nm23-H1 expression and loss of heterozygosity in colon adenocarcinoma

BACKGROUND: The discovery that genetic alterations in oncogenes and tumour suppressor genes accompany tumour formation in many human tumours has encouraged the search for genes that promote or suppress tumour spread and metastasis; nm23 is a promising candidate for a metastasis suppressing gene.AIMS: To evaluate whether expression of nm23-H1 protein or loss of heterozygosity (LOH) of the nm23-H1 gene is associated with colon cancer progression. MATERIALS/METHODS: Paraffin wax embedded tissue sections were analysed immunohistochemically. DNA isolated from normal and tumour tissue was used for LOH analysis using a variable nucleotide tandem repeat (VNTR) marker located in the untranslated 5' region of the nm23-H1 gene. RNA isolated from tumour and normal tissue was used for "real time" RT-PCR. RESULTS: Of 102 adenocarcinomas examined, 58.8% stained weakly for nm23-H1 protein. There was a negative correlation between nm23-H1 positivity and tumour histological grade. In VNTR analysis, 70.2% of patients were informative and 27.4% of tumours had nm23-H1 LOH. There was a positive correlation between nm23-H1 LOH and both tumour histological grade and Dukes's stage. Expression of nm23-H1 mRNA was increased in 22 of 30 colon tumours compared with normal tissue. No significant correlation was found between nm23-H1 mRNA expression and histological grade or Dukes's stage of tumours. CONCLUSIONS: These findings suggest that nm23-H1 protein expression in early stages may have a role in suppressing metastasis in sporadic colon cancer, whereas at a later stage both reduced nm23-H1 protein expression and LOH of the nm23-H1 gene may play role in colon cancer progression and metastasis.     

Reduced nm 23-H1 messenger RNA expression in metastatic lymph nodes from patients with papillary carcinoma of the thyroid.

The nm 23 gene product, which possesses nucleoside diphosphate kinase activity, is a possible mediator of cancer cell invasion and metastasis. It has been divided into two distinct gene products, nm23-H1 and nm23-H2. We have developed a method for detecting nm 23-H1 and nm 23-H2 RNA using the polymerase chain reaction, based on the amplification of complementary DNA copies of nm 23-H1 and nm 23-H2 RNA. Using this method, the nm 23-H1 and nm 23-H2 messenger (m)RNA levels in 35 thyroid papillary carcinomas, 11 metastatic lymph nodes from patients with thyroid papillary carcinomas, five thyroid follicular adenomas, and three normal thyroid tissue samples were studied. Both nm 23-H1 and nm 23-H2 mRNA were expressed ubiquitously in normal and malignant thyroid tissues. However, in metastatic lymph nodes no (3 of 11) or weak expression (8 of 11) of nm 23-H1 mRNA was observed, the extent of which was inversely proportional to the degree of cancer cell occupancy, whereas nm 23-H2 mRNA was expressed and the levels were similar to those in other tissue tested. These results show that nm 23-H1 only may play a role in cancer cell invasion and metastasis although the exact mechanisms involved have yet to be elucidated.     

Comparison of p53 gene mutations in paired primary and metastatic gastric tumor tissues.

Our previous study revealed that mutations of the p53 gene were detected by cDNA sequencing in one of four (25%) primary gastric tumors and in five of six (83%) gastric cancer cell lines. It was of interest that all five cell lines established from metastatic lesions had p53 gene mutations, while the single cell line established from a primary tumor lacked an abnormality. Thus, the current study was initiated to determine the frequency of p53 mutations in 10 pairs of samples from primary gastric carcinomas and their lymph node metastases, in addition to morphologically normal gastric mucosa. In addition, we correlated the findings with other relevant molecular markers including the metastasis associated nm23-H1 gene and loss of heterozygosity (LOH) using multiple polymorphic markers for chromosome 17p and sequencing the entire open reading frame (ORF) of the p53 gene. Five of ten (50%) patients were constitutionally heterozygous for one or more 17p and/or p53 probes (pYNZ 22, BamHI RFLP; pMct35.1, Mspl RFLP; php53cl, Bg/II RFLP), while none had LOH at the 17p and/or p53. A Bg/II RFLP for analysis of possible nm23-H1 somatic allelic deletion revealed no LOH out of four informative cases. One paired sample demonstrated the substitution of valine for isoleucine at codon 41 (GTT to ATT) in both primary gastric tumor and metastasis. Another metastatic sample demonstrated the substitution of proline for threonine at codon 278 (CCT to C/ACT) in addition to a non-mutated codon, while only the wild-type p53 sequence was present in the paired primary gastric tumor tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

胃肠癌nm23H1基因遗传不稳定性及其与临床病理特性的关系

目的： 研究中国人17号染色体D17S396位点微卫星不稳定性（MSI）和杂合性缺失（LOH），对胃肠癌nm23H1蛋白表达的影响，阐明nm23H1基因遗传不稳定性与胃癌、结肠癌进展的关系，为临床治疗提供实验依据。方法: 采用石蜡包埋组织抽提DNA、PCR-单链构象多态性（SSCP）、常规银染、Envision免疫组织化学和Leica-Qwin计算机图像分析等方法，对40例石蜡包埋胃癌标本和30例石蜡包埋结肠癌标本及其相应的正常组织，进行D17S396位点MSI、LOH的检测和nm23H1蛋白表达研究。 结果: D17S396位点MSI检出率在胃癌、结肠癌的TNM Ⅰ+Ⅱ期高于Ⅲ+Ⅳ期，并且胃癌MSI发生率随着淋巴结转移的发生而降低。LOH检出率在胃癌、结肠癌的TNM Ⅲ+Ⅳ期高于Ⅰ+Ⅱ期，并随淋巴转移的发生而增高。nm23H1蛋白阳性率在胃癌、结肠癌的TNMⅠ+Ⅱ期显著高于Ⅲ+Ⅳ期，无淋巴结转移组显著高于淋巴结转移组。 结论: MSI和LOH通过相互独立的途径调控胃癌、结肠癌的进展。MSI是胃癌、结肠癌的早期分子标志,LOH多发生于胃癌、结肠癌的晚期阶段并赋予癌细胞高侵袭、预后差的表型。     

散发性胆囊癌nm23-H1基因遗传不稳定性与错配修复基因hMLH1和hMSH2蛋白表达的研究

目的： 研究人类17号染色体D17S396位点微卫星不稳定性和杂合性缺失，对nm23-H1蛋白表达的影响，同时检测错配修复基因hMLH1和hMSH2蛋白的表达，为揭示nm23-H1基因、hMLH1和hMSH2基因与肿瘤发生和转移机制提供实验依据。方法: 采用石蜡包埋组织抽提DNA、PCR-SSCP、常规银染、Envision免疫组织化学等方法，对50例胆囊癌及其相应的正常组织，进行D17S396位点MSI、LOH的检测和nm23-H1、hMLH1和hMSH2蛋白表达研究。结果: ①原发性胆囊癌D17S396位点遗传不稳定发生率为42.55%，LOH的发生率与肿瘤组织分化程度差异显著（P <0.05）；在肝脏侵润和淋巴转移组高于无肝脏侵润和无淋巴转移组(P <0.01)，在NevinⅣ+Ⅴ期高于Ⅰ+Ⅱ+Ⅲ期(P <0.01)；而MSI发生率则相反；②nm23-H1蛋白阳性率为46.81%，在淋巴转移组低于无淋巴转移组(P <0.01)；NevinⅣ+Ⅴ期低于Ⅰ+Ⅱ+Ⅲ期(P <0.05)；③hMLH1和hMSH2蛋白阳性率分别为51.06%和42.55%，hMLH1蛋白表达在有无淋巴转移组和Nevin分期有显著差异(P <0.01)，肝脏侵润组低于无肝脏侵润组(P <0.05)；④MSI阳性组中hMLH1蛋白阳性率显著高于MSI阴性组(P <0.05)。LOH阳性组中nm23-H1和hMSH2蛋白阳性率显著低于LOH阴性组（P <0.05）；⑤hMSH2蛋白阳性组中nm23-H1蛋白表达明显高于hMSH2蛋白阴性组（P<0.05）。结论:nm23-H1基因的遗传不稳定性可能是胆囊癌发生、发展的一个重要分子机制。nm23-H1基因的MSI和LOH，通过相互独立的途径调控胆囊癌的发生和转移。hMLH1/hMSH2表达异常可能是胆囊癌的早期分子事件。提高胆囊癌局部nm23-H1、hMLH1和hMSH2蛋白的表达，可减缓肿瘤的侵润转移并提高预后率。     

Reduced protein expression of metastasis-related genes (nm23, KISS1, KAI1 and p53) in lymph node and liver metastases of gastric cancer

PURPOSE: Metastasis remains an incurable common complication in patients with gastric cancer. A variety of theories have been proposed to explain the inefficiency of the metastatic process. To compare protein expression of metastasis-related genes (nm23, KISS1, KAI1 and p53) between primary tumours and metastatic tumours may be useful in illustrating these theories. METHODS: Metastasis-related tissue microarrays (including normal tissues, primary tumours, nodal metastases and liver metastases) were constructed. The protein expression of nm23, KISS1, KAI1 and p53 in lymph node and liver metastases from advanced gastric cancer specimens was mainly examined by immunohistochemical staining in relation to primary tumours. RESULTS: Immunohistochemical staining showed reduced protein expression of nm23, KISS1 and KAI1 in lymph node and liver metastases compared with primary tumours. Results for p53 were to the contrary. CONCLUSIONS: Our investigations revealed a tendency of reduced protein expression of metastasis suppressor genes nm23, KISS1 and KAI1 in gastric cancer with the progress of metastasis. This means that the progression theory is an important determinant of metastatic efficiency.     

Co-downregulation of PTEN, KAI-1, and nm23-H1 tumor/metastasis suppressor proteins in non-small cell lung cancer

The multistep process of carcinogenesis implies the accumulation of multiple molecular defects. Alteration of tumor suppressor and metastasis suppressor genes are the important steps. Increasing experimental evidence indicates that decreased expression of tumor-metastasis/suppressor genes and gene products are involved in the progression of a variety of human malignancies. In the present study, we have extended this analysis to non-small cell lung carcinomas (NSCLC). The expression and prognostic significance of the tumor suppressor gene PTEN and metastasis suppressor genes nm23-H1 and KAI-1 was evaluated in NSCLCs. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissues from 53 bronchogenic adenocarcinomas and 51 squamous cell carcinomas using monoclonal antibodies against PTEN, nm23H-1, and KAI-1 proteins. Immunohistochemical results were correlated with tumor stage, grade, lymph nodes positivity, metastasis, and patient survival. Significant co-expression of PTEN, nm23-H1 and KAI-1 was observed in NSCLC (P<.001 to .002). The immunohistochemical expression of these proteins was significantly higher in stages 1 and 2 compared with stages 3 and 4 (P=.04 for PTEN and KAI-1, P=.039 for nm23-H1). When all stages were considered together, loss of immunoreactivity for PTEN, nm23-H1 and KAI-1 was found in advanced NCSCLs (P=.015 for PTEN, P=.001 for KAI-1, P=.004 for nm23-H1), which is suggestive of co-downregulation of these proteins in the process of tumor progression. On multivariate analysis, negative staining for PTEN (P=.014), KAI-1 (P=.034), and nm23-H1 (a trend toward association for nm23-H1 reached near significance P=.08) correlated with disease-related death. Positive lymph node status was associated with negative immunostaining for PTEN (P=.007) but no correlation was observed for nm23-H1 and KAI-1. Loss of expression was linked to distant metastasis (P=.006 for PTEN, P=.002 for nm23H1, P=.001 for KAI-1). On multivariate analysis, co-downregulation of PTEN (P=.009), KAI-1 (P=.02), and nm23-H1 (P=.011) independently predicted shortened survival in NSCLC. Although NSCLC exhibits strong co-expression of PTEN, nm23-H1 and KAI-1, there is a loss of these proteins in high-stage tumors. Co-downregulation of PTEN, KAI-1, and nm23-H1 significantly correlates with distant metastasis and predicts shortened survival. Our study supports a role of these tumor suppressor and metastasis suppressor genes in the evolution and progression of NSCLC.     

Immunohistochemical analysis of the nm23 gene products in testicular seminoma

The nm23 gem, has been ldenwied as a metastasis suppressor gene. To clam the role of nm23 as a metastasis sup pressor gene In testicular seminoma, the expression of the nm23-Hl and -H2 proteins (human nucleoside-dlphosphate kinase-A and -B) was Immunohistochemically examined in 43 patients. Thirty-six (84%) and 21 (49%) of the 43 primary tumors were posithre for the nm23-H1 and -H2 proteins, respecthrely. There was no significant difference in either nmH1 or -H2 expression between the 24 primary non-invashre tumors and the 19 primary invasive tumors, or between the 31 primary tumors without metastasis and the 12 primary tumors with metastasls. In all, and 5 of 6 meta-static tumors, the expression of nm23H1 and -H2 proteins was obsenred, respectively, and the expression was not decreased in the metestetlc tumors, compared to the primary tumors. In conclusion, the lmmunohistochemlcal expression of both the nm23-Hl and -H2 gene products is not associated with the metastatic status or the invasive status of testicular seminoma, and it Is unlikely to be a useful non-metastatic Indicator for testicular seminoma. Further studies are needed to elucidate the biological role of nm23.     

Expression of urokinase-type plasminogen activator,its receptor,and its inhibitor in gastric adenocarcinoma tissues.

The plasminogen and plasmin system, which is mainly regulated by urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1), is generally believed to play a role in cancer invasion and metastasis. This study was conducted to investigate the role of uPA, uPAR and PAI-1 in the invasion and metastasis of gastric adenocarcinoma. The expression of mRNAs for uPA and PAI-1 was determined by Northern blot analysis in nine primary gastric cancer tissues, nine paired metastatic lymph nodes and normal gastric mucosa. The mRNA of uPA was not or faintly detected in normal mucosa, while the expression was increased in both primary gastric cancer tissues and metastatic lymph nodes to a similar degree. The mRNA expression for PAI-1 in the gastric cancer tissues was not different from that in the paired metastatic lymph nodes and normal mucosae. uPAR was determined by immunohistochemical staining, demonstrating that five (56%) and six (67%) out of nine primary gastric cancer tissues and nine paired metastatic lymph nodes were positive, respectively and the intensity was stronger in metastatic lymph nodes. The results support the concept that most gastric cancer cells may have an innately moderate level of uPA and uPAR, and that increase of uPAR expression can be considered to be closely associated with cancer invasion and metastasis.     

PCR－SSCP检测胃癌中nm23－H_1的基因突变

提取２０例胃癌及相应正常胃组织ＤＮＡ为样品，ＰＣＲ－ＳＳＣＰ方法快速筛查出４例胃癌组织中存在ｎｍ２３－Ｈ_１基因突变。此结果支持ｎｍ２３－Ｈ_１基因与肿瘤转移抑制密切相关。     

Expression of the nm23 homologues nm23-H4, nm23-H6, and nm23-H7 in human gastric and colon cancer

Eight members of the nm23-gene family have been described. The involvement of nm23-H1 and nm23-H2 in tumour progression and metastasis, as well as in gene regulation and apoptosis, has been shown in numerous studies. Whether nm23-H4, -H6, and -H7 play a role in tumours is, however, largely unknown. This study describes data on the expression of these three nm23 homologues in human colon and gastric cancer by real-time RT-PCR and immunohistochemistry. Increased expression of these genes, most strikingly nm23-H4 and -H7, was observed in the majority of tumours analysed. No correlation with tumour stage according to the TNM classification was found. In contrast, by immunohistochemical analysis, nm23-H4 and -H6 overexpression correlated with the intestinal tumour type in gastric cancer tissues, whereas no increased immunoreactivity for the three nm23 proteins was noted in the diffuse type tumour specimens. These findings indicate that nm23-H6, and particularly nm23-H4 and -H7, may be involved in the development of colon and gastric carcinoma, the latter possibly in a type-specific manner. A contribution to tumour progression or metastasis could not, however, be proven. Elucidation of the specific mechanisms by which the nm23 homologues nm23-H4, -H6, and -H7 are involved in tumour development requires further studies.     

NM-23 gene loss of heterozygosity and protein expression in high-stage laryngeal squamous cell carcinomas.

Tumor suppressor genes that reduce metastatic potential have been described in a variety of different tumor types. One of the main tumor metastasis suppressor genes is nm-23, which is a nucleoside diphosphate kinase. Two isotypes, nm-23H1 and nm-23H2, have been cloned and map to chromosome 17q21.3. In a variety of tumors, including colon cancer and breast cancer, loss of expression of nm-23 is associated with lymph node metastasis. In other organ systems, however, this relationship is not seen. In head and neck squamous cell carcinomas (HNSCC), there have been conflicting results regarding the association between nm-23 protein expression and metastatic potential. To further explore the tumor metastasis suppressor function of nm-23 in HNSCC, we studied high-stage laryngeal carcinomas, tumors with and without cervical lymph node metastasis for nm-23 protein expression and loss of heterozygosity of the gene locus. Twenty-five cases were included (11 cases with and 14 cases without metastasis). Loss of heterozygosity for the nm-23 gene locus was seen in 7 of 22 (32%) informative tumors. Using immunohistochemistry, most tumors expressed nm-23, though decreased expression was seen in 10 of 25 (40%) cases. Only 2 tumors showed negative expression. We did not find a correlation between either protein expression or loss of heterozygosity with metastatic disease or any other adverse prognostic factors in this group of high-stage laryngeal squamous cell carcinomas. These data imply that nm-23 may be tumor suppressor gene involved in HNSCC but that it may not function as a tumor metastasis suppressor in high-stage laryngeal carcinoma.     

nm23—H1过表达与乳腺癌和皮肤癌转移的相关性

目的：对比研究乳腺癌与皮肤癌转移抑制基因ｎｍ２３－Ｈ１表达的意义。方法：用单克隆抗体免疫组织化学Ｓ－Ｐ法检测８１例乳腺癌及１００便皮肤癌。ｎｍ２３－Ｈ１阳性细胞数超过３０％的癌细胞定为过度表达。结果：乳腺癌中导管原位癌、无转移及有转移浸润性导管癌的过表达率分别为８２％、７７％和３３％。皮肤癌中基底细胞癌、无转移及有转移鳞状细胞癌的过表达率分别为７９％、６１％和２７％,判别有显著意义Ｐ〈０．００５％     

Overexpression of tissue inhibitors of metalloproteinase-1 and -2 in the stroma of gastric cancer.

The fundamental event of cancer invasion and metastasis is the complicated interaction of cancer cells with host cells, in which event, a number of proteases and their inhibitors are involved. Matrix metalloproteinases are the potent proteases in degrading the basement membrane and extra cellular matrix and are inhibited by specific endogeneous inhibitors, tissue inhibitors of metalloproteinases-1(TIMP-1) and TIMP-2. The expression of mRNA for TIMP-1 and -2 was investigated by Northern blot analysis in specimens taken from 27 patients with primary gastric adenocarcinoma; 25 samples from the primary site, six from the metastatic lymph nodes and two from the peritoneal fluids. The expression for TIMP-1 and -2 was compared in primary gastric cancer tissues, metastatic lymph nodes and normal gastric mucosae. TIMP-1 mRNA was overexpressed in 24 (96%) out of 25 primary cancer tissues compared with the paired normal mucosae, while TIMP-2 was in 10 (40%). In six specimens of metastatic lymph nodes, TIMP-1 and -2 were overexpressed in 6 (100%) and 4 (67%) specimens, respectively. Of two specimens prepared from the peritoneal fluids, all specimens overexpressed TIMP-1 compared with the those of primary cancer tissues, while one (50%) specimen overexpressed TIMP-2. Immunohistochemical staining was done to investigate the localization of TIMP-1 and -2, demonstrating that the immunoreactivity for TIMP-1 and -2 was clearly detected in the cytoplasm of the stromal cells. These results suggest that both TIMP-1 and -2 are overexpressed by stromal cells in most of primary and some metastatic gastric cancer tissues and that TIMP-1 and TIMP-2, produced by stromal cells, may play an important role in inhibiting the proteolytic activity of matrix metalloproteinases originated from cancer cells, in gastric cancer.     

中国人肺鳞癌nm23H1基因遗传不稳定性的研究

目的 研究nm23H1基因5'端非转录区微卫星位点的微卫星不稳定(MSI)和杂合性缺失(LOH)对肺鳞癌(SLC)nm23H1蛋白表达的影响,以探讨nm23H1基因遗传不稳定性与肺鳞癌进展的关系,为肺鳞癌临床治疗和预后提供实验依据.方法 采用新鲜组织标本抽提DNA,应用荧光PCR-单链构象多态性(FPCR-SSCP)方法、免疫组织化学染色法,Leica-Qwin计算机图像分析等方法,进行nm23H1基因遗传不稳定性的研究.结果 在能提供信息(杂合子)的44例肺鳞癌患者中,MSI、LOH检出率和nm23H1蛋白阳性表达率分别为11.36%、25.00%和50.00%.在TNM Ⅰ、Ⅱ、Ⅲ期中,MSI的检出率分别为8.70%、10.00%和18.18%,而LOH分别为30.43%、20.00%和18.18%;MSI和LOH在淋巴结转移组的检出率为10.00%和20.00%,而无淋巴结转移组则为12.50%和29.17%.然而,以上各组在统计学上均无显著差异(P＞0.05).本研究中所有MSI(共5例)全部发生在分化良好(G1为2例和G2为3例)的存活患者(1年生存率)中,但MSI的检出率与肺鳞癌分化程度及患者生存状态并无统计学上的相关性(P＞0.05).nm23H1蛋白阳性表达率在TNM Ⅰ期(65.22%)、无淋巴结转移组(66.67%)显著高于TNM Ⅲ期(18.18%)、淋巴结转移组(30.00%)(P＜0.05).另外,统计学分析表明,MSI和LOH的检出率与nm23H1蛋白表达无关(P＞0.05).计算机图像定量分析显示,在各临床病理参数影响下,各组nm23H1蛋白的表达强度也没有差异(P＞0.05).结论 nm23H1蛋白可能对抑制肺鳞癌淋巴结转移有重要作用.nm23H1基因5'端非转录区微卫星的MSI和LOH对nm23H1蛋白的表达无影响,也未发现其与肺鳞癌发生、发展具有相关性.     

Squamous cell lung carcinomas: the role of nm23-H1 gene

 This analysis of 32 pairs of human squamous cell lung carcinomas and normal matched control DNA demonstrates that loss of heterozygosity (LOH) is infrequent at the nm23-H1 locus, affecting only 2 of the 18 informative cases. Both LOH cases were in the tumor stage IIIA. One tumor was of poor and the other of moderate histological grade. These and an additional 34 tumor samples were also analyzed immunohistochemically for the presence of nm23-H1 protein. Of the 66 cases tested for the presence of nm23-H1 protein 54 were negative. Eight samples exhibited up to 35% positive cells (with weak immunostaining intensity) and four between 35% and 70% (moderate immunostaining intensity); no sample showed more than 70% positive cells. Noncancerous lung parts contained no nm23-H1 protein. nm23-H1 expression was independent of TNM stage, grade, tumor size, and patient’s survival. Two samples with LOH were negative for nm23-H1 protein. We therefore conclude that neither loss of heterozygosity of the nm23-H1 gene nor the intensity of specific protein expression are related to squamous cell lung carcinoma development and progression. Received: 27 January 1997 / Accepted: 9 May 1997     

乳腺癌组织中uPA、uPAR及nm23-H1的表达

目的　观察乳腺癌组织中uPA、uPAR、nm2 3 H1的表达并探讨与腋窝淋巴结转移的关系。方法　用免疫组化EnVi sion两步法检测 6 9例乳腺癌组织中uPA、uPAR和nm2 3 H1表达的分布情况 ,观察其与肿瘤的分化程度以及与腋窝淋巴结转移的关系。结果　 (1)uPA阳性表达定位于癌细胞胞质 ;uPAR和nm2 3 H1阳性表达定位于癌细胞胞膜及胞质 ,多数癌旁乳腺上皮细胞呈nm2 3 H1阳性表达 ;高分化乳腺癌 (Ⅰ级 )uPA和uPAR表达阳性率 (30 0 %和 2 5 0 %)低于中低分化乳腺癌 (Ⅱ、Ⅲ级 ) (分别为 6 8 1%、72 7%和 70 0 %、74 1%) (P <0 0 5 ) ;nm2 3 H1表达阳性率在乳腺癌组织不同分化程度间差异无显著性 (P >0 0 5 ) ;(2 )腋窝淋巴结有转移者uPA和uPAR的表达阳性率 (73 2 %和 75 6 %)高于无淋巴结转移者 (35 7%和35 7%) (P <0 0 5 ) ;有腋窝淋巴结转移者nm2 3 H1的表达阳性率 (2 4 4 %)显著低于无淋巴结转移者 (5 0 0 %) (P <0 0 5 ) ;uPA、uPAR和nm2 3 H1的表达与淋巴结转移的个数均无关 ;(3)uPA阳性表达的癌组织其nm2 3 H1表达阳性率 (15 0 %)低于uPA阴性表达的癌组织 (6 2 1%) (P <0 0 5 )。结论　uPA和uPAR的高表达与乳腺癌腋窝淋巴结转移密切相关 ;uPA、uPAR和nm2 3 H1可以作为乳腺癌侵袭与淋巴结转移的     

甲状腺滤泡癌和乳头状癌细胞黏附分子与转移抑制基因nm23-H1蛋白表达的关系

目的 探讨黏附分子CD44、上皮性钙黏附蛋白（E-cad )和转移抑制基因nm23-H1与甲状腺滤泡源性癌分化、浸润转移的关系。方法 采用免疫组织化学SP法和EnVision法检测42例滤泡癌和54例乳头状癌中CD44、E-cad和nm23-h1的表达。结果 CD44主要表达于癌细胞及浸润淋巴细胞膜,低分化滤泡癌和有转移乳头状癌CD44表达分别高于高分化滤泡癌和无转移乳头状癌,E-cad阳性物质和nm23-H1阳性率高于滤泡癌,转移癌的阳性率和表达强度低于原发灶。甲状腺滤泡原性癌CD44检测阳性率高于E-cad和nm23-H1。在滤泡癌中E-cad与nm23-H1的表达之间呈正相关关系,而在乳头状癌中呈正相关趋势。CD44与E-cad的表达、CD44与nm23-H1的表达之间在滤泡癌和乳头状癌均呈负相关趋势。结论 综合检测CD44、E-cad和nm23对甲状腺滤泡源性癌的诊断、预后评估具有一定参考价值。     

APC gene loss of heterozygosity, mutations, E1317Q, and I1307K germ-line variants in sporadic colon cancer in Croatia

Colorectal carcinomas are characterized by multiple genetic aberrations that occur during tumorigenesis. Several tumor suppressor genes associated with colorectal carcinoma have been identified: MCC, APC, p53, nm23-H1, DCC, DPC4. We examined 73 cases of sporadic human colon cancer and corresponding normal tissue samples to evaluate the loss of heterozygosity (LOH) at the APC gene loci. The purpose of this study was also to evaluate whether the LOH at the APC gene is associated with clinicopathological characteristics in sporadic colon cancer. We also investigated presence and the frequency of the most common APC gene mutations and APC E1317Q and I1307K germ-line variants in Croatian colorectal cancer patients. Five markers in all patients were found to be heterozygous and informative for LOH analysis. LOH at the APC locus was detected in 30.1% of tumors were examined. The majority of APC gene LOH was observed in Dukes' B (55.6%) and in the moderately differentiated tumors (42.9%). Only 1309 APC gene mutation was detected in our samples. In one tumor sample, a new sporadic mutation of the APC gene in codon 1374 was detected. APC E1317Q and I1307K germ-line variants were not detected in our population. But APC E1317Q sporadic mutation was found in one tumor sample.     

Expression of p53 and NDP-K/nm23 in gastric carcinomas--association with metastasis and clinicopathologic parameters.

To evaluate the role of p53 and NDP-K/nm23(nm23) protein as a prognostic factor and their relation to metastasis of cancer, we studied metastatic and nonmetastatic gastric carcinoma specimens by immunohistochemical staining. Among the 101 specimens examined, 37(36.6%) showed positivity in staining for p53 protein and 64(63.4%) showed no detectable p53 protein in tumor cells. p53 overexpression was correlated with depth of invasion, lymphatic invasion, lymph node metastasis and distant metastasis. Out of 101 specimens, 35 cases had no staining for nm23. 62 cases(61.4%) exhibited a cytoplasmic staining on most cells and 42 cases (41.6%) had nuclear staining. In 16 of 101 cases(15.8%), a mild to moderate membranous staining was observed in some cells. Cytoplasmic nm23 expression was negatively correlated with lymph node metastasis(P < 0.01) and distant metastasis(P < 0.01). The nuclear nm23 expression showed negative correlation with depth of invasion(P < 0.01), lymphatic invasion(P < 0.01), lymph node metastasis(P < 0.01), and distant metastasis(P < 0.04). The membranous nm23 expression revealed negative correlation with lymphatic invasion(P < 0.02), lymph node metastasis(P < 0.01) and distant metastasis(P < 0.02).