High Nm23 Expression Research Articles

Clinical Implication and the Hereditary Factors of NM23 in Hepatocellular Carcinoma Based on Bioinformatics Analysis and Genome–Wide Association Study

NM23 expression is closely associated with hepatocellular carcinoma (HCC) recurrence, but the hereditary factors influencing NM23 levels are unknown. Using public database, the diagnostic value of NM23 in HCC was investigated. A total of 424 hepatitis B virus- (HBV-) related HCC patients were enrolled to perform a genome–wide association study for identifying candidate variants associated with NM23 expression level. Additionally, a logistic regression model, haplotypes, and survival analysis were performed in the subsequent analysis. We identified high NM23 expression levels that have a diagnostic accuracy in HCC tissues and had a poor recurrence-free survival in HBV-related HCC patients. Variants near Psoriasis susceptibility 1 candidate 1 (PSORS1C1) and StAR related lipid transdomain containing 3 (STARD3) are associated with NM23 expression. The PSORS1C1 haplotype TGCACA and the STARD3 haplotype GG have favorable cumulative effects on NM23 expression. Further, variants in PSORS1C1 were associated with either overall survival (rs556285588, rs3095301, and rs3131003) only or overall survival and recurrence-free survival (rs560052000 and rs541820233) both in HCC patients. Our findings suggested that variants at the PSORS1C1 and STARD3 loci play an important role in NM23 regulation. Moreover, variants in PSORS1C1 are potential biomarkers for the prediction of postoperative clinical outcomes in HBV-related HCC patients. Thus, variants in PSORS1C1 and STARD3 are associated with NM23 expression and clinical outcomes of HBV-related HCC patients, which may be regarded as potential biomarkers for this disease.

The role of NM23 in patients with colorectal cancer: A systematic review and meta-analysis.

This meta-analysis was carried out to evaluate the relationship between NM23 expression and the prognosis of patients with colorectal cancer. We searched PubMed, EMBASE and Web of Science for relevant articles. The pooled odd ratios (ORs) and corresponding 95%CI were calculated to evaluate the prognostic value of NM23 expression in patients with colorectal cancer, and the association between NM23 expression and clinicopathological factors. In total, 2289 patients were pooled from 24 available studies. The incorporative OR combined by 16 studies with overall survival showed that high NM23 expression was associated with better overall survival (OR=0.67, 95%CI: 0.49-0.93, P=0.02, I 2=56%, Ph=0.004). And a new estimate without heterogeneity was produced when only combining high-quality studies (OR=0.70, 95%CI: 0.56-0.86, P=0.0007, I 2=46%). In disease free survival (DFS), we also obtained a good prognosis (OR=0.30, 95%CI: 0.14-0.68, P=0.004). Although we failed to find any significance in N status (P=0.10), elevated NM23 expression was related to well tumor differentiation (OR=0.60, 95%CI: 0.44-0.820, P=0.001) and Dukes' A&B (OR=0.55, 95%CI: 0.32-0.95, P=0.03). These results indicated that over-expressed NM23 might be an indicator of good prognosis, well tumor differentiation and Dukes' A&B of patients with colorectal cancer, but no significance was found in N status.

Prognostic value of epidermal growth factor receptor and nm23 expression in patients with rectal cancer and its guiding significance for treatment

Objective To evaluate the predictive value of epidermal growth factor receptor (EGFR) and nm23 expression and its guiding role of choosing chemotherapy regimen in post-operation patients with rectal carcinoma. Methods The expression of EGFR and nm23 in 243 specimens of rectal carcinoma tissues was examined by immunohistochemistry. The clinical and pathological data were recorded, and patients were followed up for more than five years. Kaplan-Meier estimates, Cox proportional hazard regression and hierarchical analyses were employed to assess the correlation between the expression of EGFR and nm23 in rectal carcinoma and the progression free survival (PFS) of patients treated with the different surgical methods and chemotherapy. Results EGFR and nm23 were expressed proportionately in rectal cancer tissues. Kaplan-Meier showed that EGFR expression is negatively related to the PFS of the post-operative patients. The median PFS was 21.0 months in the patients with high expression, and that was 37.8 months in the patients with low expression (χ2=8.687, P=0.003). The nm23 expression was positively associated with the PFS of the post-operative patients. The median PFS was 35.4 months in the patients with high expression, and that was 13.4 months in the patients with low expression (χ2=15.593, P=0.001). The median PFS was longer in the patients with low EGFR expression and high nm23 expression (median PFS=62.9 months, χ2=18.227, P=0.000). The univariate analyses revealed that the patients with low EGFR expression and high nm23 expression had longer PFS than in those with high EGFR expression and low nm23 expression[hazard ratio (HR)=2.290, 95% confidence interval (CI): 1.548-3.387, P=0.000]. Multivariate analysis (Cox) showed that low EGFR expression and high nm23 expression was an independent combined predictor of longer PFS (HR=1.966, 95%CI: 1.319-2.929, P=0.001). In addition, hierarchical analysis also suggested that post-Dixon operation patients with low EGFR expression and high nm23 expression had significantly longer survival time than other patients, and also were more sensitive to chemotherapy with FOLFOX4 regimen than other patients (median PFS=61.1 months, χ2=8.218, P=0.004). Conclusion EGFR and nm23 have predictive value for the prognosis of post-operative patients with rectal carcinoma and are an ideal combination of predictive factors. Key words: Epidermal growth factor receptor; nm23; Rectal carcinoma

Prognostic and clinicopathological value of NM23 expression in patients with breast cancer: A systematic review and meta-analysis

It is hypothesized that, NM23, as a metastasis suppressor gene, may be a good indicator of patients with breast cancer in most reports. The aim of our meta-analysis was to determine the prognostic value of NM23 in patients with breast cancer synthetically, by searching 3 databases, PubMed, EMBASE, and Web of Science, for relevant articles. The inclusion criteria, exclusion criteria, and the standard-of-quality assessment were used according to a previous protocol. The pooled odd ratios (ORs) and corresponding 95% CI were calculated to assess the primary end point, survival data, and the secondary end point, associations between NM23 expression and clinicopathological factors. Finally, funnel plots and Egger׳s linear regression test were used to assess the potential publication bias. Overall, 792 articles were retrieved in the initial search of databases, and 4968 patients were eventually pooled from 26 available studies selected out by 2 independent reviewers. The incorporative OR showed that elevated NM23 expression was associated with better overall survival (OR = 0.62; 95% CI: 0.52-0.74; P < 0.00001; I2 = 0%; Ph = 0.46). In disease-free survival, we also obtained a good prognosis (OR = 0.30; 95% CI: 0.18-0.48; P < 0.00001; I2 = 46%; Ph = 0.13). In addition, high-NM23 expression was correlated with well or moderate histologic grade, negative lymph node metastasis, and early tumor staging. Furthermore, publication bias was detected in overall survival but not in disease-free survival, and it could also be verified by Egger׳s test (P = 0.009 and P = 0.687, respectively). These results implied that NM23 might be an indicator of good prognosis in patients with breast cancer, although further researches need to be performed to confirm the prognostic value of NM23.

Hierarchical investigating the predictive value of p53, COX2, EGFR, nm23 in the post-operative patients with colorectal carcinoma.

The aim of this study was to evaluate the correlations between p53, COX2, EGFR, nm23 expression and the progression free survival (PFS) of post-operative patients with colorectal carcinoma. Immunohistochemistry was used to detect the expression of p53, COX2, EGFR and nm23 in 459 specimens from colorectal carcinoma patients. Kaplan-Meier estimates, Cox proportional hazard regression analyses and hierarchical analyses were performed on the collected data. Kaplan-Meier estimates analysis suggested that EGFR expression was as a negative predictor, the median PFS of patients with EGFR high expression was 21.73 months, and the median PFS of patients with low EGFR expression was 57.83 months (χ2=20.880, P<0.001); nm23 expression was positive predictive factor for the prognosis of patients with colorectal carcinoma, the median PFS of patients with high nm23 expression was 37.77 months, and the median PFS was 21.47 months in the patients with low nm23 expression (χ2=7.364, P=0.007). Cox regression analysis revealed that comparing with the patients with low expression of EGFR, the patients with high EGFR expression were at higher risk of tumor progression (HR=1.667, P=0.004); Comparing with the patients with high nm23 expression, the patients with nm23 low expression had a higher risk of tumor progression (HR=0.412, P<0.001); and the risk of tumor progression was higher in the patients with high EGFR expression and low nm23 expression (HR=0.245, P<0.001). Hierarchical analysis showed that EGFR expression mainly correlates with the PFS of TNM stage I-II colorectal cancer patients, the median PFS was 33.53 months in the TNM stage I-II colorectal cancer patients with high EGFR expression patients; The median PFS of the TNM stage I-II colorectal cancer patients with low EGFR expression was 70.43 months (χ2=9.530, P=0.002); The median PFS was 19.2 months in the TNM stage III-IV colorectal cancer patients with high expression EGFR, the PFS of the TNM stage III-IV colorectal cancer patients with low EGFR expression was 37.87 months (χ2=7.97, P=0.005). nm23 expression mainly correlates with the PFS of TNM stage III-IV colorecatal cancer patients. The median PFS was 47.27 months in TNM stage I-II colorectal cancer patients with nm23 high expression, the median PFS was 48.85 months in TNM stage I-II colorectal cancer patients with low nm23 expression (χ2=0.101, P=0.750); The median PFS was 28.8 months in TNM stage III-IV colorectal cancer patients with nm23 high expression, the median PFS was 14.7 months in TNM stage III-IV colorectal cancer patients with low nm23 expression (χ2=13.213, P<0.001). EGFR is mainly a predictive factor for the prognosis of post-operative patients with TNM stage I-II colorectal cancer, and nm23 is important for predicting the prognosis of patients with stage III-IV, and EGFR and nm23 could be as predictor of combination.

NM23, un exemple de gène suppresseur de métastase

Metastasis suppressor genes – unlike tumor suppressor genes – are defined by their capacity to control metastatic dissemination in vivo without affecting growth of the primary tumor. The first of these metastasis suppressor genes, NM23, was identified in 1988. Since then, expression of NM23 has been studied widely in human tumor cohorts, often with contradictory results. Not only is NM23 overexpressed in most human solid tumors when compared to healthy tissues, but also low expression of NM23 correlates with metastasis and poor clinical prognosis in the advanced stages of a number of epithelial cancer types, including melanoma, breast, colon, and liver carcinoma. This does not hold true, however, for other cancer types such as neuroblastoma and hematological malignancies, in which high NM23 expression correlates with more aggressive disease. Genetic alterations in the NM23 gene – loss of heterozygosity, spontaneous mutations and polymorphisms – are rarely found in tumors; thus, the metastatic potential of tumor cells is probably affected by NM23 protein levels. Three lines of evidence demonstrate the anti-metastatic activity of NM23: first, overexpression of NM23 in metastatic cell lines reduces their metastatic potential in xenograft models; second, the incidence of lung metastases is elevated in NM23 knockout mice prone to develop hepatocellular carcinoma, and, third, silencing NM23 by RNA interference confers a “metastatic phenotype” on non-invasive human epithelial liver and colon cancer cell lines. It appears that NM23 is crucial for inhibiting invasive migration, so acting at early stages of metastatic dissemination. The mechanistic basis of the metastasis suppressor function of NM23 and its regulated expression still remains obscure, however. Reactivation of expression of the endogenous NM23 gene in tumor cells, or stimulation of the pathways it controls, constitutes a promising avenue for anti-metastatic therapy.

Clinical Significance of High nm23-H1 Expression in Intraepithelial Neoplasia and Early-Stage Squamous Cell Carcinoma of the Uterine Cervix

Seventy-two cervical pathology specimens, consisting of samples of cancer and high- and low-grade intraepithelial neoplasia, were used in a study exploring the involvement of nm23-H1/NDP kinase in carcinogenesis or recurrence. Additionally, the relationships between immunohistochemical expression of nm23-H1 and various clinicopathological variables for early-stage cervical cancer were evaluated. The nm23-H1 expression for high-grade cervical intraepithelial neoplasia and squamous cell carcinoma samples was significantly elevated when compared to low-grade analogs. Only deep stromal invasion was significantly associated with high nm23 expression. Moreover, a high cumulative recurrence hazard was demonstrated for the high nm23 expression group. In conclusion, high nm23-H1 expression may induce cellular proliferation for the progression from low- to high- grade intraepithelial neoplasia, with the subsequent emergence of invasive carcinoma as well as deep stromal invasion, and can be used as an indicator of prognosis.

Loss of nm23 expression predicts distal metastases and poorer survival for breast cancer.

The nm23 gene, originally identified by differential hybridization of metastatic murine melanoma cell lines has been associated with decreased metastatic potential. In this study, we evaluated the utility of nm23 expression levels as a predictive and a prognostic biomarker for distal metastases and poor survival in a Chinese cohort of 168 breast cancer patients. Our study indicates that high nm23 expression is associated with older age (older than 35 years) and smaller tumor size. There is no statistically significant association between nm23 expression and pathologic type or axillary metastasis. High nm23 expression is associated with the absence of distal metastases. Nearly 80% of women with high nm23 expression are alive after 10 years compared to 25% with low expression; at five years the cumulative survival proportions are 86% and 46%, respectively. The Cox model for survival indicates that controlling for tumor size and presence of axillary metastases at diagnosis, the hazard for women with low nm23 expression is nearly 4 times that of women with high nm23 expression. Low nm23 expression is predictive of distal metastases and appears to be a risk factor that is independent of the presence or absence of positive axillary nodes at diagnosis.

The gene NM23-M2 Is frequently mutated in leukemia

Abstract In more than 15 retrovirally induced primary mouse leukemias, we identified proviral integrations in or near the promoter region of the nm23-M2 gene. Nm23-M2 belongs to a family of highly conserved genes, encoding nucleoside diphosphate kinases. Furthermore, nm23-M2 is a transcription factor for the c-Myc proto-oncogene. Nm23-H2, the human homologue of nm23-M2, as well as the isoform nm23-H1, have been identified as indicators for poor prognosis in human hematopoietic malignancies. Whether this high nm23 expression is the result of mutations has never been documented. Here, we show that nm23-M2 is frequently mutated in mouse leukemias. We also demonstrate that in normal hematopoietic progenitors, expression of nm23-M2 is tightly controlled by hematopoietic growth factors (HGFs) at a post-transcriptional level. Association of nm23-M2 mRNA with polysomes, required for translation, was strictly dependent on HGFs. Preliminary studies suggest that nm23-M2 mutations in leukemias result in HGF-independent association of the mRNA with polysomes. Nucleotide sequencing demonstrated the presence of fusion transcripts of the retroviral long terminal repeat (LTR) and nm23-M2. Thus, the virus integration causes alterations 5' of the nm23-M2 mRNA, highly suggesting that the post-transcriptional regulation of the gene is affected. Our studies domonstrate a novel mechanism of aberrant proto-oncogene expression, i.e. altered translational regulation, instead of up regulation of proto-oncogene mRNA levels.

Differential Expression of nm23 H-1 Protein in Conjunctival Melanoma and Potential Precursor Lesions

Loss of nm23 gene expression is believed to enhance metastatic spread in diverse human tumors, including skin melanoma. The purpose of this work was to determine the pattern and prognostic relevance of nm23 protein immunoexpression in conjunctival melanoma and potential precursor lesion. Formaldehyde-fixed, paraffin-embedded conjunctival specimens comprising 85 melanocytic lesions (nevi, primary aquired melanosis with and without atypia and primary and locally recurrent malignant melanomas) from 73 patients were used. Sections from all specimens were examined by light microscopy to assess diverse prognostic parameters. Additional sections were then immunostained for nm23 H-1 protein and the immunoreactivity was assessed semi-quantitatively. Survival data for all patients were retrieved from the National Causes of Death Registry of Sweden.Nm23 H-1 protein was differentially expressed in conjunctival melanocytic lesions, however loss of immunoexpression was not more common in melanocytic lesions asociated with a high risk of malignant transformation. Also, primary and recurrent conjunctival melanomas showed an essentially similar nm23 expression pattern and we could not associate the pattern of nm23 immunoexpression with an increased risk for malignant transformation or locally recurrent disease. While there was a tentative separation between cause-specific survival curves after excision for low and high nm23 expression conjunctival melanoma, there was no statistically significant association with metastatic death of patients. However, loss of nm23 protein immunoexpression may still be of some importance as a marker for prognosis in conjunctival melanoma because the present study could only detect large differences in survival. Our results suggest that any potential prognostic value of nm23 immunoexpression would be independent of other markers, underlining the importance of further studies.

High levels of Nm23 gene expression in advanced stage of thyroid carcinomas

The product of Nm23 gene has been proposed as a candidate tumour metastasis suppressor protein. A strong association has been observed between reduced expression of Nm23 gene and acquisition of metastatic behaviour in some tumour cells including breast cancer and melanoma, but not in others such as colon cancer, neuroblastoma, and cervical cancer. In the present study, we examined the abundance of Nm23 mRNA in 39 thyroid tissue specimens including five multinodular goitres, one follicular adenoma, 26 papillary and three follicular carcinomas, and four anaplastic carcinomas. Nm23 was found to be expressed in all the tissue specimens. The expression was, however, variable in different stages of thyroid carcinoma. In stages I through III of differentiated thyroid carcinoma, the average level of Nm23 gene expression was comparable to that in multinodular goitres. In advanced stage of thyroid carcinoma (stage IV and anaplastic), 2-fold increase of Nm23 expression was noted. No mutations were found in the coding region of the gene. Nm23 mRNA level cannot, therefore, be used as a marker of low metastatic potential in thyroid carcinomas. The association of high level Nm23 expression with anaplastic thyroid carcinoma suggests its correlation with rapid cell proliferation.