Expression of nm23-H1 in transitional cell carcinoma of the upper urinary tract

Transitional cell carcinoma of the upper urinary tract is an uncommon neoplasm. Relatively little information is available regarding the clinical relevance of molecular markers. This study was performed to examine the importance of nm23-H1 gene expression (NM23-H1) in this type of tumors. Immunohistochemical expression of NM23-H1 was analyzed in 90 cases of upper urinary tract cancer, and was compared for its prognostic significance with conventional biological indicators. High expression of NM23-H1 was found in 7 cases (8%), intermediate expression in 32 cases (36%), and low expression in 51 cases (57%). Reduced NM23-H1 (defined as intermediate or low level of expression) was associated with a higher histological grading (p=0.002), invasive tumor growth (p=0. 002), or an increased proliferating cell nuclear antigen labeling index (p=0.004). NM23-H1 tended to inversely relate to later recurrence or long-term survival (p=0.06), but, only tumor staging was found to be significant in predicting clinical outcome (p=0.002). nm23-H1 appears to function as a tumor suppressor for upper urinary tract cancer, however, evaluation of NM23-H1 provides limited prognostic information.     

The NM23 gene and its expression in oral squamous cell carcinoma.

The murine nm23, a putative metastasis suppressor, has three human homologues, NM23-H1, -H2, and -H3b. Several reports have suggested a low metastatic potential for neoplasms with a high expression of NM23-H1 gene, while other studies have not shown this relationship. These apparent differences in the role of NM23 in metastasis suppression might be explained by unability to discriminate between the expression of the two genes NM23-H1 and NM23-H2. The NM23-H2 product is not related to tumor progression and metastasis suppression. Two studies on human oral squamous cell carcinoma (OSCC) have been reported, both showing the NM23 product to be a metastasis suppressor factor. However, none of these two studies distinguished NM23-H1 from NM23-H2. The aim of this study was to detect the protein expression pattern of NM23-H1 product in 24 OSCCs by immunohistochemistry in paraffin-embedded tissues using a monoclonal antibody non-cross-reactive with NM23-H2. The NM23-H1 positive group showed lower frequency of lymph node metastasis, and a better grading than the NM23-H1 negative group supporting the role of NM23-H1 as metastasis suppressor factor which may be useful for predicting tumor metastasis in OSCC.     

Reappraisal of the role of NM23-H1 in colorectal cancers

BACKGROUND AND OBJECTIVES: A number of evidence indicate that downregulation of the nm23-H1 gene may be relevant to metastatic progression of many kinds of human cancer. However, its role in colorectal cancers remains controversial. To address the issue, this study was performed to investigate the clinical relevance of nm23-H1 in patients with colorectal cancers. METHODS: Immunohistochemical expression of nm23-H1 protein product (NM23-H1) was studied in a total of 146 colorectal cancer patients and compared for its prognostic value at a mean follow-up of 54 months. RESULTS: There was no apparent correlation between NM23-H1 expression and clinicopathological indicators, including Dukes category, lymphatic metastasis, distant metastasis, histological grading, and tumor location (P < 0.1, respectively). In addition, determination of NM23-H1 expression status did not provide independent prognostic information compared with conventional pathological staging. CONCLUSIONS: The results indicate that nm23-H1 gene does not play an important part in the progression of colorectal carcinogenesis.     

转移抑制基因nm23-H1参与肺癌Ras信号传导机理研究

背景与目的nm23-H1基因已被证实为一种肿瘤转移抑制基因,但其作用机理尚不明了,本研究探讨nm23-H1参与肺癌Ras信号传导的机理。方法应用脂质体法将pEGFP-nm23-H1野生型和突变型质粒(WT,H118F,S120G,P96S,S44A)转染人大细胞肺癌细胞株L9981,采用免疫共沉淀与Western blot方法检测野生型和突变型nm23-H1蛋白与Ras支架蛋白KSR的关系。结果在转染了野生型和突变型质粒的五个细胞株中,鼠抗nm23-H1免疫沉淀物在86KDa处可检测到KSR的阳性条带,而各组KSR的量应用单因素方差分析比较无显著性差异(F=0.190,P=0.938)。结论本研究结果表明nm23-H1与KSR存在相互作用,但这种相互作用与nm23-H1有无突变及突变位点无关,nm23-H1可能是通过KSR参与肺癌Ras信号传导的。     

NM23, an example of a metastasis suppressor gene

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.     

NM23-H1 immunostaining is inversely associated with tumour staging but not overall survival or disease recurrence in colorectal carcinomas.

The NM23-H1 gene product has been recently identified as a potential metastasis suppressor. Studies on breast carcinomas have shown an inverse correlation between NM23-H1 status and stage of carcinogenesis and overall survival. However, in colorectal cancer, conflicting data have been reported. This study aimed to investigate whether NM23-H1 immunostaining is correlated with tumour stage, overall survival, disease recurrence, tumour differentiation, age and sex in colorectal carcinomas for the Singapore population using chi-square analysis. The staining was performed on 141 paraffin-embedded surgical specimens collected between 1991 and 1992 using a monoclonal anti-NM23-H1 antibody. Follow-up of patients was until time of death or for 5 years. There was a very significant inverse association between tumour staging and NM23-H1 status (P = 0.0004). However, NM23-H1 expression was not significantly correlated to overall 5-year survival, disease recurrence, tumour differentiation, age or sex. Thus, although NM23-H1 may be involved in suppressing metastasis, NM23-H1 immunohistochemistry has no prognostic value in colorectal cancer. This is the first report of a significant inverse association of NM23-H1 status with tumour staging in colorectal cancer which showed no correlation with overall survival or disease recurrence. Our result thus cautions against the practice of equating an inverse relation of genetic markers with tumour staging to survival or disease recurrence.     

Expression of nm23-H1 in uveal melanoma

Uveal melanoma (UM) is the most common malignant intraocular tumor in adults. Despite the high accuracy of clinical diagnosis and advances in local treatment, more than 50% of UM patients develop metastasis within 10 years of initial diagnosis. NM23 is one of the human metastasis suppressor genes. Reduced nm23-H1 expression is correlated with high metastatic potential in many different cancers. The purpose of this study is to investigate the expression of nm23-H1 in UM and its potential value as a prognostic marker. Immunostaining of nm23-H1 was verified in five human UM cell lines with different metastatic potentials. The expression level of nm23-H1 mRNA was evaluated with one-step quantitative real-time PCR. The invasion ability of the cell lines was assessed before and after silencing nm23-H1 with small interference RNA. Thirty-two cases of paraffin-embedded specimens of human UM were immunostained with nm23-H1 monoclonal antibody. The immunostaining was evaluated in a semiquantitative fashion based on extent and intensity. The real-time PCR results of five human UM cell lines showed that expression of nm23-H1 was higher in cell lines with low metastatic potential compared with those with high metastatic potential (P<0.05). The invasive ability of the UM cell lines increased after silencing nm23-H1 expression with small interference RNA (P<0.05). The immunostaining of nm23-H1 was cytoplasmic in all cell lines and UM patients samples. The increased immunostaining intensity of nm23-H1 in patients' samples was associated with better survival rate (Kaplan-Meier test P=0.0097). The expression of nm23-H1 was not correlated with other prognostic factors. It can be concluded that nm23-H1 may be a prognostic marker to predict the survival rate of UM patients and it has the potential to identify high-risk patients.     

nm23-H1 expression in salivary adenoid cystic carcinoma in relation to metastasis and survival

The expression of nm23-H1, product of putative metastasis suppressor gene, was evaluated immunohistochemically in 31 cases of adenoid cystic carcinoma (ACC) of salivary glands and correlated with their clinicopathologic features. All benign salivary gland tumors of various types, which were used as a non-metastatic control, showed obvious nm23-H1 expression. The immunoreactivity of tumor cells was stronger than that of normal salivary gland components, although the distribution patterns of positive cells considerably varied between tumor types. In ACC, 16 cases (52%) showed the reduction of nm23-H1 immunoreactivity either in positive cell frequency or staining intensity. These cases were referred to as negative cases. The incidence of negative cases was 67% (10/15) and 38% (6/16) of the cases with and without metastasis, respectively. Furthermore, metastatic tumors showed decreased immunoreactivity of this protein compared with their primary tumors. The prognosis of patients with a nm23 negative tumor was generally poorer than that with a positive tumor. These results may suggest that the reduction of nm23-H1 protein has an implication for metastasis of ACC.     

Correlation between nm23-H1 overexpression and clinicopathological variables in human anal canal carcinoma.

To improve life expectancy prognostic factors other than TNM have been investigated. It is thought that nm23 protein may play a specific biological role in suppressing tumor metastasis. The purpose of this study was to elucidate the clinical significance of nm23 expression in human anal canal carcinoma. Immunostaining using anti-nm23 monoclonal antibody was performed in 22 anal canal tumors. The results were correlated with clinicopathological variables. Six cases out of 22 (27.3%) were nm23-positive. Significant association was found between nm23-H1 expression and depth of invasion, lymph node involvement and prognosis (p<0.05). There was no significant association between nm23-H1 expression, histologic type and age of the patients. nm23-H1 expression was not seen in our cases with metastasis and this may be related to nm23 gene alterations not being detectable by the monoclonal antibody used or to the presence of a subset of tumors in which nm23 gene abnormalities had not yet occurred at the time of tumor excision or biopsy. Overexpression of nm23-H1 protein in anal canal carcinoma may have implications for its metastatic potential. nm23-H1 expression would provide a more accurate evaluation of outcome for individual patients and thus improve treatment planning.     

PTEN及nm23-H1蛋白表达在非小细胞肺癌转移中的意义

背景与目的PTEN及nm23-H1基因均被证实是肿瘤转移的抑制基因,目前大多数研究都停留在基础研究上,本研究通过检测PTEN及nm23-H1蛋白在非小细胞肺癌(NSCLC)中的表达,以探讨它们的临床意义及相互关系。方法应用免疫组织化学法检测60例非小细胞肺癌组织中PTEN及nm23-H1基因蛋白的表达。结果NSCLC无淋巴结转移组PTEN蛋白阳性表达率为79.31%,高于NSCLC伴有淋巴结转移组41.94%,两者差异有统计学意义(P<0.01);无淋巴结转移组nm23-H1蛋白阳性表达率为82.76%,高于NSCLC伴有淋巴结转移组45.16%,两者差异有统计学意义(P<0.01)。PTEN和nm23-H1蛋白表达在NSCLC中一致性较好(Kappa=0.4366,Z=3.3905,P<0.01),两基因可能有协同作用。结论PTEN及nm23-H1蛋白表达均与NSCLC的淋巴结转移有关,PTEN和nm23-H1蛋白均可作为预测肿瘤转移的重要指标,对两种蛋白进行免疫组织化学联合检测,可能更有利于肺癌预测淋巴结转移及预后。     

肿瘤转移抑制基因nm23-H1对不同宫颈癌细胞侵袭和增殖的作用

背景与目的：nm23-H1是一种多效性基因,其抑癌作用有一定的组织特异性。本研究目的在于探讨nm23-HI对不同宫颈癌细胞增殖和侵袭的作用。方法：将真核表达载体pcDNA3．1-nm23-HI转染入宫颈癌细胞,Transwell小室法检测转染前后细胞侵袭性改变。M1Tr法绘制生长曲线,比较细胞增殖能力。流式细胞仪检测细胞周期改变。结果：与亲本细胞Caski、SiHa和空载体转染细胞Caski-3．1、SiHa-3．1相比．pcDNA3．1-nm23-H1转染细胞Caski—N和SiHa—N的侵袭力和增殖受到明显抑制（P〈0．05）,G2／M期和S期细胞比例降低（P〈0．05）,而G。／G．期细胞比例明显增加（P〈0．05）。nm23-H1对HeLa细胞增殖、侵袭及细胞周期均无明显影响（P〉0．05）。结论：nm23-H1对不同宫颈癌细胞的增殖和侵袭等细胞表型可产生细胞特异性的抑制作用。     

乳腺癌组织中p53、nm23-H1基因表达及其与绝经状态、淋巴结转移的相关性

[目的]研究乳腺癌患者中p53和nm23-H1基因表达,及其与绝经状态及腋窝淋巴结转移的关系.[方法]采用免疫组织化学SP方法检测60例乳腺癌组织中p53和nm23-H1的表达.[结果]60例乳腺癌患者中,p53和nm23-H1的阳性表达率分别为73.3%(44/60)和66.7%(40/60);在绝经前患者中p53和nm23-H1的阳性表达率分别为66.7%(16/24)和50.0%(12/24),而在绝经后患者中两者的阳性表达率分别为77.8%(28/36)和77.8%(28/36).在绝经后患者中p53和nm23-H1基因的阳性表达与腋窝淋巴转移呈显著性相关(P=0.019和P=0.019).[结论]p53可能参与绝经前妇女乳腺癌的发生,可能促进绝经后乳腺癌的转移;而nm23-H1可能参与绝经后乳腺癌的转移.     

Expression of nm23-H1 gene product in nasopharyngeal carcinoma and its clinical significance

Objective: The nm23 gene is one of the tumor metastatic suppressor genes. The expression of nm23-H1 has been reported to be inversely associated with metastatic potentiality in a number of human carcinomas, including breast, colorectal, gastric, hepatocellular and gallbladder carcinomas. In this study, the immunohisto-chemical staining of nm23-H1 protein in human naso-pharyngeal carcinoma (NPC) was examined, and the relationship between nm23-H1 and both metastasis and prognosis of patients with NPC was also investigated. Methods: Routine LSAB immunohistochemistry with the nm23-H1 monoclonal murine antibody was employed to study the expression of nm23-H1 protein in 95 paraffin-embedded specimens of NPC treated at our hospital. The clinical pathologic data and results of follow-up were also retrieved. Comparisons between patients with and without expression of nm23-H1 protein with respect to metastasis, loco-regional recurrence and survival were performed using Log rank test. Multivariate prognostic analyses were performed by using Cox’s regression model. Results: Nm23-H1 negative expressive tumors were associated with a higher incidence of lymph-node metastasis (86.7%) than those of nm23-H1 positive (48.6%,P<0.01). Nm23-Hl negative expressive tumors were associated with a high incidence of recurrence and distant metastasis after radiotherapy (P<0.05). A significant association was found between expression of nm23-H1 and prognosis (P<0.01). The expression of nm23-H1 indicated favorable prognosis. Conclusion: It was suggested that nm23-H1 negative expression was significantly associated with lymph-node metastasis, recurrence and distant metastasis. Nm23-H1 may have value for predicting the prognosis of NPC.     

膀胱癌中nm23-H1基因突变及表达的意义

目的：探讨ｎｍ２３－Ｈ１基因在膀胱癌中突变及表达的意义。方法：应用半定量逆转录聚合酶链反应（ＲＴ－ＰＣＲ）和银染单链构象多态性（ＳＳＣＰ）方法检测ｎｍ２３－Ｈ１基因在２５例膀胱癌组织及１５例对照组织中突变和表达情况。结果：对照粘膜中未检测出ｎｍ２３－Ｈ１基因突变,而在２５例膀胱癌组织中发现６例出现ＰＣＲ产物单链泳动状态异常,异常率为２４％。癌组织和对照组织均有ｎｍ２３－Ｈ１基因ｍＲＮＡ的表达,８８     

Overexpression of h-prune in breast cancer is correlated with advanced disease status.

PURPOSE: The h-prune gene is involved in cellular motility and metastasis formation in breast cancer through interacting with the nm23-H1 protein. The aim of this study was to better define the clinical and pathologic role of h-prune in breast cancer patients. EXPERIMENTAL DESIGN: Using immunohistochemistry, we assessed h-prune and nm23-H1 protein expression in two series of breast cancer patients: (i) in 2,109 cases with pathologic reports on primary tumors and (ii) in 412 cases with detailed clinical information. To assess the role of DNA amplification in gene activation, the h-prune copy number was evaluated by fluorescence in situ hybridization analysis in 1,016 breast cancer cases. RESULTS: In the patients tested (n = 2,463), 1,340 (54%) had an increased level of h-prune expression; a positive immunostaining for nm23-H1 was observed in 615 of 2,061 (30%) cases. Overexpression of h-prune was associated with multiple gene copy number at chromosome 1q21.3 in a very limited fraction of cases (68 of 1,016; 6.7%), strongly indicating that alternative pathways induce h-prune activation in breast cancer. Multivariate Cox regression analysis showed that neither h-prune overexpression nor decreased nm23-H1 immunostaining is independent prognostic factors. However, a significant association of h-prune overexpression with either advanced lymph node status (P = 0.017) or presence of distant metastases (P = 0.029) was observed. CONCLUSIONS: Although not significantly correlated with overall survival, positive h-prune immunostaining identifies subsets of breast cancer patients with higher tumor aggressiveness. Further investigations using larger collections of advanced breast cancer patients are required for assessing the predictive role of h-prune in breast cancer.     

大肠癌中nm23-H1的表达与淋巴结转移的关系

 目的　探讨大肠癌中nm23-H1的表达与淋巴转移的关系。方法　应用免疫组化方法研究96例大肠癌中nm23-H1蛋白的表达。结果　nm23-H1蛋白低表达与淋巴结或远处转移显著相关(P<0.05);nm23-H1蛋白低表达预测大肠癌转移的灵敏性为88.4%,特异性为79.3%。结论　检测nm23-H1蛋白可以预测大肠癌淋巴结或远处转移,从而可能成为临床治疗的判断依据。     

转移抑制基因nm23-H1在人肺癌中的表达

目的　探讨人肺癌中nm 2 3 H1基因的表达水平与肺癌发生、发展和转移的关系。方法　应用免疫组织化学法对 6 9例人肺癌组织中nm2 3 H1基因表达产物NDPK的表达水平及其与肺癌淋巴结转移的关系进行研究。结果　人肺癌组织中nm2 3 H1的表达水平与其性别、年龄、PTNM分期、组织类型无明显关系 ,而与肺癌细胞分化程度以及淋巴结转移有密切关系。肺癌组织中的nm2 3 H1表达低于癌旁正常肺组织 (P <0 .0 5 ) ,有淋巴结转移的肺癌原发灶中nm 2 3 H1的表达水平低于无淋巴结转移的肺癌原发灶 (P <0 .0 5 ) ,肺癌转移灶 (淋巴结 )中的nm2 3 H1的表达水平明显低于肺癌原发灶 (P <0 .0 1) ,分化差的肺癌中的nm 2 3 H1表达水平低于分化较好的肺癌 (P <0 .0 5P <0 .0 0 5 )。结论　nm 2 3 H1基因与肺癌淋巴结转移有关 ,并可能参与肺癌淋巴结转移过程中的调节并起转移抑制基因的作用 ,nm2 3 H1基因表达水平的降低预示肺癌的转移和预后不良。nm2 3 H1基因可能是监测肺癌患者病情发展及评估预后的有用指标。     

nm23-H1基因转染前后人高转移大细胞肺癌细胞株的比较蛋白质组学研究

背景与目的肿瘤转移抑制基因nm23-H1基因调控肺癌细胞转移潜能的确切机理尚未明了,本研究旨在探讨人高转移大细胞肺癌细胞株(L9981)和转染nm23-H1基因的人高转移大细胞肺癌细胞株(L9981-nm23-H1)的差异表达蛋白,为阐明肺癌转移的分子机制、发现早期诊断肺癌转移的分子标志和新的治疗靶点提供实验依据。方法应用固相pH梯度双向凝胶电泳分离L9981和L9981-nm23-H1细胞株的总蛋白,对25个差异明显的蛋白质点进行质谱鉴定和生物信息学分析。结果研究观察到nm23-H1基因转染使人L9981细胞株蛋白质组的表达谱发生了明显变化:5个蛋白质表达缺失,9个新的蛋白表达,16个蛋白质表达下调,12个蛋白质表达上调。这些蛋白质主要涉及细胞骨架蛋白、信号转导蛋白、细胞代谢相关蛋白、发育增殖相关蛋白及肿瘤侵袭相关蛋白。结论 nm23-H1基因转染L9981后,蛋白质表达谱发生了显著的变化,这些差异蛋白质可能是逆转肺癌侵袭转移的生化基础,本研究结果可能为阐明肺癌转移的分子机制提供线索。     

MTA1和nm23-H1蛋白表达与乳腺癌生物学行为之间的关系

目的探讨肿瘤转移相关基因（NTA1）和nm23-H1蛋白表达与乳腺癌生物学行为之间的关系。方法运用免疫组化S-P法检测56例乳腺癌组织中NTAl、nm23-H1蛋白的表达。结果56例乳腺癌组织中39例NTA1蛋白阳性表达,阳性率为69．6％,NTA1高表达与乳腺癌组织学分级、临床分期和淋巴结转移关系密切（P〈0．05）;3l例nm23-H1蛋白阳性表达,阳性率为55．4％,nm23-H1低表达与乳腺癌组织学分级、临床分期和淋巴结转移关系密切（P〈0．05）;乳腺癌组织中NTA1、nm23-H1蛋白表达呈负相关（P〈0．05）。结论NTA1和nm23-H1蛋白表达与乳腺癌分化程度、淋巴结转移和预后关系密切,可作为诊断乳腺癌患者转移复发的参考指标,并有望成为乳腺癌基因治疗的新靶点。