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1.
Leuk Res ; 66: 39-48, 2018 03.
Article in English | MEDLINE | ID: mdl-29407582

ABSTRACT

The NM23 gene is overexpressed in many hematological malignancies and its overexpression predicts poor treatment outcomes. NM23 overexpression is thought to suppress myeloid differentiation of leukemia cells, but the molecular mechanism is unknown. In breast cancer cells, the lysophosphatidic acid (LPA) receptor EDG2/lpa1 was downregulated by NM23-H1 overexpression, and this reciprocal expression pattern was associated with suppressed or induced cell motility/metastasis. Here, we examined the relationship between EDG2 and NM23 expression during myeloid differentiation of leukemia cells. NM23 expression decreased and EDG2 expression increased during all-trans retinoic acid (ATRA)-induced myeloid differentiation of HL-60, NB4, and THP-1 leukemia cells. Moreover, this inverse correlation was more evident when myeloid differentiation was enhanced by ellagic acid, an inhibitor of NM23 activity. In contrast, there was no inverse correlation between EDG2 and NM23 expression during erythroid differentiation of HEL and K562 cells. ATRA plus LPA enhanced the motility of leukemia cells as well as breast cancer cells in an EDG2-dependent manner. These results suggest a common molecular mechanism between myeloid differentiation of leukemia cells and migration of breast cancer cells depending on NM23 and EDG2 expression levels.


Subject(s)
Cell Differentiation , Down-Regulation , Gene Expression Regulation, Leukemic , Leukemia/metabolism , Myeloid Cells/metabolism , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Neoplasm Proteins/biosynthesis , Receptors, Lysophosphatidic Acid/biosynthesis , Up-Regulation , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , HL-60 Cells , Humans , K562 Cells , Leukemia/genetics , Leukemia/pathology , Lysophospholipids/pharmacology , MCF-7 Cells , Myeloid Cells/pathology , NM23 Nucleoside Diphosphate Kinases/genetics , Receptors, Lysophosphatidic Acid/genetics , Tretinoin/pharmacology , U937 Cells
2.
Biomed Res Int ; 2017: 8047183, 2017.
Article in English | MEDLINE | ID: mdl-28401162

ABSTRACT

The prognostic value of reduced NM23 expression for gastric cancer (GC) patients is still contradictory. Thus, we conducted a meta-analysis to quantitatively evaluate the association of NM23 expression with GC risk and clinical features by analyzing 27 publications. The result of our meta-analysis indicated that NM23 expression is markedly reduced in gastric cancer tissues (OR = 3.15; 95% CI = 1.97-5.03; P < 0.001). Furthermore, NM23 expression was negatively correlated with N stage, TNM stage, and histological grade. However, NM23 expression was not correlated with T stage, lymphatic invasion, vascular invasion, and 5-year overall survival rate. In conclusion, reduced NM23 expression correlated with gastric cancer risk, but its association with GC clinical features remains inconclusive. Therefore, large-scale and well-designed studies, which use uniform antibody and criterion of NM23 positive expression, are required to further validate the role of the NM23 in predicting GC progression.


Subject(s)
Biomarkers, Tumor/biosynthesis , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Prognosis , Stomach Neoplasms/genetics , Biomarkers, Tumor/genetics , Disease Progression , Disease-Free Survival , Gene Expression Regulation, Neoplastic , Humans , NM23 Nucleoside Diphosphate Kinases/genetics , Neoplasm Staging , Risk Factors , Stomach Neoplasms/pathology
3.
Pak J Pharm Sci ; 29(4 Suppl): 1339-42, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27592483

ABSTRACT

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.


Subject(s)
Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , Matrix Metalloproteinase 2/biosynthesis , Matrix Metalloproteinase 2/genetics , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Adult , Aged , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Female , Humans , Immunohistochemistry , Lymphatic Metastasis/genetics , Lymphatic Metastasis/pathology , Male , Middle Aged , NM23 Nucleoside Diphosphate Kinases/genetics , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Prognosis
4.
Sci Rep ; 6: 31085, 2016 08 03.
Article in English | MEDLINE | ID: mdl-27484146

ABSTRACT

Pluripotent stem cells (PSCs), including embryonic and induced pluripotent stem cells (iPSCs), show atypical cell cycle regulation characterized by a high proliferation rate and a shorter G1 phase compared with somatic cells. The mechanisms by which somatic cells remodel their cell cycle to achieve the high proliferation rate of PSCs during reprogramming are unclear. Here we identify that the Ink4 protein p18, which is expressed at high levels in somatic cells but at low levels in PSCs, is a roadblock to successful reprogramming. Mild inhibition of p18 expression enhances reprogramming efficiency, while ectopic expression of p18 completely blocks reprogramming. Mechanistic studies show that expression of wild-type p18, but not a p18(D68N) mutant which cannot inhibit Cdk4/6, down-regulates expression of Cdk4/6 target genes involved in DNA synthesis (TK, TS, DHFR, PCNA) and cell cycle regulation (CDK1 and CCNA2) and thus inhibits reprogramming. These results indicate that p18 blocks reprogramming by targeting Cdk4/6-mediated cell cycle regulation. Taken together, our results define a novel pathway that inhibits somatic cell reprogramming, and provide a new target to enhance reprogramming efficiency.


Subject(s)
Cell Cycle , Cellular Reprogramming , Cyclin-Dependent Kinase 4/biosynthesis , Cyclin-Dependent Kinase 6/biosynthesis , Mutation, Missense , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Pluripotent Stem Cells/metabolism , Amino Acid Substitution , Animals , Cell Line , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 6/genetics , Humans , Mice , NM23 Nucleoside Diphosphate Kinases/genetics
5.
J Clin Exp Hematop ; 54(3): 171-7, 2014.
Article in English | MEDLINE | ID: mdl-25501107

ABSTRACT

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.


Subject(s)
Biomarkers, Tumor/biosynthesis , Lymphoma, T-Cell, Peripheral/enzymology , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Cell Differentiation/physiology , Humans , Lymphoma, T-Cell, Peripheral/genetics , Lymphoma, T-Cell, Peripheral/pathology , NM23 Nucleoside Diphosphate Kinases/genetics , Prognosis
6.
Oncotarget ; 5(17): 7392-405, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25277180

ABSTRACT

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.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/pathology , Drug Resistance, Neoplasm/physiology , Head and Neck Neoplasms/pathology , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Adult , Aged , Antineoplastic Agents/therapeutic use , Blotting, Western , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/metabolism , Cell Line, Tumor , Cisplatin/therapeutic use , Female , Flow Cytometry , Gene Knockdown Techniques , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/metabolism , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , NM23 Nucleoside Diphosphate Kinases/analysis , Proportional Hazards Models , Squamous Cell Carcinoma of Head and Neck , Transfection , Young Adult
7.
Biochimie ; 105: 110-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25010650

ABSTRACT

NDPK-A, NDPK-B and NDPK-D are three enzymes which belong to the NDPK group I isoforms and are not only involved in metabolism process but also in transcriptional regulation, DNA cleavage, histidine protein kinase activity and metastasis development. Those enzymes were reported to bind to membranes either in mitochondria where NDPK-D influences cardiolipin lateral organization and is thought to be involved in apoptotic pathway or in cytosol where NDPK-A and NDPK-B membrane association was shown to influence several cellular processes like endocytosis, cellular adhesion, ion transport, etc. However, despite numerous studies, the role of NDPK-membrane association and the molecular details of the binding process are still elusive. In the present work, a comparative study of the three NDPK isoforms allowed us to show that although membrane binding is a common feature of these enzymes, mechanisms differ at the molecular scale. NDPK-A was not able to bind to model membranes mimicking the inner leaflet of plasma membrane, suggesting that its in vivo membrane association is mediated by a non-lipidic partner or other partners than the studied phospholipids. On the contrary, NDPK-B and NDPK-D were shown to bind efficiently to liposomes mimicking plasma membrane and mitochondrial inner membrane respectively but details of the binding mechanism differ between the two enzymes as NDPK-B binding necessarily involved an anionic phospholipid partner while NDPK-D can bind either zwitterionic or anionic phospholipids. Although sharing similar secondary structure and homohexameric quaternary arrangement, tryptophan fluorescence revealed fine disparities in NDPK tertiary structures. Interfacial behavior as well as ANS fluorescence showed further dissimilarities between NDPK isoforms, notably the presence of distinct accessible hydrophobic areas as well as different capacity to form Gibbs monolayers related to their surface activity properties. Those distinct features may contribute to explain the differences in the protein behavior towards membrane binding.


Subject(s)
Membrane Proteins/chemistry , NM23 Nucleoside Diphosphate Kinases/chemistry , Nucleoside Diphosphate Kinase D/chemistry , Cell Membrane/enzymology , Gene Expression Regulation, Enzymologic , Humans , Liposomes/metabolism , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Mitochondrial Membranes/enzymology , NM23 Nucleoside Diphosphate Kinases/biosynthesis , NM23 Nucleoside Diphosphate Kinases/genetics , Nucleoside Diphosphate Kinase D/biosynthesis , Nucleoside Diphosphate Kinase D/genetics , Nucleoside-Diphosphate Kinase/biosynthesis , Nucleoside-Diphosphate Kinase/chemistry , Nucleoside-Diphosphate Kinase/genetics , Phosphorylation , Protein Conformation
8.
J Biol Chem ; 289(25): 17709-20, 2014 Jun 20.
Article in English | MEDLINE | ID: mdl-24811176

ABSTRACT

IKKß functions as a principal upstream activator of the canonical NF-κB pathway by phosphorylating IκB, leading to its proteasomal degradation. Because IKKß is considered a therapeutic target, understanding its regulation may facilitate the design of efficient regulators of this molecule. Here, we report a novel IKKß-interacting molecule, NME1L, a splicing variant of the NME1 protein. NME1 has attracted attention in cancer research because of its antimetastatic activity and reduced expression in multiple aggressive types of cancer. However, the effect was just moderate but not dramatic in anti-cancer activities. We found that only NME1L interacts with IKKß. Exogenous expression of NME1L resulted in a potent decrease in TNFα-stimulated NF-κB activation, whereas knockdown of NME1/NME1L with shRNA enhanced activity of NF-κB. NME1L down-regulates IKKß signaling by blocking IKKß-mediated IκB degradation. When NME1L was introduced into highly metastatic HT1080 cells, the mobility was efficiently inhibited. Furthermore, in a metastasis assay, NME1L-expressing cells did not colonize the lung. Based on these results, NME1L is a potent antimetastatic protein and may be a useful weapon in the fight against cancers.


Subject(s)
Alternative Splicing , I-kappa B Kinase/metabolism , NF-kappa B/metabolism , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Cell Line, Tumor , HEK293 Cells , Humans , I-kappa B Kinase/genetics , NF-kappa B/genetics , NM23 Nucleoside Diphosphate Kinases/genetics , Neoplasm Metastasis , Neoplasm Proteins/genetics , Neoplasms/genetics , Neoplasms/pathology
9.
Am J Physiol Gastrointest Liver Physiol ; 306(10): G873-85, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24674776

ABSTRACT

The intermediate-conductance Ca(2+)-activated K(+) channel KCa3.1/KCNN4 plays an important role in the modulation of Ca(2+) signaling through the control of the membrane potential in T lymphocytes. Here, we study the involvement of KCa3.1 in the enlargement of the mesenteric lymph nodes (MLNs) in a mouse model of inflammatory bowel disease (IBD). The mouse model of IBD was prepared by exposing male C57BL/6J mice to 5% dextran sulfate sodium for 7 days. Inflammation-induced changes in KCa3.1 activity and the expressions of KCa3.1 and its regulators in MLN CD4(+) T lymphocytes were monitored by real-time PCR, Western blot, voltage-sensitive dye imaging, patch-clamp, and flow cytometric analyses. Concomitant with an upregulation of KCa3.1a and nucleoside diphosphate kinase B (NDPK-B), a positive KCa3.1 regulator, an increase in KCa3.1 activity was observed in MLN CD4(+) T lymphocytes in the IBD model. Pharmacological blockade of KCa3.1 elicited the following results: 1) a significant decrease in IBD disease severity, as assessed by diarrhea, visible fecal blood, inflammation, and crypt damage of the colon and MLN enlargement compared with control mice, and 2) the restoration of the expression levels of KCa3.1a, NDPK-B, and Th1 cytokines in IBD model MLN CD4(+) T lymphocytes. These findings suggest that the increase in KCa3.1 activity induced by the upregulation of KCa3.1a and NDPK-B may be involved in the pathogenesis of IBD by mediating the enhancement of the proliferative response in MLN CD4(+) T lymphocyte and, therefore, that the pharmacological blockade of KCa3.1 may decrease the risk of IBD.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Inflammatory Bowel Diseases/physiopathology , Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism , Lymph Nodes/metabolism , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Animals , DNA-Binding Proteins/biosynthesis , Dextran Sulfate , Disease Models, Animal , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/drug therapy , Lymph Nodes/pathology , Male , Mice , Mice, Inbred C57BL , Nuclear Proteins/biosynthesis , Pyrazoles/therapeutic use , Ubiquitin-Protein Ligases , Up-Regulation
10.
Acta Otolaryngol ; 133(8): 874-80, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23768014

ABSTRACT

CONCLUSIONS: Nuclear nm23-H1 expression may be useful in identifying elderly patients operated for laryngeal squamous cell carcinoma (LSCC) at higher risk of recurrence. Further studies are needed to clarify the biological role of nm23-H1 in elderly patients with LSCC and to determine how to restore nm23-H1 loss of expression/function. OBJECTIVES: Nowadays more than 50% of cancer cases are elderly patients and this percentage is expected to be 70% by 2030. Despite advances in LSCC diagnosis and treatment, patient survival has not improved in the last two decades. Novel, effective strategies should rely also on receptor-mediated LSCC-targeted therapy. nm23-H1 protein is related to the tumor cells' metastatic potential, and low nm23-H1 expression in carcinomas often correlates with a poor prognosis. METHODS: Immunohistochemistry and image analysis were used to investigate the prognostic value of nm23-H1 expression and subcellular localization in a series of 54 elderly patients consecutively undergoing primary surgery for LSCC. RESULTS: On univariate analysis, the disease recurrence rate correlated inversely with nuclear nm23-H1 expression (p = 0.014), and disease-free survival (DFS) was longer in patients whose nuclear nm23-H1 levels were ≥2.0% (p = 0.022). On multivariate analysis, nuclear nm23-H1 expression (hazard ratio (HR) 2.77, p = 0.022) and N stage (HR 3.49, p = 0.007) were prognostically significant in terms of DFS.


Subject(s)
Biomarkers, Tumor/biosynthesis , Carcinoma/metabolism , Laryngeal Neoplasms/metabolism , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Neoplasm Recurrence, Local/metabolism , Aged , Aged, 80 and over , Carcinoma/pathology , Female , Humans , Laryngeal Neoplasms/pathology , Male , Multivariate Analysis , NM23 Nucleoside Diphosphate Kinases/metabolism , Prognosis , Retrospective Studies
11.
BMC Neurosci ; 13: 123, 2012 Oct 11.
Article in English | MEDLINE | ID: mdl-23057762

ABSTRACT

BACKGROUND: Diva (death inducer binding to vBcl-2 and Apaf-1)/BclB is a Bcl-2 family member, which is known for its function in apoptosis. Diva/BclB has been shown to interact with NDPKB/Nm23H2, which is involved in cellular differentiation. Thus far, there has been no direct evidence of Diva/BclB having a role in differentiation. In the present study, we investigated the expression of Diva/BclB and NDPKB/Nm23H2 during differentiation in PC-12 cell line. RESULTS: Our results show that after differentiation, Diva/BclB expression was decreased and reciprocally, NDPKB/Nm23H2 expression was increased and it translocated into the nucleus. Overexpression of NDPKB/Nm23H2 promoted PC-12 neuronal differentiation by increasing neurite outgrowth and arresting cell cycle progression. There was a concurrent downregulation of Diva/Boo when NDPKB/Nm23H2 was overexpressed, which mirrors the effect of NGF on PC-12 cell differentiation. Overexpression of Diva/BclB did not change the expression level of NDPKB/Nm23H2, but inhibited its nuclear localization. Cells that overexpressed Diva/BclB presented a decreased percentage of differentiated cells and average neurite length was shortened. This was due to an increase in the formation of Diva/BclB and NDPKB/Nm23H2 complexes as well as Diva/BclB and ß-tubulin complexes. Concomitantly, there was a decrease in formation of NDPKB/Nm23H2 and ß-tubulin complexes. Overexpression of Diva/BclB also resulted in a higher percentage of S-phase cells. CONCLUSION: Our results showed a novel role for Diva/BclB in neuronal differentiation. Its downregulation during neuronal differentiation may be necessary to allow NDPKB/Nm23H2 and ß-tubulin interaction that promotes NDPKB/Nm23H2 mediated differentiation.


Subject(s)
Cell Differentiation/physiology , NM23 Nucleoside Diphosphate Kinases/antagonists & inhibitors , Neurons/cytology , Nucleoside-Diphosphate Kinase/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/physiology , Animals , Cell Cycle/physiology , Gene Expression Regulation/physiology , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Neurites/metabolism , Neurons/metabolism , Nucleoside-Diphosphate Kinase/biosynthesis , PC12 Cells , Protein Transport/physiology , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Rats , Signal Transduction/physiology , Tubulin/metabolism
13.
Leuk Lymphoma ; 53(8): 1569-76, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22251158

ABSTRACT

We have previously identified NME2 (Nm23-H2) as a tumor antigen in a patient with chronic myeloid leukemia (CML). Here we investigated the association between NME2 and Bcr-Abl. NME2 protein was highly overexpressed in the cytoplasm of peripheral blood mononuclear cells from 29/30 patients with CML at diagnosis and 10/10 patients resistant to imatinib. Protein was overexpressed in the absence of increased levels of mRNA and was limited to Bcr-Abl + populations, being absent from Bcr-Abl - patient cells, normal donors and 14/15 acute myeloid leukemia (AML) samples. Furthermore, the Bcr-Abl dependent overexpression of NME2 protein was reversed specifically by tyrosine kinase inhibitor (TKI) treatment of Ba/F3 expressing wild-type and TKI-sensitive, but not TKI-resistant, mutants of Bcr-Abl. The post-transcriptional up-regulation of the tumor antigen NME2 is therefore a common and specific property of CML closely associated with Bcr-Abl activity.


Subject(s)
Fusion Proteins, bcr-abl/metabolism , Gene Expression Regulation, Leukemic , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , NM23 Nucleoside Diphosphate Kinases/biosynthesis , RNA Processing, Post-Transcriptional , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/metabolism , Benzamides , Cytoplasm/metabolism , Drug Resistance, Neoplasm , Female , Humans , Imatinib Mesylate , In Situ Hybridization, Fluorescence , Karyotyping , Leukocytes, Mononuclear/cytology , Male , Middle Aged , Piperazines/pharmacology , Pyrimidines/pharmacology
14.
Med Oncol ; 29(1): 263-71, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21221850

ABSTRACT

The purpose of this study was to evaluate the prognostic value of expression of EGFR and nm23 in patients with advanced-stage nasopharyngeal carcinoma (NPC). The study population comprised 127 patients with stage III-IVa NPC with sufficient pretreatment tumor biopsy specimens from 2003 to 2004 and clinical follow-up data. The expression of EGFR and nm23 was detected by immunohistochemistry. Survival analysis was performed using Kaplan-Meier method. The correlation between pretreatment expression of EGFR and nm23, and the effectiveness of chemoradiotherapy was analyzed. The EGFR expression was correlated with primary lesion stage and clinical stage (P = 0.001, 0.002, respectively). There was a statistically significant association between nm23 expression and local lymph node stage (P = 0.000). The positive EGFR expression had a higher recurrent rate than the negative (P = 0.015). The positive nm23 expression had a lower distant metastasis rate than the negative (P = 0.021). Negative expression of EGFR had a significantly better 5-year OS and DFS than positive expression (P = 0.015, 0.013, respectively). Positive expression of nm23 had a significantly higher 5-year OS and DFS than negative expression (P = 0.001, 0.006, respectively). Multivariate analysis indicated that both pretreatment EGFR and nm23 expression were strong independent factors for the overall survival of patients with NPC (P = 0.000, 0.000, respectively). Our data suggested that EGFR and nm23 can serve as reliable biomarkers for prognosis prediction in patients with NPC who may benefit from alternate treatment strategy and targeted treatment.


Subject(s)
Biomarkers, Tumor/analysis , ErbB Receptors/biosynthesis , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Carcinoma , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/mortality , Neoplasm Staging , Prognosis , Young Adult
15.
J Surg Oncol ; 104(2): 181-6, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21495034

ABSTRACT

INTRODUCTION: The purpose of this study was to evaluate the value of nm23-H1 and proliferating cell nuclear antigen (PCNA) expression as well as other confirmed prognostic factors in predicting the clinical outcome after definitive surgery of pathologic stage I non-small cell lung cancer (NSCLC). METHODS: Four hundred fifty-two consecutive and non-selected patients who underwent definitive surgery for stage I NSCLC were included in this study. Formalin-fixed paraffin-embedded specimens were stained for nm23-H1 and PCNA, the correlation between the staining and its clinicopathological parameters, and its prognostic power were analyzed statistically. RESULTS: Of the 452 patients studied, 320 cases (70.8%) were high expression for nm23-H1. A total of 182 carcinomas (40.3%) were PCNA high expression tumors. PCNA expression correlated with serum CEA level (P < 0.001), and differentiation (P < 0.001). In univariate analysis by log-rank test, serum CEA level, pT stage, differentiation, nm23-H1 expression, and PCNA expression were significant prognostic factors (P = 0.037, 0.021, <0.001, 0.042, and 0.014, respectively). In multivariate analysis, pT stage and nm23-H1 expression maintained its independent prognostic influence on overall survival (P = 0.041 and 0.003, respectively). CONCLUSIONS: nm23-H1 may be a good biomarker to be applied in clinic to predict the prognosis of patients with completely resected pathologic stage I NSCLC.


Subject(s)
Biomarkers, Tumor/biosynthesis , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Proliferating Cell Nuclear Antigen/biosynthesis , Adult , Aged , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Staging , Prognosis
16.
J Virol ; 85(7): 3596-606, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21270158

ABSTRACT

The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), and the induction of an invasive cellular phenotype by KSHV following de novo infection is an important pathogenic component mediating tumor progression. The metastasis suppressor gene known as Nm23-H1 regulates tumor cell invasiveness, but whether KSHV itself regulates Nm23-H1 expression or subcellular localization, and whether this impacts cell invasiveness, has not been established. We found that KSHV increases expression and nuclear translocation of Nm23-H1 and that nuclear translocation of Nm23-H1 is regulated by the KSHV-encoded latency-associated nuclear antigen (LANA). Moreover, activation of the Ras-BRaf-MAPK (mitogen-activated protein kinase) signal transduction pathway, secretion of promigratory factors associated with this pathway, and cell invasiveness are dependent on KSHV regulation of Nm23-H1. Finally, induction of cytoplasmic overexpression of Nm23-H1 using a pharmacologic inhibitor of DNA methylation reduced KSHV-associated Ras-BRaf-MAPK pathway activation and suppressed KSHV-induced invasiveness. These data provide the first evidence for KSHV regulation of Nm23-H1 as a mechanism for KSHV induction of an invasive cellular phenotype and support the potential utility of targeting Nm23-H1 as a therapeutic approach for the treatment of KS.


Subject(s)
Antigens, Viral/metabolism , Gene Expression Regulation , Herpesvirus 8, Human/pathogenicity , Host-Pathogen Interactions , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Nuclear Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Survival , Humans
17.
Cancer Res ; 71(3): 1177-86, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21169412

ABSTRACT

Nm23-H1 plays complex roles in the development of diverse cancers including breast carcinoma, high-grade lymphomas, and acute myeloid leukemia (AML). In the case of AML and lymphomas, serum Nm23-H1 protein is elevated with the highest levels correlating with poorest prognosis. A recent study identified that this association is most likely causal in AML and that Nm23-H1 acts as an AML cell survival factor. In this study, we report heterogeneity in the ability of AML samples to bind and respond to Nm23-H1, and we offer evidence that binding is essential for improved survival. Further, we show that the subset of AMLs that bind Nm23-H1 do not do so through the putative Nm23-H1 receptor MUC1*. Although rNm23-H1 promoted the survival of the most primitive blasts within responding AMLs, it was not these cells that actually bound the protein. Instead, rNm23-H1 bound to more mature CD34(lo)/CD34(-) and CD11b(+) cells, revealing an indirect survival benefit of Nm23-H1 on primitive blasts. In support of this finding, the survival of purified blast cells was enhanced by medium conditioned by more mature cells from the clone that had been stimulated by rNm23-H1. Levels of interleukin 1ß (IL1ß) and IL6 in rNm23-H1 conditioned medium mirrored the potency of the conditioned media to promote blast cell survival. Furthermore, Nm23-H1 expression was significantly associated with IL1ß and IL6 expression in primary uncultured AML samples. These findings have implications for the role of Nm23-H1 in AML and its use as a prognostic marker. Additionally, they offer the first evidence of novel cross-talk between cell populations within the tumor clone.


Subject(s)
Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , NM23 Nucleoside Diphosphate Kinases/metabolism , Antigens, CD34/metabolism , CD11b Antigen/metabolism , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Flow Cytometry , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , K562 Cells , Mucin-1/biosynthesis , NM23 Nucleoside Diphosphate Kinases/biosynthesis , NM23 Nucleoside Diphosphate Kinases/pharmacology , Proto-Oncogene Proteins c-kit/metabolism
18.
Cell Signal ; 23(3): 579-85, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21111809

ABSTRACT

ß-adrenoceptors (ßAR) play a central role in the regulation of cAMP synthesis and cardiac contractility. Nucleoside diphosphate kinase B (NDPK B) regulates cAMP signalling by complex formation with Gßγ dimers thereby activating and stabilizing heterotrimeric G(s) proteins, key transducer of ßAR signals into the cell. Here, we explored the requirement of NDPK B for basal and ßAR-stimulated cAMP synthesis and analysed the underlying mechanisms by comparing wild-type NDPK B (WT) and its catalytically inactive H118N mutant. Stable overexpression of both WT- and H118N-NDPK B in cardiomyocyte derived H10 cells increased the plasma membrane content of G(s) and caveolin-1 and thus enhanced the isoproterenol (ISO)-stimulated cAMP-synthesis by about 2-fold. Conversely, the loss of NDPK B in embryonic fibroblasts from NDPK A/B-depleted mice was associated with a severe reduction in membranous G(s) protein and carveolin-1 content causing a marked decrease in basal and ISO-induced cAMP formation. Re-expression of NDPK B, but not of NDPK A, was able to rescue this phenotype. Both, re-expression of WT- and H118N-NDPK B induced the re-appearance of G(s) and caveolin-1 at the plasma membrane to a similar extent. Accordingly, WT- and H118N-NDPK B similarly enhanced ISO-induced cAMP formation. In contrast, the catalytically inactive H118N-NDPK B was less potent and less effective in rescuing basal cAMP production. Identical results were obtained in neonatal rat cardiac myocytes after siRNA-induced knockdown and adenoviral re-expression of NDPK B. Our data reveal that NDPK B regulates G(s) function by two different mechanisms. The complex formation of NDPK B with G(s) is required for the stabilization of the G protein content at the plasma membrane. In addition, the NDPK B-dependent phosphotransfer reaction, which requires the catalytic activity, specifically allows a receptor-independent, basal G(s) activation.


Subject(s)
Cyclic AMP/biosynthesis , NM23 Nucleoside Diphosphate Kinases/metabolism , Receptors, Adrenergic, beta/physiology , Animals , Cell Line , GTP-Binding Protein alpha Subunits, Gs/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , NM23 Nucleoside Diphosphate Kinases/biosynthesis , NM23 Nucleoside Diphosphate Kinases/genetics , Protein Binding , Rats , Receptors, Adrenergic, beta/genetics , Recombinant Proteins/biosynthesis , Signal Transduction/physiology
19.
Biomed Environ Sci ; 23(4): 267-72, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20934113

ABSTRACT

OBJECTIVE: To evaluate the relationship of expressions of nucleoside diphosphate kinase (nm23) and proliferating cell nuclear antigen (PCNA), as well as apoptosis, with the prognosis of HCC patients by analyzing their pathological and clinical data. METHODS: The expressions of nm23 and PCNA were analyzed by immunohistochemistry and the apoptotic phenomena were detected by TUNEL technique in the liver samples from 43 HCC tissues, 39 para-neoplastic tissues, and 10 normal tissues. The mean apoptosis index (AI) and proliferative index (PI) in individual sample were calculated. RESULTS: As shown by the detection, 32.6% of carcinomas had negative nm23 signal in tumor tissues, whereas all para-neoplastic and normal tissues had positive nm23. The AI in nm23 positive HCC was significantly higher than that in nm23 negative one, with statistical difference (P<0.05). Furthermore, the expressions of nm23, and the values of AI and PI were contrastively analyzed with some main pathological and clinical data of HCC. It revealed that HCC with extrahepatic metastasis showed remarkable correlation with the negative nm23 (P=0.013) and higher PI values of HCC (P=0.015). The disease-free survival in HCC patients with negative nm23 expression was significantly poorer than that in patients with positive nm23 expression. CONCLUSIONS: These data suggest that expressions of nm23 protein in tumor tissues are correlated with occurrences of metastasis and length of survival of the HCC patients, which may be an indicator for their prognosis.


Subject(s)
Biomarkers, Tumor/biosynthesis , Carcinoma, Hepatocellular/enzymology , Liver Neoplasms/enzymology , Liver/enzymology , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Adult , Aged , Apoptosis , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Case-Control Studies , Cell Proliferation , Disease Progression , Disease-Free Survival , Female , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Kaplan-Meier Estimate , Liver/pathology , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Proliferating Cell Nuclear Antigen/biosynthesis
20.
Cancer Res ; 70(19): 7710-22, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20841469

ABSTRACT

Loss of NM23-H1 expression correlates with the degree of metastasis and with unfavorable clinical prognosis in several types of human carcinoma. However, the mechanistic basis for the metastasis suppressor function of NM23-H1 is obscure. We silenced NM23-H1 expression in human hepatoma and colon carcinoma cells and methodologically investigated effects on cell-cell adhesion, migration, invasion, and signaling linked to cancer progression. NM23-H1 silencing disrupted cell-cell adhesion mediated by E-cadherin, resulting in ß-catenin nuclear translocation and T-cell factor/lymphoid-enhancing factor-1 transactivation. Further, NM23-H1 silencing promoted cellular scattering, motility, and extracellular matrix invasion by promoting invadopodia formation and upregulating several matrix metalloproteinases (MMP), including membrane type 1 MMP. In contrast, silencing the related NM23-H2 gene was ineffective at promoting invasion. NM23-H1 silencing activated proinvasive signaling pathways involving Rac1, mitogen-activated protein kinases, phosphatidylinositol 3-kinase (PI3K)/Akt, and src kinase. Conversely, NM23-H1 was dispensable for cancer cell proliferation in vitro and liver regeneration in NM23-M1 null mice, instead inducing cellular resistance to chemotherapeutic drugs in vitro. Analysis of NM23-H1 expression in clinical specimens revealed high expression in premalignant lesions (liver cirrhosis and colon adenoma) and the central body of primary liver or colon tumors, but downregulation at the invasive front of tumors. Our findings reveal that NM23-H1 is critical for control of cell-cell adhesion and cell migration at early stages of the invasive program in epithelial cancers, orchestrating a barrier against conversion of in situ carcinoma into invasive malignancy.


Subject(s)
Adherens Junctions/genetics , NM23 Nucleoside Diphosphate Kinases/genetics , Neoplasms/genetics , Actins/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adherens Junctions/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement/genetics , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Cytoskeleton/metabolism , Cytoskeleton/pathology , Gene Silencing , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Matrix Metalloproteinase 14/metabolism , NM23 Nucleoside Diphosphate Kinases/biosynthesis , Neoplasm Invasiveness , Neoplasms/metabolism , Neoplasms/pathology , Wnt Proteins/metabolism
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