nm23-H1 protein expression in anal canal carcinoma: does it correlate with prognosis?

BACKGROUND AND OBJECTIVES: Anatomic extent is not the sole axis of classification of tumors and of tumor patients relevant to treatment planning and estimation of prognosis. This results in the need to demonstrate an improvement in prognostic assessment and choice of therapy achieved by consideration of factors other than TNM. nm23 protein does prevent tumor from metastasizing and may also play a role in the control of growth and development. The purpose of this study was to elucidate the clinical significance of nm23 expression in human anal canal carcinoma and to evaluate its influence on the outcome of patients after surgery or radiochemotherapy. METHODS: Twenty-two patients affected by anal canal carcinoma were evaluated. Each section was incubated with monoclonal antibody nm23 NDPK-A. Immunostaining was considered positive when at least 10% of the tumor cells were immunostained. RESULTS: nm23 immunoreactivity was detected in 6/22 (27.3%) tumors. No significant association was found between nm23 expression and prognosis. CONCLUSIONS: The mechanisms causing enhanced nm23-H1 expression in anal canal carcinoma are unknown. Although the level and expression were not correlated with prognosis, activation of nm23-H1 gene might be a prerequisite for oncogenesis in this type of tumor, while an alternate possibility is the modification of cellular characteristics in relation to proliferation and/or differentiation as a consequence of oncogenesis.     

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.     

非黑素性皮肤癌中nm23-H1的表达和意义

目的　探讨nm2 3 H1在非黑素性皮肤癌的表达和意义。方法　用单克隆抗体免疫组织化学S P法检测在非黑素性皮肤癌 46例 ,nm2 3 H1阳性细胞数 >3 0 %的癌细胞为过度表达。结果　正常皮肤、基底细胞癌、无转移及有转移的鳞状细胞癌的阳性表达率分别为 10 0 %、81 8%、65 %及 2 1% ,其差别有显著意义 (P <0 0 5 )。结论　nm2 3 H1基因在非黑素性皮肤癌的浸润及淋巴结转移中起重要作用。     

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.     

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。     

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     

nm23-H1 expression in nasopharyngeal carcinoma: correlation with clinical outcome

The expression levels of nm23-H1 mRNA and its protein in human nasopharyngeal carcinoma (NPC) were detected to clarify the relationship between nm23-H1 and metastasis and prognosis of patients with NPC. nm23-H1 mRNA expression in fresh tissues from 78 patients with NPC was investigated by in situ hybridization and RT-PCR. Routine labeling streptavidin-biotin immuno-histochemistry with the nm23-H1 murine monoclonal antibody was employed to study the expression of nm23-H1 protein in paraffin-embedded specimens from 231 patients with NPC treated in our hospital. The clinical pathologic data and results of follow-up were collected. Comparisons between expression of nm23-H1 protein or mRNA and clinical outcome were performed using the χ² test. Multivariate prognostic analyses were performed by the Cox regression model. We found that nm23-H1-negative tumors were associated with a higher incidence of lymph-node metastasis (84.2%) than nm23-H1-positive ones (32.8%, p < 0.01). The distant metastasis and loco-regional recurrence rates in the nm23-H1-negative group were 55.8% and 31.68%, respectively but only 17.2% and 11.5%, respectively, in the nm23-H1-positive group (p < 0.01). A significant association was found between expression of nm23-H1 protein and prognosis (p < 0.01). Expression of nm23-H1 protein indicated favorable prognosis, suggesting that the absence of nm23-H1 protein expression was significantly associated with lymph-node metastasis, recurrence and distant metastasis in NPC. Expression of the nm23-H1 gene may be valuable for assessing the prognosis of NPC. Int. J. Cancer (Pred. Oncol.) 79:596–600, 1998. © 1998 Wiley-Liss, Inc.     

The role of nm23-H1 in the progression of transitional cell bladder cancer.

The nm23 gene was initially cloned as a metastasis suppressor gene, but the clinical relevance of nm23-H1 as a metastasis suppressor or prognostic indicator for human cancers remains enigmatic. Given that gene expression is regulated at the tissue-specific level, we studied the molecular mechanisms of nm23-H1 expression in human bladder cancer cell lines and the clinical importance of protein product (NM23-H1) in association with patient outcome (n = 257) by immunohistochemistry. We demonstrated that nm23-H1 is expressed in bladder cancer cells without genomic alterations. High NM23-H1 expression was found in 39 cases (15.2%), intermediate expression in 119 cases (46.3%), and low NM23-H1 in 99 cases (38.5%). NM23-H1 was inversely related to staging classification or tumor size (P < 0.05), with the most significant difference being observed between pTa tumors and those of pT1-pT3 bladder cancer (P = 0.01). Reduced NM23-H1, defined as intermediate and low levels of expression, tended to have a higher risk of tumor metastasis (P = 0.06) or poor longtime survival (P = 0.07). In the subset of grade 2 bladder tumors, reduced NM23-H1 significantly correlated with the occurrence of tumor metastasis or poor patient survival (P < 0.05). These findings overall suggest that nm23-H1 may play an important role in suppressing the early step of carcinogenesis and thus act as an invasion suppressor for human bladder cancer. A prospective study is required to clarify the potential of the molecular marker in prediction of disease progression.     

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.     

Immunohistochemical detection of nm23-H1/NDP kinase in childhood thyroid carcinoma

Childhood thyroid cancer is known to be aggressive. High incidence of lymph node and distant metastasis are characteristic features of these cases. In adult, reduced expression of nm23-H1/nucleoside diphosphate (NDP) kinase has been correlated with cancer invasion and metastasis in some tumor types. Therefore, we examined the expression of nm23-H1 gene product in childhood thyroid carcinomas in Japan. 27 primary thyroid carcinomas and 8 metastatic lymph nodes were analyzed by immunohistochemistry using monoclonal antibody H1-229. 21 out of 23 cases (91%) of papillary carcinomas were positively immunostained, whereas none of the 4 follicular carcinomas showed any immunoreactivity. No correlation was found between the nm23-H1/NDP kinase antigen expression and nodal involvement or distant metastasis in primary tumors. However, only 50% (4 out of 8) of metastatic lymph nodes from papillary carcinoma were positively stained, demonstrating a significant decrease comparing to those of primary sites. These data indicate that the expression of nm23-H1/NDP kinase cannot predict tumor metastatic potential in childhood thyroid cancer.     

nm23—H1基因在大肠癌中的表达与肝转移及预后的关系

目的：探讨ｎｍ２３－Ｈ１蛋白表达与大肠癌肝转移及预后的关系。方法：对１０１例大肠癌存档石蜡块进行重新切片，采用ｎｍ２３－Ｈ１单克隆抗体进行免疫组化染色（ＬＳＡＢ法）。结果：ｎｍ２３－Ｈ１蛋白表达与年龄、性别、肿瘤大小、部位、组织类型、浆膜侵犯无关；与Ｄｕｋｅｓ分期、淋巴结转移有关；手术时有肝转移组较无肝转移组低，手术后有肝转移复发组较无肝转移复发组低（Ｐ＜００１）。Ｃｏｘ模型分析显示ｎｍ２３－Ｈ１是大肠癌预后的一个保护性指标。结论：ｎｍ２３－Ｈ１基因对大肠癌肝转移和预后具有重要作用。ＬＳＡＢ法检测大肠癌组织中ｎｍ２３－Ｈ１蛋白表达可能是预测大肠癌肝转移及预后的生物学指标之     

nm23-H_1mRNA表达与肾母细胞瘤临床行为的关系

应用Northernblot分子杂交技术，检测30例肾母细胞瘤及其对应正常肾组织中nm23－H1mRNA表达。通过nm23－H1mRNA水平的比较及其与临床病理的分析，发现肾母细胞瘤nm23－H1mRNA呈低表达，随着病程的演进和转移的出现，肿瘤细胞中nm23－H1mRNA表达水平呈显著性降低，与肿瘤的病理类型无显著相关性（P＞0．05）。提示nm23－H1RNA低表达可能是肾母细胞瘤演进和转移的重要因素。     

nm23-H1基因在喉癌中杂合性丢失和微卫星序列不稳定性分析及表达的研究

目的　探讨nm2 3 H1基因在喉鳞状细胞癌中杂合性丢失 (LOH)及表达情况。方法　选择nm2 3 H1基因内部及附近 5个微卫星多态标记 ,对 72例喉癌标本进行杂合性丢失和微卫星序列不稳定性检测 ,同时以RT PCR方法分析 38例配对喉鳞状细胞癌标本中nm2 3 H1基因表达情况。结果　LOH涉及至少 1个位点的频率高达 76 .39% ,5个位点均有LOH ,以D17S16 6 5处频率最高 ,达 38.10 %。 3个位点出现MI ,最高为 12 .70 %。nm2 3 H1基因杂合性丢失及微卫星不稳定与淋巴结转移、临床分期和肿瘤分化无显著相关性 (P >0 .0 5 ) ,但D17S16 6 5位点高LOH频率与低分化相关 (P <0 .0 5 )。癌、癌旁及转移淋巴结中nm2 3 H1表达不同 ,但差异无统计学意义 ,表达水平与淋巴结转移无关 (P >0 .0 5 )。结论　nm2 3 H1基因可能在喉鳞癌发生中起作用 ,杂合性丢失可能是影响基因功能的主要机制。     

食管鳞状细胞癌中nm23-H1和p53蛋白表达及其相互关系

目的:探讨食管鳞癌组织中p53和nm23-H1蛋白的表达与癌组织分化浸润转移的关系,以及探讨两者之间的相关性,并进一步分析癌组织中p53和nm23-H1蛋白表达对食管癌患者的预后意义。方法:采用免疫组织化学(S-P法)方法对100例人食管鳞癌组织中的p53和nm23-H1蛋白的表达情况进行检测。结果:100例食管鳞癌组织中,nm23-H1阳性表达者70例(阳性率为70%),p53阳性表达者64例(阳性率为64%)。nm23-H1蛋白表达与食管癌淋巴结转移有关(P<0.025),与食管鳞状细胞癌的分化程度、肿瘤部位、浸润深度、病变长度以及患者性别、年龄无关(P>0.05)。p53蛋白表达与食管鳞状细胞癌的分化程度、浸润深度有关(P<0.05),与食管癌淋巴结转移、肿瘤部位、病变长度、患者性别、年龄无关(P>0.05)。高分化鳞癌组织中p53明显低表达(29.2%);低分化鳞状细胞癌组织中p53表达明显增高(71.4%)。食管外膜受累者p53表达较高(56%);仅发生食管粘膜和(或)粘膜下浸润组的癌组织中未发现有p53蛋白的表达。食管癌组织中nm23-H1蛋白低(高)表达与p53高(低)表达之间有明显相关性(P<0.01)。nm23-H1和p53蛋白表达亦与食管癌的TNM分期密切相关(P<0.05)。食管癌TNM分期越晚,其癌组织中nm23-H1蛋白表达越低,p53蛋白表达越高。结论:nm23-H1基因低表达与p53基因高表达可能在食管鳞状细胞癌浸润转移过程中发挥重要作用。nm23-H1可以作为食管鳞状细胞癌患者预后的基因标记,其蛋白表达产物的检测可以用于患者预后的判断,并为患者治疗方案的制定提供参考。     

p53和nm23-H1蛋白表达与食管癌浸润转移的关系

Objective To study the relationship between expression of p53 and nm23-H1 and differentiation, invasiveness and metastasis in human esophageal carcinoma, and the correlation between expression of p53 and nm23-H1. Methods Expression of p53 and nm23-H1 in 50 patients with squamous cell carcinoma of esophagus was detected by using immuno-histochemical S-P methods. Results 35 cases (70%) and 32 cases (64%) of esophageal squamous cell carcinoma were positive for nm23-H1 protein and p53 protein, respectively. The expression of nm23-H1 was related to lymphatic metastasis (P<0.025), but not related to tumor differentiation, invasiveness, tumor location, tumor length, patient's gender and age (P>0.05). The lymphatic metastasis location positive group had a very lower expression of nm23-H1 and the negative rate was 70.8%, but the negative group had a higher expression and the positive rate was 65.4%. The expression of p53 was related to tumor differentiation and invasiveness (P<0.05), but not related to lymphatic metastasis, tumor location, tumor length, patient's gender and age(P>0.05). Among the three groups, the high differentiation group had the lowest expression of p53 and the positive rate was 29.2%, but the low differentiation group had the highest positive rate (71.4%). As for tumor invasiveness, the group of outer membrane of esophagus infiltrated had the highest p53 protein positive rate (56%), but in the group, of mucous or submucous layer infiltrated p53 protien was not detectable. The low expression of nm23-H1 and the high expression of p53 were also correlated. The expression of nm23-H1 and p53 were both correlated with TNM stage of esophageal carcinoma (P<0.05). The better esophageal carcinomas differentiated, the lower nm23-H1 expressed and higher p53 expressed. Conclusion Low expression of nm23-H1 and high expression of p53 play an important role in the progression of squamous cell carcinoma of esophagus. Nm23-H1 might beta gene markef in the prophecy of patients' prognosis and benefit tumor treatment clinically.     

Breast-cancer in the elderly - detection and treatment modalities in 341 women

We examined nm23-H1 protein levels in human oligodendrogliomas by immunohistochemistry. This class of brain tumor does not form spontaneous metastases, but its progression from benign (oligodendroglioma) toward malignant phenotype (oligodendroglioma transitionale and glioblastoma oligodendrogliale) can be followed. Two types of tumors, ODG-II and ODG-T, were highly positive for nm23 protein. However, there was no clear correlation between the extent of protein expression and tumor aggressiveness. No nm23 protein was detected in nonproliferative normal brain tissues and was found in only a few ODG-I specimens. As cell proliferation becomes more pronounced (OGD-II, ODG-T), nm23 protein becomes detectable in almost all samples. However, of the glioblastoma oligodendrogliale samples examined, 76% were negative for nm23-H1 protein. suggesting a change in nm23-H1 gene expression with increasing neoplastic progression. Our findings are in contrast to a proposed role of nm23-H1 protein as a tumor metastasis suppressor and support that it cannot serve as a reliable prognostic tumor indicator in all cases. However, our findings may contribute to a better understanding of glial tumor development and improve the accuracy of tumor diagnosis.     

p53和nm23-H1在鼻咽癌组织中的表达及其意义

目的 探讨p53和nm23-H1蛋白在鼻咽癌中的表达及其与临床的相关性.方法 应用免疫组织化学方法对鼻咽癌40例、慢性鼻咽炎22例组织中p53和nm23-H1蛋白的表达进行检测,同时与临床相关资料进行对比研究.结果 慢性鼻咽炎组p53及nm23-H1蛋白的阳性率分别为1.0％、27.2％,而鼻咽癌组为92.5％、55.0％.在nm23-H1蛋白表达阳性的22例鼻咽癌组织中p53阳性表达9例（40.9％）,在nm23-H1表达阴性的18例中p53蛋白阳性表达17例（94.4％）.鼻咽癌组织中p53和nm23-H1蛋白的表达明显高于慢性鼻咽炎组织.p53蛋白表达与鼻咽癌淋巴结转移、临床分期和病理学分级呈正相关,与肿瘤T分级无关;nm23-H1蛋白表达与鼻咽癌淋巴结转移及临床分期呈负相关,与肿瘤T分级无关.结论 抑癌基因p53和nm23-H1在鼻咽癌的发生、发展及转移过程中起着协同、调控作用,可成为临床诊断和评价预后的重要生物学标志.     

Nm23 expression in human gastric cancers - possible correlation of nm23 with lymph-node metastasis

In order to elucidate the relationship between nm23 and metastasis in human gastric cancers, we analyzed gene and protein expression of nm23-H1 using Northern blot and immunohistochemical techniques. nm23-H1 gene expression was identified in 17 out of 19 gastric cancer tissues. The signals in the tumor tissues presenting regional lymph node metastasis seem to be lower than those in the tumor tissues without regional lymph node metastasis, suggesting a role of nm23-H1 in the regional lymph node metastasis in the gastric cancers. However, the protein expression detected immunohistochemically was not correlated to the gene expression, partly because of difficulty in quantifying the amount of protein. Expression of the nm23-H1 gene as well as the nm23-H1 protein in the tumor tissues was higher than those in the corresponding normal mucosae. This suggests a linkage of nm23-H1 in the process of the gastric cancer progression. We also analyzed the sequence abnormalities of the nm23-H1 gene in the gastric cancer tissues using a direct sequencing technique, no mutations were observed.     

卵巢癌高频转移细胞模型中nm23-H1基因表达的相关性研究

目的 筛选高频转移卵巢恶性肿瘤细胞，研究不同转移潜能的细胞和nm23的相关性。方法 通过反复动物接种和体外培养，观察动物肺转移状况，筛选高频转移细胞株，比较原发肿瘤和转移肿瘤的特征，并应用Northera-blot方法测定各类肿瘤细胞nm23 mRNA表达水平。结果 8株卵巢恶性肿瘤细胞中4株有较高转移潜能。多次培养接种可筛选出高频转移细胞亚群。测定各类细胞nm23 mRNA表达水平与肿瘤转移特性呈负相关。结论 由基因分子水平决定的肿瘤转移趋势在不同肿瘤种类及细胞亚群中有明显差异；卵巢癌中nm23 mRNA和蛋白的表达与其转移能力的降低有密切关系，可作为判定卵巢癌预后的敏感指标。