Nm23 Expression Research Articles

Prognostic significance of co‐expression of nm23 and p57 protein in hepatocellular carcinoma

To investigate the unbalance of proliferation and apoptosis and the functions of cell-cycle proteins and apoptotic factor in metastasis of hepatocellular carcinoma (HCC) and their effect in prognosis. Proliferation index and apoptosis index, as well as seven relatively molecular markers, namely p15, p34, p53, p57, p73, survivin and nm23, were evaluated by immunohistochemistry and TUNEL in HCC tissues and compared to adjacent non-cancerous tissues and normal liver tissues. Furthermore, the prognostic significance by follow-up and mutual relationships for each clinicopathologic factor and molecular marker were analysed. The dysregulation between proliferation and apoptosis and the abnormal expression of seven molecular markers were observed in HCC tissues. The unbalance of proliferation and apoptosis and abnormal expressions of p15, p34, p57 and nm23 were correlated with TNM stage and extrahepatic metastasis. In particular, the abnormal co-expression of nm23/p57 correlated with advanced TNM stage and bigger tumor size and was an independent prognostic factor of HCC. The unbalance of proliferation and apoptosis and abnormal expression of cell-cycle proteins promote metastasis of HCC. Moreover, the abnormal co-expression of nm23/p57 may be a useful molecular marker for metastasis and unfavourable prognosis for HCC.

Expressions of Nucleoside Diphosphate Kinase (nm23) in Tumor Tissues are Related with Metastasis and Length of Survival of Patients with Hepatocellular Carcinoma

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. 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. 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. 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.

Expression of nm23, BRCA-1, ki-67 and their clinical significance in breast cancer

Expression of nm23, BRCA-1, ki-67 and their clinical significance in breast cancer

PTEN as prognostic and predictive marker in postoperative radiotherapy for squamous cell cancer of the head and neck.

5519 Background: The tumor suppressor PTEN is known to control a variety of processes related to cell proliferation, survival and growth. In this study we analyzed the influence of PTEN expression on the outcome of randomized clinical trial of conventional (CF) versus 7-days-a-week postoperative radiotherapy (p-CAIR) for squamous cell cancer of the head and neck. Methods: The patients with cancer of the oral cavity, oropharynx and larynx were randomized to receive 63 Gy in fractions of 1.8 Gy given 5-days-a-week or 7-days-a-week (Suwinski et al. Radiother Oncol. 2008;87:155-163). Out of 279 patients enrolled to the study 147 paraffin blocks were available for immunohistochemical assesment of PTEN (73 CF, 74 p-CAIR) To evaluate the effect of fractionation relative to PTEN expression the data on loco-regional tumor control (LRC) were analyzed using Kaplan-Meier method and compared using Cox f- test. The prognostic value of PTEN was tested using multivariate Cox model. Results: Tumors with high intensity of PTEN staining had significant gain in LRC from p-CAIR (5 year LRC 93% vs 69%, for p=CAIR vs. CF, p=0.01, RR=0.25). By contrast, tumors with low intensity of PTEN did not gain from p-CAIR (5 year LRC 56% vs 47%, p=0.49, RR=0.94). Intensity of PTEN highly affected LRC in a whole group of 147 patients (5 year LRC 80% vs. 52% for high vs. low PTEN, p=0.0008, RR=0.32). We have previously analyzed the prognostic and predictive potential of the other variables and markers in the same group of patients, including neck node involvement, EGFR, nm23, Ki-67, p-53, cyclin D1, tumor site and margins (Suwinski et al. Int J Radiat Oncol Biol Phys. 2009 Sep 2, Epub). A multivariate Cox analysis now indicates that the prognostic potential of PTEN exceeds that of the other variables that significantly and independently affect LRC (RR is 2.8, 2.0, 1.9 and 1.9 for PTEN, neck node involvment, EGFR and nm23 expression respectively, p=00004). Conclusions: These results suggest that PTEN may serve as a prognostic and predictive marker in postoperative radiotherapy for high-risk squamous cell cancer of the head and neck. No significant financial relationships to disclose.

Expression of CDX-2,PTEN,E-cadherin and NM23 in gastric cancer and its clinical significance

Objective To investigate the expression of CDX-2,PTEN,E-cadherin and NM23 in gastric cancer and its clinical significance.Methods Immunohistochemical S-P method was used to detect expression of CDX-2,PTEN,E-cadherin and NM23 in 77 gastric cancer specimens and 30 normal stomach mucosal tissues,and then the relationship of the expression with clinical pathology parameters was analyzed.Results The positive rates of CDX-2,PTEN,E-cadherin and NM23 were significantly higher in gastric cancer tissues than those in the normal gastric tissues(P 0.05).The expression of CDX-2,PTEN,E-cadherin and NM23 was correlated with the differentiation,histological type,infiltration,lymph node metastasis and TNM stage of the tumors(P 0.05),but not with patients' gender,age or tumor size(P 0.05).The 1-,3-and 5-year survival rates of CDX-2,PTEN,E-cadherin and NM23 positive patients were higher than those of negative patients(P 0.05,P 0.01).Conclusion The expression of CDX-2,PTEN,E-cadherin,NM23 in gastric cancer is related to the differentiation,infiltration,lymph node metastasis and TNM stage of gastric cancer,and detecting their expression in gastric cancer may help to judge the prognosis of gastric cancer.

Abstract 5767: LPA1 antagonist, Debio 0719, acts as a metastasis suppressor in breast cancer

Abstract The control of micrometastatic cancer is vital to clinical success in the adjuvant or post-treatment (minimal residual disease) settings. Over twenty metastasis suppressor genes (MSGs) have been validated; when over-expressed, they exert no significant effect on primary tumor growth but significantly reduce metastasis. Translation of this basic research to the clinic is difficult, as it is virtually impossible to re-express a gene in every tumor cell. An alternate approach is to identify genes whose expression is inversely correlated with MSGs that can be used as potential therapeutic targets. We identified LPA1, a G-Protein Coupled Receptor (GPCR) for the bioactive lipid lysophosphatidic acid (LPA), as a being inversely correlated with the Nm23-H1 MSG levels in multiple cell lines and a panel of human primary breast carcinomas. These data suggest a novel hypothesis that LPA1 inhibitors may be effective in halting micrometastatic disease in breast cancer patients with low Nm23-H1 expressing, aggressive tumors. To test this we used the 4T1 murine mammary carcinoma model system due to its highly aggressive nature and low Nm23 expression levels. Stably transfected murine or human Nm23 expressing 4T1 clones significantly decreased the motility of the 4T1 cells and expressed lower levels of LPA1. Treatment of the cells with a small molecule LPA1 specific inhibitor, Debio 0719, at an IC50 of 50nM significantly reduced the migration of all 4T1 parental cells towards both 1% FBS and LPA (10uM), while having minimal effects on tumor cell growth as measured by MTT assay. To assess the effects of this LPA1 inhibitor in vivo, 4T1 parental, vector control and Nm23-M1 expressing clones were orthotopically injected into the mammary fat pad of Balb/c mice at day 0. On day two after injection the mice receiving the 4T1 parental cells were randomized between vehicle control and treatment group. The treated group received Debio 0719 which was administered subcutaneously (twice daily, 15 mg/kg). Primary tumors were resected from all mice at day 10 and mice were subsequently allowed to continue until day 70 before sacrifice. The compound had no significant effect on primary tumor sizes and, as such, would have been a no-go for traditional drug development. However, mice treated with Debio 0719 had significantly decreased lung and liver metastasis, 84% and 86% respectively (P &amp;lt; 0.0001 for both). This reduction in metastasis is similar to that seen in the 4T1 Nm23-M1 expressing clones. Subsequent immunohistochemical studies have revealed that while there is no change in proliferative index in the primary tumors between treated and non-treated mice, there was a significant difference in Ki67 staining between the untreated liver metastasis (19%) and treated (5%). The data indicate that Debio 0719 acts as a metastasis suppressor, reducing metastatic foci and can induce dormancy in the metastatic site. As such, it represents a new class of potential therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5767.

Significance of nm23 Immunoexpression in the Prognosis of Renal Cell Carcinoma

Non-metastatic gene 23 (nm23) is a metastasis suppressor gene that is expressed in all tissues and decreased nm23 expression may be linked to poor prognosis. By immunohistochemical staining of nm23 protein antibodies this study examined the prognostic value of nm23 protein expression in 54 renal cell carcinoma (RCC) patients and analysed its relationship with tumour, node, metastases (TNM) surgical stage, Fuhrman nuclear grade, lymph node involvement and survival. Of the 54 RCC cases studied, 11 (20.4%) showed positive lymph node involvement while 43 (79.6%) were lymph node negative. There was no difference in nm23 protein expression between cases with and without lymph node involvement. In addition, nm23 protein expression was not related to TNM stage, Fuhrman nuclear grade or survival. More extensive studies are required to understand the effect of nm23 protein expression on the biological behaviour of RCC.

The Nm23-H1 metastasis suppressor as a translational target

Nm23 was the first of what has become a field of over 20 known metastasis suppressor genes (MSGs). Since the discovery of Nm23 in 1988, a variety of mechanisms have been attributed to its activity, including a histidine kinase activity, binding of other proteins to regulate metastatic formation, and altered gene expression downstream of Nm23. Here, we will review current efforts to translate the previous work done on this MSG into the clinic, including high-dose medroxyprogesterone acetate (MPA), which has been shown to upregulate Nm23 expression. In addition, we will detail a new potential target downstream of Nm23. LPA1 is one of a group of known cell surface receptors for lysophosphatidic acid (LPA), which has been shown to be inversely correlated with Nm23 expression. A specific LPA1 antagonist could conceivably mimic the effects of Nm23 by downregulating the activity of the LPA1 pathway, which would be of considerable interest for potential clinical use.

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

Plakoglobin (gamma-catenin) is a homolog of beta-catenin with similar dual adhesive and signaling functions. The adhesive function of these proteins is mediated by their interactions with cadherins, whereas their signaling activity is regulated by association with various intracellular partners. In this respect, beta-catenin has a well-defined oncogenic activity through its role in the Wnt signaling pathway, whereas plakoglobin acts as a tumor/metastasis suppressor through mechanisms that remain unclear. We previously expressed plakoglobin in SCC9 squamous carcinoma cells (SCC9-P) and observed a mesenchymal-to-epidermoid transition. Comparison of the protein and RNA profiles of parental SCC9 cells and SCC9-P transfectants identified various differentially expressed proteins and transcripts, including the nonmetastatic protein 23 (Nm23). In this study, we show that Nm23-H1 mRNA and Nm23-H2 protein are increased after plakoglobin expression. Coimmunoprecipitation and confocal microscopy studies using SCC9-P and various epithelial cell lines with endogenous plakoglobin expression revealed that Nm23 interacts with plakoglobin, cadherins and alpha-catenin. Furthermore, Nm23-H2 is the primary isoform involved in these interactions, which occur prominently in the cytoskeleton-associated pool of cellular proteins. In addition, we show that plakoglobin-Nm23 interaction requires the N-terminal (alpha-catenin interacting) domain of plakoglobin. Our data suggest that by increasing the expression and stability of Nm23, plakoglobin has a role in regulating the metastasis suppressor activity of Nm23, which may further provide a potential mechanism for the tumor/metastasis suppressor function of plakoglobin itself.

Transcatheter arterial chemoembolizaion on the expression of nm23, Tissue inhibitor of metalloproteinase-2 and extrahepatic metastasis in hepatocellular carcinoma

Objective To investigate the effects of transcatheter arterial chemoembolization(TACE) on the expression of nm23, tissue inhibitor of metalloproteinase-2 (TIMP-2) and extrahepatic metastasis in hepatocellular carcinoma (HCC). Methods The specimens were collected from resectable HCC in 72 patients. Patients were divided into two groups. In one group, TACE was performed before tumor resection (Group A, n=36). In another group, the tumors were resected directly without preoperative TACE (Group B, n=36). The expression and distribution of nm23, TIMP-2 in the tumor tissue and liver parenchyma in the two groups were compared. All patients were followed up for 24 months,and the incidence of extrahepatic metastasis was compared between the two groups. Chi-square test was applied to compare the expression levels of nm23-H1 and TIMP-2. Results The number of cases of strong, moderate and no expression of nm23 were 24, 6 and 6 cases in group A respectively, and were 9, 6 and 21 cases in group B. Statistical differences were found between the two groups(X~2=15.52, P 0.05). Conclusions TACE could enhance the expression of nm23-H1 and TIMP-2 in tumor tissues. Therefore, the potential of metastasis of tumor cells might be prohibited by TACE. Key words: Carcinoma,hepatocellular; Neoplasm metastasis; nm23-H1; Tissue inhibitor ofmetalloproteinase-2

NM23-H2, an ERβ Associated Protein, as a Prognostic Marker in Breast Cancer.

Abstract Purpose: Endocrine therapy is a well established therapy for estrogen receptor (ER) positive breast cancer. Two ER have been identified but currently only ERα is used in clinical practice. The role of ERβ in breast cancer is less well understood. Two human NM23 genes exist, NM23-H1 and NM23-H2. Several studies have shown an inverse relationship between overexpression of NM23-H1 in breast cancer and disease aggressiveness. NM23-H2, a metastasis suppressor protein, was recently identified as ERβ associated protein in vascular wall of atherosclerotic lesions, but the prognostic significance of this protein and its association with ERβ has not being studied in breast carcinoma. The purpose of this study was to investigate whether NM23-H2 is expressed in breast cancer and its potential clinical implications.Material and Methods: A cohort of 427 patients with diagnosis of primary invasive breast carcinoma between the period of 1994 to 1997 was used for this study. They all were patients diagnosed and treated at the Leeds Teaching Hospitals, UK. Immunohistochemistry was used primarily to identify the expression of NM23-H2 in this study. Regulation of NM23-H2 in vitro in MCF-7 cells was assessed by Western blotting. p&amp;lt;0.05 was considered statistically significant.Results: Patients ages were 27-92 years (median = 58 years, IQ range 47-69 years) with median follow up of 110 months. Tumour size varied from 1 and 130 mm (median=22.7mm, IQ range 14-26mm). Seventy eight percent were invasive ductal carcinoma NST and 11.5% were invasive lobular; 3.9% were special type (tubular, mucinous); and 6.6% were mixed type. Twenty-three percent of the tumours were grade 1, 43.3% were grade 2 and 33.7% were grade 3. Axillary metastases were present in 51% of the cases. NM23-H2 expression was variable between tumours and demonstrated only in the cytoplasm of breast carcinomas. The percentage of staining ranged from 0% to 100% (median 80%).NM23-H2 was strongly correlated with ERβ1 and ERα (p &amp;lt;0.001; correlation coefficient 0.252 and 0.176 respectively). No correlation was found between NM23-H2 with age, size, grade or lymph node status. NM23-H2 when expressed at levels higher than 30% was associated with improved overall survival (p= 0.030). In a multivariate Cox hazard analysis, NM23-H2 overexpression was a significant predictor of better survival independent of tumor grade, lymph node status, size or ERα. MCF-7 cells treated with 17β-estradiol (E2) expressed higher levels of NM23-H2(17.5kDa) compared with serum treated cells.Conclusion: This is the first time to our knowledge that the expression of NM23- H2 in breast cancer and its association with ERβ has been investigated. Our data provide evidence that immunohistochemical overexpression of NM23 H2 is associated with ERβ and ERα in breast cancer and with improved survival. NM23-H2 might be a good prognostic marker in breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4148.

Predicting the Effect of Accelerated Fractionation in Postoperative Radiotherapy for Head and Neck Cancer Based on Molecular Marker Profiles: Data From a Randomized Clinical Trial

To determine the prognostic and predictive values of molecular marker expression profiles based on data from a randomized clinical trial of postoperative conventional fractionation (p-CF) therapy versus 7-day-per-week postoperative continuous accelerated irradiation (p-CAIR) therapy for squamous cell cancer of the head and neck. Tumor samples from 148 patients (72 p-CF and 76 p-CAIR patients) were available for molecular studies. Immunohistochemistry was used to assess levels of EGFR, nm23, Ki-67, p-53, and cyclin D1 expression. To evaluate the effect of fractionation relative to the expression profiles, data for locoregional tumor control (LRC) were analyzed using the Cox proportional hazard regression model. Survival curves were compared using the Cox f test. Patients who had tumors with low Ki-67, low p-53, and high EGFR expression levels and oral cavity/oropharyngeal primary cancer sites tended to benefit from p-CAIR. A joint score for the gain in LRC from p-CAIR based of these features was used to separate the patients into two groups: those who benefited significantly from p-CAIR with respect to LRC (n = 49 patients; 5-year LRC of 28% vs. 68%; p = 0.01) and those who did not benefit from p-CAIR (n = 99 patients; 5-year LRC of 72% vs. 66%; p = 0.38). The nm23 expression level appeared useful as a prognostic factor but not as a predictor of fractionation effect. These results support the studies that demonstrate the potential of molecular profiles to predict the benefit from accelerated radiotherapy. The molecular profile that favored accelerated treatment (low Ki-67, low p-53, and high EGFR expression) was in a good accordance with results provided by other investigators. Combining individual predictors in a joint score may improve their predictive potential.

CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer

The aim of this study was to examine the expression of CD44v6, CD54, Cdx2, CXCL5, Cyclin B1, MMP-7, nm23, RCAS1 and Survivin in primary gastric cancer and to investigate whether these molecules were useful in predicting the lymph node status. They were selected as candidates for indicators of lymph node metastasis from various kinds of cancer-associated genes reported previously. In 135 cases of radically resected primary gastric adenocarcinoma, we investigated the association between the expression of these molecules and clinocopathologic factors by immunohistochemistry. The results revealed that the expression of CD44v6 and MMP-7 were significantly associated with lymph node status. By contrast, nuclear Cdx2 expression was found to be inversely correlated with lymph node metastasis. Moreover, multivariate analysis demonstrated that CD44v6, MMP-7 and nuclear Cdx2 were independent predictors for lymph node status. In conclusion, our results suggest that positive expression of both CD44v6 and MMP-7, and negative expression of nuclear Cdx2 may serve as powerful predictors of lymph node metastasis in gastric cancer. Combined evaluation of these markers could be further useful to predict lymph node status clinically.

Identification of antigenic proteins associated with trichloroethylene-induced autoimmune disease by serological proteome analysis

Although many studies indicated that trichloroethylene (TCE) could induce autoimmune diseases and some protein adducts were detected, the proteins were not identified and mechanisms remain unknown. To screen and identify autoantigens which might be involved in TCE-induced autoimmune diseases, three groups of sera were collected from healthy donors (I), patients suffering from TCE-induced exfoliative dermatitis (ED) (II), and the healed ones (III). Serological proteome analysis (SERPA) was performed with total proteins of TCE-treated L-02 liver cells as antigen sources and immunoglobins of the above sera as probes. Highly immunogenic spots (2-fold or above increase compared with group I) in group II and III were submitted to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and tandem mass spectrometry sequencing. Western blot analysis was followed using commercial antibodies and individual serum. Six proteins were identified. Among them, Enoyl Coenzyme A hydratase peroxisoma 1 and lactate dehydrogenase B only showed stronger immunogenicity for group II sera, while Purine nucleoside phosphorylase, ribosomal protein P0 and proteasome activator subunit1 isoform1 also showed stronger immunogenicity for group III sera. Noteworthy, NM23 reacted only with group II sera. Western blot analysis of NM23 expression indicated that all of the individual serum of group II showed immune activity, which confirmed the validity of SERPA result. These findings revealed that there exist autoantibodies in group II and III sera. Besides, autoantibodies of the two stages of disease course were different. These autoantigens might serve as biomarkers to elucidate mechanisms underlying TCE toxicity and are helpful for diagnosis, therapy and prognosis of TCE-induced autoimmune diseases.

Expression of p53, bcl-2 and nm23 Proteins in Squamous Cell Lung Cancer

The evaluation of lung cancer molecular profiles is an essential element of the therapeutic process in that type of neoplasm. The analysis of apoptotic and metastasis-linked proteins is an important goal because of the key role of those processes in carcinogenesis. The aim of this study was to evaluate the expression of apoptosis regulatory proteins p53 and bcl-2 as well as antimetastatic marker nm23 in squamous cell lung cancer, taking into account the clinical and pathological data. Thirty tissue specimens from patients undergoing therapeutic or diagnostic thoracic surgery were included in the study. All markers were assessed with immunohistochemistry method on paraffin-embedded tissue. Nm23 expression was observed less frequently in specimens with cancer cell emboli in blood vessels or lymph node metastasis. In cancers with lymph node metastasis, the coexpression of p53 and bcl-2 was found statistically more often than in lymph node negative cases. There was no correlation between p53, bcl-2 and nm23 expression and 2-years survival time. Our study indicates a marked heterogeneity of p53, bcl-2 and nm23 expression in squamous cell lung cancer and the potentially unfavorable influence of p53 and bcl-2 coexpression. Less frequent nm23 expression seems to be connected with morphological signs of metastatic process.

Expression of p53, cyclin D1 and EGFR correlates with histological grade of adult soft tissue sarcomas: a study on tissue microarrays

Soft tissue sarcomas (STSs) are rare heterogeneous tumors with variable clinical course and outcome. The management of STSs depends upon the accurate histopathological diagnosis and assessing their histological grade. Currently, core needle biopsies are becoming increasingly popular for diagnosing STSs but value of histological grading is limited from this type of specimens. To evaluate the immunohistochemical expression of p53, mdm-2, cyclin D1, p16, nm23, EGFR and Ki-67 labelling index in adult STSs patients and their association with histological grade of STSs, we analysed 101 primary untreated STSs of the limbs and trunk using the tissue microarray technique on formalin-fixed, paraffin-embedded tissue samples. The cases consisted of 15 G1, 28 G2 and 58 G2 sarcomas. Ki-67 labelling index (LI) was calculated from whole block sections for the possibility to select the most proliferative regions. The LI ranged from 1.26 to 75.5% (median 26.7%) and strongly correlated with the mitotic count (p rs for adult patients with STSs and may assist in establishment of the histological grade in STSs.

Low‐grade fibromyxoid sarcoma versus fibromatosis: A comparative study of clinicopathological and immunohistochemical features

We have studied 11 cases of low-grade fibromyxoid sarcoma (LGFMS) and 15 cases of fibromatosis with respect to clinicopathological features and immunohistochemical expression of Ki-67, nm23, cyclinD1, and p53, in order to investigate the differential diagnosis between this two groups. Formalin-fixed, paraffin-embedded sections from 11 cases of LGFMS and 15 cases of fibromatosis were studied histologically and immunohistochemically. The immunostainings were semiquantitatively evaluated using the Allred score system. Microscopically, LGFMS was composed of bland spindle cells arranged in a whorled pattern showing alternating myxoid zones and fibrous stroma zones with prominent arcade curvilinear capillaries. Cytological atypia, mitotic figures, and tumor necrosis were absent in all 11 cases of LGFMS. In contrast, fibromatosis was less cellular and more fascicular, containing more collagen and showing no alternating fibrous and myxoid zones as compared with LGFMS. The immunostaining scores of nm23 in LGFMS were significantly lower than that in fibromatosis. The immunostaining scores of Ki-67, p53, and cyclinD1 in LGFMS were significantly higher than that in fibromatosis. Thus, we consider that LGFMS can be distinguished from fibromatosis by clinicopathological features, and assessments of the immunohistochemical expression level of cyclinD1, p53, nm23, and Ki-67 are helpful in the differential diagnosis.

Inverse Correlation of NM23 Expression with Lysophosphatidic Acid Receptor EDG2/lpa1 Expression of Human Leukemia Cells during Myeloid Differentiation Induced by All-Trans Retinoic Acid

Overexpression of the nm23 gene is found in many hematological malignancies, and predicts poor treatment outcome. Because the amount of intracellular NM23-H1 protein is inversely correlated with differentiation and exogenous over expression of the nm23-H1 in myeloid leukemia cells reduced the sensitivity to induction of myeloid differentiation, nm23-overexpression is considered to function as a differentiation-suppressor. However, the molecular mechanism of this phenomenon is unknown. Recently, lysophosphatidic acid (LPA) receptor EDG2/lpa1 was identified as a gene down-regulated by nm23-H1 and associated with cell motility/metastasis suppressor functions in breast cancer cells. Although the clinical significance of nm23-H1 overexpression in leukemia is completely opposite to that in breast cancer, there might be a common molecular mechanism between the metastasis-suppressing activity and differentiation-inhibiting activity of nm23-H1 overexpression, because many functional characteristics of macrophages/neutrophils are similar to those of motile and metastatic tumor cells. Here, we examined the EDG2/lpa1 expression level and its association with NM23 expression level and myeloid differentiation of leukemia cells. EDG2 and NM23 proteins were expressed at different levels in all leukemia cells tested (HL-60, NB4, THP-1, U937, K562, HEL, BALM-1, BALM-3, MOLT4, Jurkat). During all-trans retinoic acid (ATRA)-induced myeloid differentiation of HL-60 cells, the NM23 expression decreased and EDG2 expression inversely increased. Similar effects of ATRA were observed in myeloid differentiation of NB4 and THP-1 cells. NM23 expression levels and EDG2 expression levels modulated by ATRA treatment were inversely correlated (Spearman's correlation coefficient, rs = −0.7538, p = 0.0237). However, these correlations were not found in the erythroid differentiation of ATRA-treated HEL and K562 cells. Cell motility is required for myeloid differentiation; therefore, there might be a common mechanism, the inhibition of cell motility thorough EDG2 down-regulation by NM23-H1 overexpression, between differentiation-inhibiting activity in leukemia cells and motility-inhibiting activity in breast cancer cells. The discrepancy in the clinical significance of NM23-H1 overexpression between leukemia and breast cancer might be resolved.

Immunohistochemical analysis of nm23 protein expression in thyroid papillary carcinoma and follicular neoplasm

Introduction We aimed at assessing the significance of nm23 gene expression in papillary and follicular carcinomas, the two most common differentiated thyroid carcinomas. Materials and methods During a cross-sectional study, 173 paraffin blocks, including 131 papillary thyroid carcinomas, 12 follicular carcinomas and 30 follicular adenomas were stained with nm23 marker by immunohistochemistry method. Cytoplasmic staining in more than 10% of the tumor cells was considered as positive, and α<0.05 was established as the level of statistical significance for the evaluation of the correlation between nm23 expression and age, sex, tumor size, vascular /capsular invasion and lymph node involvement. Results nm23 was positive in 40% of the follicular adenoma, 67.2% of the papillary carcinoma and 66.7% of the follicular carcinoma. p value was more than 0.05 in the assessment of the relationship between nm23 and all of the above-mentioned parameters in differentiated thyroid carcinomas. nm23 expression did not significantly differentiate between follicular adenoma and carcinoma. Conclusion According to our results, there is no relationship between nm23 immunoreactivity and age or sex of the patients. Also, nm23 cannot be considered as a useful marker for the evaluation of invasion in differentiated thyroid carcinomas or in distinctions between follicular adenoma and carcinoma.

A clinicopathological study of nm23-H1 expression in classical Hodgkin’s lymphoma

BackgroundWe carried out immunohistochemistry to examine the expression of nm23-H1 in Hodgkin and Reed–Sternberg cells in patients with classical Hodgkin’s lymphoma (CHL). Patients and methodsWe evaluated 128 patients with CHL [87 patients with nodular sclerosis (NS) and 41 patients with mixed cellularity (MC)] for CD15, CD20, Ki-67, EBER, TIA-1, and nm23-H1 by immunohistochemistry. ResultsCD15 was expressed in 79%, CD20 in 11%, Ki-67 in 93%, EBER in 34%, TIA-1 in 11%, and nm23-H1 in 60% of the CHL patients. NS patients showed a significantly higher rate of nm23-H1 expression than MC patients (P < 0.001). The serum nm23-H1 level was significantly higher in patients with positive nm23 expression. Univariate analysis showed that stage IV, poor performance status, low hemoglobin level, low serum albumin level, age of 45 years or older, TIA-1-positive status, and nm23-H1-positive status were associated with significantly shorter progression-free survival. Multivariate analysis with these factors showed TIA-1 and cytoplasmic nm23-H1 expression to be significant and independent prognostic factors. ConclusionsOur results indicate that nm23-H1 expression is a prognostic factor for CHL and that it is as important as serum nm23-H1, both of which are useful for planning the treatment strategy.