NME2) isoforms. Mutations in this gene have been identified in aggressive neuroblastomas. Two transcript variants encoding different isoforms have been found for this gene. Co-transcription of this gene and the neighboring downstream gene (NME2) generates naturally-occurring transcripts (NME1-NME2), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nucleoside diphosphate kinase A
Source:NCBIAccessed: 11 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Nucleoside-Diphosphate Kinase
  • Vascular Endothelial Growth Factors
  • Xenograft Models
  • Transcription Factors
  • Tumor Suppressor Gene
  • Uveal Neoplasms
  • Gene Expression
  • p53 Protein
  • Subcellular Fractions
  • Salivary Glands
  • Transcription
  • Cancer DNA
  • Ureteral Neoplasms
  • Urokinase-Type Plasminogen Activator
  • Survival Rate
  • Immunohistochemistry
  • Monomeric GTP-Binding Proteins
  • Neuroblastoma
  • NM23 Nucleoside Diphosphate Kinases
  • Molecular Sequence Data
  • Neoplasm Proteins
  • Polymerase Chain Reaction
  • Staging
  • Squamous Cell Carcinoma
  • Lymphatic Metastasis
  • Transfection
  • Eye Cancer
  • Breast Cancer
  • TGFA
  • Cervical Cancer
  • alpha-Fetoproteins
  • Uterine Cancer
  • Bladder Cancer
  • von Willebrand Factor
  • NME1
  • Chromosome 17
  • Biomarkers, Tumor
  • bcl-2-Associated X Protein
  • Cancer Gene Expression Regulation
  • Lung Cancer
  • Neoplasm Metastasis
  • Recombinant Fusion Proteins
  • Messenger RNA
  • Up-Regulation
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NME1 (cancer-related)

Guo XQ, Li XY
The expression and clinical significance of metastasis suppressor gene and matrix metalloproteinase-2 in esophageal squamous cell of carcinoma.
Pak J Pharm Sci. 2016; 29(4 Suppl):1339-42 [PubMed] Related Publications
To investigate the expression and clinical significance of metastasis suppressor gene and matrix metalloproteinase-2 in esophageal squamous cell of carcinoma. choose 30 cases of specimens of esophageal squamous cell carcinoma which are removed in surgery and confirmed by pathology and 30 cases of specimens of normal esophageal mucosa. Use immunohistochemistry SP method to detect the expression of nm23-H1, MMP-2 protein in esophageal squamous cell carcinoma and normal esophageal mucosal. The positive rate of nm23-H1 protein in esophageal squamous cell carcinoma was 43.3% (13/30), while that in normal esophageal mucosa was 100% (30/30), which has a significant difference between them (χ2=22. 083, P<0.05). The positive rate of MMP-2 protein in esophageal squamous cell carcinoma was 90.0% (27/30), while that in normal esophageal mucosa was 33.3% (10/30), and there is a significant difference between them (χ2=28. 370, P<0.05); For the expression of nm23-H1 and MMP-2 in esophageal squamous cell carcinoma, there was nothing to do with sex, age and tumor size (P>0.05), but it was related to the degree of tumor differentiation, depth of invasion and lymph node metastasis (P<0.05); The expression of nm23-H1 is related to the cut end of residual cancer (P<0.05), while the expression of MMP-2 has nothing to do with the cut end of residual cancer (P>0.05); The expression of nm23-H1 and MMP-2 in esophageal squamous cell carcinoma was negatively correlated. nm23-H1 and MMP-2 have played a role in the development of esophageal cancer, which can promote the occurence of distant metastasis; The loss of expression of nm23-H1 may be related to cut end residual cancer; nm23-H1 and MMP-2 may be as an indicator for esophageal cancer metastasis and prognosis.

Iqbal B, Masood A, Lone MM, et al.
Polymorphism of Metastasis Suppressor Genes MKK4 and NME1 in Kashmiri Patients with Breast Cancer.
Breast J. 2016; 22(6):673-677 [PubMed] Related Publications
Genetic polymorphisms in metastatic suppressor genes like MKK4 and NME1 are not well studied in breast cancer. Hence, we analyzed the relationship between MKK4 and NME1 polymorphisms and breast cancer risk in Kashmir, India. The different genotypes of NME1 and MKK4 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 130 breast cancer cases and 200 age- and sex-matched controls. Conditional logistic regression models were used to assess the association of various genotypes with breast cancer. In this study, we found an inverse association between MKK4 promoter polymorphism and breast cancer risk. As compared to TT (wild) genotype, individuals with TG (heterozygous) (OR = 0.32; 95% CI = (0.17-0.58) and GG (mutant) (OR = 0.13; CI = 0.04-0.40) genotypes showed decreased risk of breast cancer. When participants were classified on the basis of lymph node involvement, a strong association between NME1 heterozygous genotype (OR = 3.82; CI = (1.54-9.44) and breast cancer was found.

Romani P, Papi A, Ignesti M, et al.
Dynamin controls extracellular level of Awd/Nme1 metastasis suppressor protein.
Naunyn Schmiedebergs Arch Pharmacol. 2016; 389(11):1171-1182 [PubMed] Related Publications
Dynamin GTPase (Dyn) plays a critical role in membrane-remodelling events underlying endocytosis. Studies in Drosophila identified a functional interaction between the Dyn homologue, encoded by the shibire (shi) gene, and Abnormal wing discs (Awd), a nucleoside diphosphate kinase (NDPK) that is the homologue of group I Nme human genes. These Drosophila studies showed that awd mutations enhance mutant shi phenotype and thus indicated the existence of a highly specific interaction between these genes. Furthermore, in human cells, it has been shown that Nme proteins promote Dyn activity in different membrane compartments through spatially controlled supply of GTP. Interestingly, Awd and Nme proteins have been detected in the extracellular environment. While no role has been inferred to extracellular Awd, presence of Nme1 in cancer patient serum is an unfavourable prognostic marker. In the present work, we used Drosophila and human cell line models to investigate the shuttling Awd/Nme1 proteins between intracellular and extracellular spaces. By using classic and reverse genetic approaches, we show that downregulation of Shi/Dyn1 activity enhances extracellular Awd/Nme1 in both Drosophila and human colon cell lines. We extended our analyses to colon cancer cell lines and found that knocking down Dyn1, besides to raise Nme1 extracellular amount, downregulates expression of molecular components that play key roles in tumour invasion. Interestingly, in vivo analyses of Drosophila larval adipocytes show that the conditional block of Shi activity greatly reduces intracellular amount of Awd confirming that Shi plays a key role in controlling the balance between intracellular and extracellular Awd.

Zhao M, Wei C, Yang X, et al.
The milk-derived hexapeptide PGPIPN inhibits the invasion and migration of human ovarian cancer cells by regulating the expression of MTA1 and NM23H1 genes.
Int J Oncol. 2016; 48(4):1721-9 [PubMed] Related Publications
Some bioactive peptides derived from natural resources or synthesized by rational design have been proved to have very good anticancer effect. We studied the inhibition of PGPIPN, a hexapeptide derived from bovine β-casein, on the invasion and metastasis of human ovarian cancer cells in vitro and its molecular mechanism. The human ovarian cancer cells studied include the cell line SKOV3 as well as the primary ovarian cancer cells from ovarian tumor tissues of 37 patients at initial debulking surgery, diagnosed as serous ovarian adenocarcinoma. We showed that PGPIPN inhibited the invasion of ovarian cancer cells with Transwell chamber assay, the migration of ovarian cancer cells with cell scratch assay and colony formation of ovarian cancer cells. The expression (mRNAs and proteins) of genes relevant to invasion and metastasis, MTA1, and NM23H1 were analyzed by real-time PCR and western blotting. PGPIPN repressed the expression of MTA1, and promoted NM23H1. The effects of PGPIPN were dose-dependent. Thus, our study suggests that PGPIPN is a potential therapeutic agent for adjuvant therapy of human malignant ovarian tumors.

Wu CH, Lin YW, Wu TF, et al.
Clinical implication of voltage-dependent anion channel 1 in uterine cervical cancer and its action on cervical cancer cells.
Oncotarget. 2016; 7(4):4210-25 [PubMed] Free Access to Full Article Related Publications
Two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry were performed to investigate the influence of human nonmetastatic clone 23 type 1 (nm23-H1), a metastasis-associated gene on proteomic alterations in cancer cells of the uterine cervix. It was validated by RT-PCR and Western blot analysis. The expression of voltage-dependent anion channel 1 (VDAC1) was increased in nm23-H1 gene silenced SiHa or CaSki cervical cancer cells. The clinical implication was shown that cervical cancer tissues with positive VDAC1 immunoreactivity exhibited deep stromal invasion (>10 mm in depth) and large tumor size (> 4 cm in diameter). Cervical cancer patients with positive VDAC1 immunoreactivity displayed higher recurrence and poorer overall survival than those with negative VDAC1. Silencing of VDAC1 reduced cell proliferation and migratory ability. Mitochondrial membrane potential was decreased and reactive oxygen species generation was increased in the VDAC1 gene-silenced cervical cancer cells. Cell cycle progression and autophagy were not changed in VDAC1 silencing cells. The cytotoxicity of cisplatin was significantly enhanced by knockdown of cellular VDAC1 and the compounds that interfere with hexokinase binding to VDAC. Therapeutic strategies may be offered using VDAC1 as a target to reduce cell growth and migration, enhance the synergistic therapeutic efficacy of cisplatin and reduce cisplatin dose-limiting toxicity.

Fu JW, Chu XQ
Correlation between non-metastatic protein 23 expression and clinicopathological features of colorectal cancer in Asians.
Genet Mol Res. 2015; 14(4):15597-608 [PubMed] Related Publications
The current meta-analysis was performed to investigate the association between non-metastatic protein 23 (NM23) expression, tumor pathology, and disease prognosis in colorectal cancer (CRC) among Asians. English and Chinese language-based electronic databases (e.g., PubMed, EBSCO, Ovid, Springerlink, Wiley, Web of Science, Wanfang databases, China National Knowledge Infrastructure, VIP databases) were searched using search terms to identify published studies relevant to NM23 and CRC with immunohistochemistry. In total, 289 studies were identified through database searches, and 16 cohort studies (4 studies in English, 12 in Chinese) were chosen for meta-analysis, which included 1592 CRC patients. The results revealed that NM23 protein expression in CRC tissue was higher in patients with Dukes stages A and B than in patients with Dukes stages C and D. The NM23 protein was expressed at higher levels in well- and moderately differentiated tumors than in poorly differentiated tumors. The 5-year survival rate was also higher in CRC patients with NM23-positive tumors than in CRC patients with NM23-negative tumors. Significantly, 5-year tumor relapse and metastasis were lower in patients with NM23-positive tumors than in CRC patients with NM23-negative tumors. The findings suggest that NM23 expression status is associated with tumor aggressiveness and survival in CRC among Asians. Importantly, CRC patients with NM23-positive tumors had a better prognosis, and thus NM23 expression maybe used as a key prognostic indicator for CRC.

You DJ, Mander S, Park CR, et al.
NME1L Negatively Regulates IGF1-Dependent Proliferation of Breast Cancer Cells.
J Cell Biochem. 2016; 117(6):1454-63 [PubMed] Related Publications
Non-metastatic cells 1 (NME1) or nm23 is the first metastasis suppressor gene discovered. It functions through various enzymatic activities and interacts with many intracellular proteins. The NME1 gene encodes two splicing variants, NME1 and NME1L. Most studies have focused on NME1 because of its abundance in cells. We previously reported NME1L-mediated suppression of NF-κB signaling by interacting with and inhibiting IKKβ. In this study, we demonstrated that NME1L, but not NME1, mediated inhibition of cell proliferation, although both NME1 and NME1L were involved in suppressing metastasis. A reporter gene assay was performed to determine the growth signaling pathway regulated by NME1L but none of the growth factors tested could induce an NF-κB-dependent luciferase expression except TNFα. Interestingly, SRE-reporter gene activation by IGF1 was significantly downregulated, along with reduction of ERK phosphorylation in NME1L expressing cells, compared to vector or NME1 expressing cells. NME1L directly interacted with KSR1, which is a scaffold for Raf-1, MEK, and ERK, that regulates ERK activation. Hence, NME1L plays a crucial role in regulation of cell proliferation by inhibiting IGF1-stimulated ERK phosphorylation through N-terminal 25 amino acid-mediated interaction with KSR1.

Dorman SN, Baranova K, Knoll JH, et al.
Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning.
Mol Oncol. 2016; 10(1):85-100 [PubMed] Related Publications
Increasingly, the effectiveness of adjuvant chemotherapy agents for breast cancer has been related to changes in the genomic profile of tumors. We investigated correspondence between growth inhibitory concentrations of paclitaxel and gemcitabine (GI50) and gene copy number, mutation, and expression first in breast cancer cell lines and then in patients. Genes encoding direct targets of these drugs, metabolizing enzymes, transporters, and those previously associated with chemoresistance to paclitaxel (n = 31 genes) or gemcitabine (n = 18) were analyzed. A multi-factorial, principal component analysis (MFA) indicated expression was the strongest indicator of sensitivity for paclitaxel, and copy number and expression were informative for gemcitabine. The factors were combined using support vector machines (SVM). Expression of 15 genes (ABCC10, BCL2, BCL2L1, BIRC5, BMF, FGF2, FN1, MAP4, MAPT, NFKB2, SLCO1B3, TLR6, TMEM243, TWIST1, and CSAG2) predicted cell line sensitivity to paclitaxel with 82% accuracy. Copy number profiles of 3 genes (ABCC10, NT5C, TYMS) together with expression of 7 genes (ABCB1, ABCC10, CMPK1, DCTD, NME1, RRM1, RRM2B), predicted gemcitabine response with 85% accuracy. Expression and copy number studies of two independent sets of patients with known responses were then analyzed with these models. These included tumor blocks from 21 patients that were treated with both paclitaxel and gemcitabine, and 319 patients on paclitaxel and anthracycline therapy. A new paclitaxel SVM was derived from an 11-gene subset since data for 4 of the original genes was unavailable. The accuracy of this SVM was similar in cell lines and tumor blocks (70-71%). The gemcitabine SVM exhibited 62% prediction accuracy for the tumor blocks due to the presence of samples with poor nucleic acid integrity. Nevertheless, the paclitaxel SVM predicted sensitivity in 84% of patients with no or minimal residual disease.

Jha HC, Shukla SK, Lu J, et al.
Dissecting the contribution of EBNA3C domains important for EBV-induced B-cell growth and proliferation.
Oncotarget. 2015; 6(30):30115-29 [PubMed] Free Access to Full Article Related Publications
Epstein-Barr virus (EBV) is an oncogenic gammaherpes virus which is linked to pathogenesis of several human lymphatic malignancies. The EBV essential latent antigen EBNA3C is critical for efficient conversion of primary human B-lymphocytes to lymphoblastic cell lines and for continued LCL growth. EBNA3C, an EBV latent antigen with oncogenic potential can bind and regulate the functions of a wide range of cellular transcription factors. In our current reverse genetics study, we deleted the full length EBNA3C, and independently the RBP-Jκ and Nm23-H1 binding sites within EBNA3C using BACmid recombinant engineering methodology. Our experiments demonstrated that deletion of the EBV EBNA3C open reading frame (ORF) and more specifically the residues 621-675 which binds Nm23H1 and SUMO-1 showed a significant reduction in the ability of the cells to proliferate. Furthermore, they exhibited lower infectivity of human peripheral blood mononuclear cells (PBMCs). We also showed that recombinant EBV with deletions of the EBNA3C ORF, as well as a recombinant with residues 621-675 within EBNA3C ORF deleted had diminished abilities to activate CD40. Our study also revealed that the full length (1-992) and 621-675 aa deletions of EBNA3C when compared to wild type EBV infected PBMCs had differential expression patterns for the phosphorylation of MAP kinases specifically p38, JNK and ERK. Regulation of β-catenin also differed among wild type and EBNA3C deleted mutants. These temporal differences in signaling activities of these recombinant viruses in PBMCs is likely important in defining their functional importance in EBV-mediated B-cell transformation.

Davalieva K, Kostovska IM, Kiprijanovska S, et al.
Proteomics analysis of malignant and benign prostate tissue by 2D DIGE/MS reveals new insights into proteins involved in prostate cancer.
Prostate. 2015; 75(14):1586-600 [PubMed] Related Publications
BACKGROUND: The key to a more effective diagnosis, prognosis, and therapeutic management of prostate cancer (PCa) could lie in the direct analysis of cancer tissue. In this study, by comparative proteomics analysis of PCa and benign prostate hyperplasia (BPH) tissues we attempted to elucidate the proteins and regulatory pathways involved in this disease.
METHODS: The samples used in this study were fresh surgical tissues with clinically and histologically confirmed PCa (n = 19) and BPH (n = 33). We used two dimensional difference in gel electrophoresis (2D DIGE) coupled with mass spectrometry (MS) and bioinformatics analysis.
RESULTS: Thirty-nine spots with statistically significant 1.8-fold variation or more in abundance, corresponding to 28 proteins were identified. The IPA analysis pointed out to 3 possible networks regulated within MAPK, ERK, TGFB1, and ubiquitin pathways. Thirteen of the identified proteins, namely, constituents of the intermediate filaments (KRT8, KRT18, DES), potential tumor suppressors (ARHGAP1, AZGP1, GSTM2, and MFAP4), transport and membrane organization proteins (FABP5, GC, and EHD2), chaperons (FKBP4 and HSPD1) and known cancer marker (NME1) have been associated with prostate and other cancers by numerous proteomics, genomics or functional studies. We evidenced for the first time the dysregulation of 9 proteins (CSNK1A1, ARID5B, LYPLA1, PSMB6, RABEP1, TALDO1, UBE2N, PPP1CB, and SERPINB1) that may have role in PCa. The UBE2N, PSMB6, and PPP1CB, involved in cell cycle regulation and progression were evaluated by Western blot analysis which confirmed significantly higher abundances of UBE2N and PSMB6 and significantly lower abundance of PPP1CB in PCa.
CONCLUSION: In addition to the identification of substantial number of proteins with known association with PCa, the proteomic approach in this study revealed proteins not previously clearly related to PCa, providing a starting point for further elucidation of their function in disease initiation and progression.

Stremitzer S, Zhang W, Yang D, et al.
Variations in genes involved in dormancy associated with outcome in patients with resected colorectal liver metastases.
Ann Oncol. 2015; 26(8):1728-33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy.
PATIENTS AND METHODS: Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns.
RESULTS: NME1 rs34214448 C>A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T>C and CD44 rs8193 C>T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C>T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C>G, NME1 rs34214448 C>A and NOTCH3 rs1044009 T>C were the dominant SNPs predicting histological response, RFS and OS, respectively.
CONCLUSION: Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.

Lehmann R, Childs L, Thomas P, et al.
Assembly of a comprehensive regulatory network for the mammalian circadian clock: a bioinformatics approach.
PLoS One. 2015; 10(5):e0126283 [PubMed] Free Access to Full Article Related Publications
By regulating the timing of cellular processes, the circadian clock provides a way to adapt physiology and behaviour to the geophysical time. In mammals, a light-entrainable master clock located in the suprachiasmatic nucleus (SCN) controls peripheral clocks that are present in virtually every body cell. Defective circadian timing is associated with several pathologies such as cancer and metabolic and sleep disorders. To better understand the circadian regulation of cellular processes, we developed a bioinformatics pipeline encompassing the analysis of high-throughput data sets and the exploitation of published knowledge by text-mining. We identified 118 novel potential clock-regulated genes and integrated them into an existing high-quality circadian network, generating the to-date most comprehensive network of circadian regulated genes (NCRG). To validate particular elements in our network, we assessed publicly available ChIP-seq data for BMAL1, REV-ERBα/β and RORα/γ proteins and found strong evidence for circadian regulation of Elavl1, Nme1, Dhx6, Med1 and Rbbp7 all of which are involved in the regulation of tumourigenesis. Furthermore, we identified Ncl and Ddx6, as targets of RORγ and REV-ERBα, β, respectively. Most interestingly, these genes were also reported to be involved in miRNA regulation; in particular, NCL regulates several miRNAs, all involved in cancer aggressiveness. Thus, NCL represents a novel potential link via which the circadian clock, and specifically RORγ, regulates the expression of miRNAs, with particular consequences in breast cancer progression. Our findings bring us one step forward towards a mechanistic understanding of mammalian circadian regulation, and provide further evidence of the influence of circadian deregulation in cancer.

Novak M, Leonard MK, Yang XH, et al.
Metastasis suppressor NME1 regulates melanoma cell morphology, self-adhesion and motility via induction of fibronectin expression.
Exp Dermatol. 2015; 24(6):455-61 [PubMed] Free Access to Full Article Related Publications
Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility and invasion in vitro and metastasis in vivo, but the underlying molecular mechanisms are not completely understood. Herein, we report a novel mechanism through which NME1 controls melanoma cell morphology via upregulation of the extracellular matrix (ECM) protein fibronectin. Expression of NME1 strongly suppressed cell motility in melanoma cell lines 1205LU and M14. The resulting sedentary phenotype was associated with a more flattened appearance and marked increases in actin stress fibre and focal adhesion formation. NME1-induced focal adhesions were colocalized with dense deposits of fibronectin, which were absent or minimal in the corresponding NME1-deficient parental lines. NME1 was a strong inducer of fibronectin mRNA and protein expression, shown with reciprocal approaches of forced NME1 expression and shRNA-mediated knock-down. Increased synthesis and ECM deposition of fibronectin was necessary for NME1-induced cell spreading, as knock-down of fibronectin opposed the effects of NME1 on cell morphology. Fibronectin knock-down also reversed the ability of NME1 to promote aggregation when cells were plated on a non-adherent substratum. Similarly, inhibiting activation of the fibronectin receptor integrin α4β1 with an anti-α4 antibody reversed the motility-suppressing effect of NME1. A positive correlation was observed between NME1 and fibronectin mRNA in clinical biopsies of normal skin, benign nevi and primary melanomas, but not in metastatic forms, suggesting the NME1/fibronectin axis represents a barrier to melanoma progression. In summary, these findings indicate fibronectin is an important effector of the motility-suppressing function of NME1 in melanoma cells.

Esposito S, Russo MV, Airoldi I, et al.
SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression.
Oncotarget. 2015; 6(19):17121-34 [PubMed] Free Access to Full Article Related Publications
Prostate Cancer (PCa)-related deaths are mostly due to metastasization of poorly differentiated adenocarcinomas often endowed with neuroendocrine differentiation (NED) areas.The SNAI2/Slug gene is a major regulator of cell migration and tumor metastasization. We here assessed its biological significance in NED, and metastatic potential of PCa.SNAI2 expression was down-regulated in most PCa epithelia, in association with gene promoter methylation, except for cell clusters forming: a. the expansion/invasion front of high-grade PCa, b. NED areas, or c. lymph node metastasis.Knockdown of SNAI2 in PC3 cells down-regulated the expression of neural-tissue-associated adhesion molecules, Neural-Cadherin, Neural-Cadherin-2, Neuronal-Cell-Adhesion-Molecule, and of the NED marker Neuron-Specific Enolase, whereas it abolished Chromogranin-A expression. The metastasis-suppressor genes, Nm23-H1 and KISS1, were up-regulated, while the pluripotency genes SOX2, NOTCH1, CD44v6, WWTR1/TAZ and YAP1 were dramatically down-regulated. Over-expression of SNAI2 in DU145 cells substantiated its ability to regulate metastasis-suppressor, NED and pluripotency genes. In PCa and lymph node metastasis, expression of SOX2 and NOTCH1 was highly related to that of SNAI2.In conclusion, I. SNAI2 silencing in PCa may turn-off the expression of NED markers and pluripotency genes, while turning-on that of specific metastasis-suppressors, II. SNAI2 expression in selected PCa cells, by regulating their self-renewal, NED and metastatic potential, endows them with highly malignant properties. SNAI2 may thus constitute a key target for modern approaches to PCa progression.

Niitsu N
The association of nm23-H1 expression with a poor prognosis in patients with peripheral T-cell lymphoma, not otherwise specified.
J Clin Exp Hematop. 2014; 54(3):171-7 [PubMed] Related Publications
nm23-H1 was originally identified as a protein that is expressed at a lower than usual level in metastatic cancer cells. The nm23 genes play critical roles in cellular proliferation, differentiation, oncogenesis, and tumor metastasis. Peripheral T-cell lymphoma (PTCL) is relatively rare, accounting for only 10% to 15% of non-Hodgkin's lymphomas. We examined whether nm23-H1 is a prognostic factor of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). PTCL is more aggressive and has a poorer prognosis than diffuse large B-cell lymphoma. nm23-H1 was positive in 44.1% of PTCL-NOS patients. nm23-H1 expression was not correlated with age, performance status (PS), lactate dehydrogenase (LDH) level, or stage. The nm23-H1-positive group had significantly shorter overall survival (OS). OS was significantly shorter in patients with the following clinicopathologic features: age > 60 years, PS of 2-4, LDH > normal, bone marrow involvement, or nm23-H1-positive lymphoma. The nm23-H1 protein may be an important prognostic factor in PTCL-NOS. Because our results suggest that nm23-HI is produced by lymphoma cells, we expect to see the development of new treatments targeting nm23 overexpression.

Coumans JV, Gau D, Poljak A, et al.
Profilin-1 overexpression in MDA-MB-231 breast cancer cells is associated with alterations in proteomics biomarkers of cell proliferation, survival, and motility as revealed by global proteomics analyses.
OMICS. 2014; 18(12):778-91 [PubMed] Free Access to Full Article Related Publications
Despite early screening programs and new therapeutic strategies, metastatic breast cancer is still the leading cause of cancer death in women in industrialized countries and regions. There is a need for novel biomarkers of susceptibility, progression, and therapeutic response. Global analyses or systems science approaches with omics technologies offer concrete ways forward in biomarker discovery for breast cancer. Previous studies have shown that expression of profilin-1 (PFN1), a ubiquitously expressed actin-binding protein, is downregulated in invasive and metastatic breast cancer. It has also been reported that PFN1 overexpression can suppress tumorigenic ability and motility/invasiveness of breast cancer cells. To obtain insights into the underlying molecular mechanisms of how elevating PFN1 level induces these phenotypic changes in breast cancer cells, we investigated the alteration in global protein expression profiles of breast cancer cells upon stable overexpression of PFN1 by a combination of three different proteome analysis methods (2-DE, iTRAQ, label-free). Using MDA-MB-231 as a model breast cancer cell line, we provide evidence that PFN1 overexpression is associated with alterations in the expression of proteins that have been functionally linked to cell proliferation (FKPB1A, HDGF, MIF, PRDX1, TXNRD1, LGALS1, STMN1, LASP1, S100A11, S100A6), survival (HSPE1, HSPB1, HSPD1, HSPA5 and PPIA, YWHAZ, CFL1, NME1) and motility (CFL1, CORO1B, PFN2, PLS3, FLNA, FLNB, NME2, ARHGDIB). In view of the pleotropic effects of PFN1 overexpression in breast cancer cells as suggested by these new findings, we propose that PFN1-induced phenotypic changes in cancer cells involve multiple mechanisms. Our data reported here might also offer innovative strategies for identification and validation of novel therapeutic targets and companion diagnostics for persons with, or susceptibility to, breast cancer.

Bozdogan O, Yulug IG, Vargel I, et al.
Differential expression patterns of metastasis suppressor proteins in basal cell carcinoma.
Int J Dermatol. 2015; 54(8):905-15 [PubMed] Related Publications
BACKGROUND: Basal cell carcinomas (BCCs) are common malignant skin tumors. Despite having a significant invasion capacity, they metastasize only rarely. Our aim in this study was to detect the expression patterns of the NM23-H1, NDRG1, E-cadherin, RHOGDI2, CD82/KAI1, MKK4, and AKAP12 metastasis suppressor proteins in BCCs.
METHODS: A total of 96 BCC and 10 normal skin samples were included for the immunohistochemical study. Eleven frozen BCC samples were also studied by quantitative real time polymerase chain reaction (qRT-PCR) to detect the gene expression profile.
RESULTS: NM23-H1 was strongly and diffusely expressed in all types of BCC. Significant cytoplasmic expression of NDRG1 and E-cadherin was also detected. However, AKAP12 and CD82/KAI1 expression was significantly decreased. The expressions of the other proteins were somewhere between the two extremes. Similarly, qRT-PCR analysis showed down-regulation of AKAP12 and up-regulation of NM23-H1 and NDRG1 in BCC. Morphologically aggressive BCCs showed significantly higher cytoplasmic NDRG1 expression scores and lower CD82/KAI1 scores than non-aggressive BCCs.
CONCLUSION: The relatively preserved levels of NM23-H1, NDRG1, and E-cadherin proteins may have a positive effect on the non-metastasizing features of these tumors.

Li Y, Tong Y, Wong YH
Regulatory functions of Nm23-H2 in tumorigenesis: insights from biochemical to clinical perspectives.
Naunyn Schmiedebergs Arch Pharmacol. 2015; 388(2):243-56 [PubMed] Related Publications
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.

Vlatković N, Chang SH, Boyd MT
Janus-faces of NME-oncoprotein interactions.
Naunyn Schmiedebergs Arch Pharmacol. 2015; 388(2):175-87 [PubMed] Related Publications
Since the identification of Nm23 (NME1, NME/NM23 nucleoside diphosphate kinase 1) as the first non-metastatic protein, a great deal of research on members of the NME family of proteins has focused on roles in processes implicated in carcinogenesis and particularly their regulation of cellular motility and the process of metastatic spread. To date, there are ten identified members of this family of genes, and these can be dichotomized into groups both taxonomically and by the presence or absence of their nucleoside diphosphate kinase activity with NMEs 1-4 encoding nucleoside diphosphate kinases (NDPKs) and NMEs 5-9 plus RP2 displaying little if any NDPK activity. NMEs are relatively small proteins that can form hetero-oligomers (typically hexamers), and given the apparent genetic redundancy of some NMEs and the number of different isoforms, it is perhaps not surprising that there remains a great deal of uncertainty regarding their function and even more regarding cellular mechanisms of action. Since residues that contribute to NDPK activity span much of the protein, it seems likely that the consequences of NME expression must be mediated through their NDPK activity, through interactions with other structures in cells including protein-protein interactions or through combinations of these. Our goal in this review is to focus on some of the protein-protein interactions that have been identified and to highlight some of the challenges that face this area of research.

Durán E, Cárdenas JM, Reina MÁ, Arriazu R
Loss of Nm23 is associated with a more favorable tumor microenvironment in patients with breast cancer.
Histol Histopathol. 2015; 30(3):345-52 [PubMed] Related Publications
AIM: Nm23 is a metastasis suppressor gene whose downregulation triggers metastatic progression. The aim of this study was to investigate the expression of Nm23 in breast carcinomas and its relationship with tumor microenvironment markers.
METHODS: A retrospective study was done (128 breast cancer patients from 2007 to 2010). Nm23, LPA1, SMA, CD34, CD8, and CD68 protein expressions were evaluated using immunohistochemistry. Image analysis was used to determine the immunostaining percentage area of Nm23, LPA1, and SMA; the number of the total vessel fraction CD34 positive; and the number of CD8+ and CD68+ cells. The mean ± SE was calculated. The differences among groups were evaluated using Student t-test for parametric data and Mann Whitney U test for nonparametric data.
RESULTS: Cases were divided into two groups: Nm23+ and Nm23-. LPA1 immunostaining was significantly increased in Nm23- group. Immunostaining percentage area of SMA was not significantly higher when Nm23 was negative. CD34 immunopositive blood vessels, number of T CD8+ cells, and the number of macrophage CD68+ cells were increased when Nm23 was absent.
CONCLUSION: Our results suggest that the absence of Nm23 causes an increase in LPA1, CD8+ and CD68+ inflammatory cells, and angiogenesis marker. Therefore, Nm23 loss could be associated with a more favorable environment for the development and dissemination of breast cancer. However, more studies are needed to determine this association.

Wang YF, Chang CJ, Chiu JH, et al.
NM23-H1 expression of head and neck squamous cell carcinoma in association with the response to cisplatin treatment.
Oncotarget. 2014; 5(17):7392-405 [PubMed] Free Access to Full Article Related Publications
We recently reported that low NM23-H1 expression of head and neck squamous cell carcinoma (HNSCC) correlated with poor patients' prognosis. Growing evidence has indicated that high tumor NM23-H1 expression contributes to a good response to chemotherapy. Therefore, we investigated the role of NM23-H1 in susceptibility of HNSCC cells to cisplatin and its clinical significance, as well as the in vitro study for validation was performed. Using immunohistochemistry, we analyzed NM23-H1 expression in surgical specimens from 46 HNSCC patients with cervical metastases receiving surgery and adjuvant chemoradiotherapy. Low tumor NM23-H1 expression correlated with locoregional recurrence of HNSCC following postoperative cisplatin-based therapy (p = 0.056) and poor patient prognosis (p = 0.001). To validate the clinical observation and the effect of NM23-H1 on cisplatin cytotoxicity, we established several stable clones derived from a human HNSCC cell line (SAS) by knockdown and overexpression. Knockdown of NM23-H1 attenuated the chemosensitivity of SAS cells to cisplatin, which was associated with reduced cisplatin-induced S-phase accumulation and downregulation of cyclin E1 and A. Overexpression of NM23-H1 reversed these results, indicating the essential role of NM23-H1 in treatment response to cisplatin. NM23-H1 may participate in HNSCC cell responses to cisplatin and be considered a potential therapeutic target.

Thakur RK, Yadav VK, Kumar A, et al.
Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin.
Nucleic Acids Res. 2014; 42(18):11589-600 [PubMed] Free Access to Full Article Related Publications
Tumor metastasis refers to spread of a tumor from site of its origin to distant organs and causes majority of cancer deaths. Although >30 metastasis suppressor genes (MSGs) that negatively regulate metastasis have been identified so far, two issues are poorly understood: first, which MSGs oppose metastasis in a tumor type, and second, which molecular function of MSG controls metastasis. Herein, integrative analyses of tumor-transcriptomes (n=382), survival data (n=530) and lymph node metastases (n=100) in lung cancer patients identified non-metastatic 2 (NME2) as a key MSG from a pool of >30 metastasis suppressors. Subsequently, we generated a promoter-wide binding map for NME2 using chromatin immunoprecipitation with promoter microarrays (ChIP-chip), and transcriptome profiling. We discovered novel targets of NME2 which are involved in focal adhesion signaling. Importantly, we detected binding of NME2 in promoter of focal adhesion factor, vinculin. Reduced expression of NME2 led to enhanced transcription of vinculin. In comparison, NME1, a close homolog of NME2, did not bind to vinculin promoter nor regulate its expression. In line, enhanced metastasis of NME2-depleted lung cancer cells was found in zebrafish and nude mice tumor models. The metastatic potential of NME2-depleted cells was remarkably diminished upon selective RNA-i-mediated silencing of vinculin. Together, we demonstrate that reduced NME2 levels lead to transcriptional de-repression of vinculin and regulate lung cancer metastasis.

Banerjee S, Jha HC, Robertson ES
Regulation of the metastasis suppressor Nm23-H1 by tumor viruses.
Naunyn Schmiedebergs Arch Pharmacol. 2015; 388(2):207-24 [PubMed] Related Publications
Metastasis is the most common cause of cancer mortality. To increase the survival of patients, it is necessary to develop more effective methods for treating as well as preventing metastatic diseases. Recent advancement of knowledge in cancer metastasis provides the basis for development of targeted molecular therapeutics aimed at the tumor cell or its interaction with the host microenvironment. Metastasis suppressor genes (MSGs) are promising targets for inhibition of the metastasis process. During the past decade, functional significance of these genes, their regulatory pathways, and related downstream effector molecules have become a major focus of cancer research. Nm23-H1, first in the family of Nm23 human homologues, is a well-characterized, anti-metastatic factor linked with a large number of human malignancies. Mounting evidence to date suggests an important role for Nm23-H1 in reducing virus-induced tumor cell motility and migration. A detailed understanding of the molecular association between oncogenic viral antigens with Nm23-H1 may reveal the underlying mechanisms for tumor virus-associated malignancies. In this review, we will focus on the recent advances to our understanding of the molecular basis of oncogenic virus-induced progression of tumor metastasis by deregulation of Nm23-H1.

Zhang Y, Luo X, Fan B, et al.
Effect of CO2 pneumoperitoneum on the proliferation of human ovarian cancer cell line SKOV-3 and the expression of NM23-H1 and MMP-2.
Arch Gynecol Obstet. 2015; 291(2):403-11 [PubMed] Related Publications
OBJECTIVE: This study aims to investigate the impacts of CO2 pneumoperitoneum on the growth of ovarian cancer in nude mice and the expression of tumor metastasis suppressor gene (NM23-H1) and matrix metalloproteinase -2 (MMP-2) in SKOV-3 ovarian cancer cell line cancer tissue.
METHOD: Forty five nude mice were used to establish ovarian cancer xenograft models by intraperitoneal injection of human ovarian cancer cell line SKOV-3. Murine xenograft models were divided into four groups: control group (only anesthetized for 0.5 h), laparotomy group (laparotomy for 0.5 h), CO2 pneumoperitoneum of 0.5 h, and CO2 pneumoperitoneum of 1 h group. Mice were killed after 12 weeks to observe intraperitoneal tumor growth and detected mRNA expression of NM23-H1 and MMP-2 in tumor tissues by RT-PCR.
RESULT: Our data show that xenograft tumors grew faster in the CO2 pneumoperitoneum groups than that in control and laparotomy groups and even faster in the CO2 pneumoperitoneum of 1 h group. The mRNA expression of NM23-H1 in CO2 pneumoperitoneum groups was significantly lower than that in control group and laparotomy group (P < 0.01). Moreover, the longer duration of CO2 pneumoperitoneum negatively correlated with lower expression of NM23-H1 (P < 0.01). In contrast to NM23-H1, MMP-2 expression was significantly higher in CO2 pneumoperitoneum groups than that in the control group and laparotomy group (P < 0.01) and positively correlated with the duration of CO2 pneumoperitoneum (P < 0.01). In addition, there was a negative correlation between the expression of NM23-H1 and MMP-2 (r = -0.984, P < 0.05).
CONCLUSION: The CO2 pneumoperitoneum could promote the proliferation and metastasis of human ovarian cancer in nude mice. This effect was positively correlated with the duration of CO2 pneumoperitoneum.

Carotenuto M, de Antonellis P, Chiarolla CM, et al.
A therapeutic approach to treat prostate cancer by targeting Nm23-H1/h-Prune interaction.
Naunyn Schmiedebergs Arch Pharmacol. 2015; 388(2):257-69 [PubMed] Related Publications
Nm23-H1 is a metastasis suppressor gene whose overexpression is associated with both reduced cell motility in various cancers and increased metastatic potential in neuroblastomas, osteosarcomas, and hematological malignances. We previously reported that Nm23-H1 exerts tumor suppressor action in prostate cancer cells and that h-Prune, which is overexpressed in various tumor types, binds Nm23-H1. Moreover, blockage of the Nm23-H1/h-Prune interaction with a competitive permeable peptide (CPP) attenuates migration of breast and neuroblastoma cells. This series of events suggests that the Nm23-H1/h-Prune protein complex regulates cancer progression and that its specific impairment could be a new therapeutic strategy in oncology. We found that CPP leads to inhibition of the AKT/mTORv and NF-kBv signaling pathways and also activates apoptosis. To obtain a proof-of-concept of our hypothesis, we used a xenograft model of prostate cancer to evaluate whether impairment of this complex using CPP results in an anti-tumoral effect. Using a mouse orthotopic model with bioluminescent imaging, we show evidences that CPP reduces prostate cancer metastases formation. In conclusion, CPP being able to impair formation of the h-Prune/Nm23-H1 complex holds promise for the treatment of prostate cancer.

Marino N, Collins JW, Shen C, et al.
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines.
Clin Exp Metastasis. 2014; 31(7):771-86 [PubMed] Free Access to Full Article Related Publications
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

Vladušić T, Hrašćan R, Krušlin B, et al.
Histological groups of human postpubertal testicular germ cell tumours harbour different genetic alterations.
Anticancer Res. 2014; 34(8):4005-12 [PubMed] Related Publications
BACKGROUND: Testicular germ cell tumours are the most common malignancies in young males. Molecular biology studies of these tumours are often contradictory. Two histological groups, seminoma and non-seminoma, differ both morphologically and in malignant behaviour. Although a common cytogenetic feature is seen, namely the amplification of the 12p chromosomal region, the development mechanisms of less aggressive seminomas and more aggressive non-seminomas are unknown.
MATERIALS AND METHODS: Occurrence of structural genetic alterations was analyzed in 18 seminomas and 22 non-seminomas for genes involved in the malignant tumour phenotype: cadherin 1, Type 1, E-cadherin (Epithelial), CDH1; adenomatous polyposis coli, APC; NME/NM23 nucleoside diphosphate kinase 1, NME1; tumour protein P53, TP53; cyclin-dependent kinase inhibitor 2A, CDKN2A; retinoblastoma 1, RB1; RAD51 recombinase, RAD51; mutS homolog 2, MSH2; MutL homolog 1, MLH1; breast cancer 1, early onset, BRCA1; BCL2-Associated X Protein, BAX; ATP-Binding Cassette, Sub-Family G (WHITE), Member 2, ABCG2. Genetic alterations, loss of heterozygosity and microsatellite instability, were analyzed using restriction fragment or microsatellite repeat length polymorphisms.
RESULTS: A difference in genetic alteration occurrence between seminomas and non-seminomas was observed.
CONCLUSION: Occurrence of genetic alterations correlates with clinical behaviour of these tumours and may indicate that such alterations could occur early in the development of seminomas and non-seminomas.

McCorkle JR, Leonard MK, Kraner SD, et al.
The metastasis suppressor NME1 regulates expression of genes linked to metastasis and patient outcome in melanoma and breast carcinoma.
Cancer Genomics Proteomics. 2014 Jul-Aug; 11(4):175-94 [PubMed] Free Access to Full Article Related Publications
NME1 is a well-documented metastasis suppressor gene, with suppressor activity demonstrated across a wide spectrum of human cancers including melanoma and carcinomas of the breast, stomach and thyroid. A primary aim of the current study was to identify profiles of genes whose expression is regulated by NME1 in cell lines of melanoma and thyroid carcinoma origin. Impact of NME1 was determined by forcing its expression transiently in cell lines using a novel Ad5-based adenoviral vector (Ad5-NME1), followed 48 h later by analysis of RNA expression profiles using the U133A microarray chip. Robust NME1 expression was achieved following infection with the Ad5-NME1 adenovirus in the human metastasis-derived cell lines WM1158 (melanoma) and WRO82 (follicular thyroid carcinoma), resulting in wide-ranging effects on gene expression in both settings. A substantial proportion of the NME1-regulated genes identified in the analyses were of clear potential relevance to metastasis, such as matrix metalloproteinase-1 (MMP1), angiopoietin-2 (ANGPT2), SERPINB9 and colony stimulating factor receptor-2B (CSFR2B). Nine genes were identified (false discovery rate <0.1) that were regulated by NME1 in both the WM1158 and WRO82 cell lines, each possessing one or more such metastasis-relevant activities as stress fiber formation and focal adhesion (PPM1E, ZYX, PFN1), chemotaxis (CCR1) epithelial-mesenchymal signaling (WNT6), differentiation and morphogenesis (TBX4, ZFP36L2), and G protein modulation (GPR52 and PFN1). In addition, a number of the NME1-regulated genes were shown to be of prognostic value for distant disease-free survival and overall survival in melanoma and breast cancer. The combined expression of three NME1-regulated genes CSFR2B, MSF4A1 and SERPINB9 provided a strongly synergistic correlation with distant disease-free survival in the basal subtype of breast cancer (p<3.5e(-5), hazard ratio=0.33). Our study demonstrates that analysis of NME1-dependent gene expression is a powerful approach for identifying potential modulators of metastatic potential in multiple cancer types, which in turn may represent useful therapeutic targets. The study also highlights NME1-dependent genes as potential prognostic/diagnostic indices, which are profoundly lacking at present in melanoma.

Kaetzel DM, Leonard MK, Cook GS, et al.
Dual functions of NME1 in suppression of cell motility and enhancement of genomic stability in melanoma.
Naunyn Schmiedebergs Arch Pharmacol. 2015; 388(2):199-206 [PubMed] Free Access to Full Article Related Publications
The NME1 gene represents the prototypical metastasis suppressor, whose expression inhibits cell motility and metastasis without impact on primary tumor growth in a number of different human cancers. This report outlines our recent efforts to define the molecular mechanisms through which NME1 both suppresses cell motility and promotes genomic integrity in the setting of human melanoma. Forced NME1 expression in a variety of melanoma-derived cell lines was shown to induce dynamic changes in cell morphology and reorganization of the actin cytoskeleton, with formation of a network of thick stress fibers and assembly of fibronectin fibrils at large focal adhesions. Moreover, NME1 expression results in adhesion reprogramming through an impact on integrin repertoire and focal adhesion dynamics. Having previously demonstrated that NME1 expression promotes repair of DNA damage induced by ultraviolet radiation (UVR) in both yeast and mammalian cells, probably via the nucleotide excision repair pathway, we have more recently demonstrated that NME1 is rapidly recruited to double-strand breaks. This preliminary result represents the first evidence of direct interactions between NME1 and DNA in the context of DNA repair and has set the stage for current efforts to probe its functional interactions with double-strand break repair pathways. Discussed herein are molecular models to explain the interactions of NME1 with such diverse cellular functions as cell motility and DNA repair, potentially through its nucleoside diphosphate kinase and 3'-5' exonuclease activities.

Matimba A, Li F, Livshits A, et al.
Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes.
Pharmacogenomics. 2014; 15(4):433-47 [PubMed] Free Access to Full Article Related Publications
AIM: We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia.
MATERIALS & METHODS: We performed genome-wide SNP association studies of 6-thioguanine and 6-mercaptopurine cytotoxicity using lymphoblastoid cell lines. We then genotyped the top SNPs associated with lymphoblastoid cell line cytotoxicity, together with tagSNPs for genes in the 'thiopurine pathway' (686 total SNPs), in DNA from 589 Caucasian UK ALL97 patients. Functional validation studies were performed by siRNA knockdown in cancer cell lines.
RESULTS: SNPs in the thiopurine pathway genes ABCC4, ABCC5, IMPDH1, ITPA, SLC28A3 and XDH, and SNPs located within or near ATP6AP2, FRMD4B, GNG2, KCNMA1 and NME1, were associated with clinical response and measures of thiopurine metabolism. Functional validation showed shifts in cytotoxicity for these genes.
CONCLUSION: The clinical response to thiopurines may be regulated by variation in known thiopurine pathway genes and additional novel genes outside of the thiopurine pathway.

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