基质金属蛋白酶26蛋白在非小细胞肺癌组织中的表达及其意义

背景与目的：基质金属蛋白酶26（matrix metalloproteinase-26,MMP-26）与多种恶性肿瘤的发生、发展及转移相关。本实验通过检测MMP-26蛋白在浸润性非小细胞肺癌（non-small cell lung cancer,NSCLC）、浸润前肺癌和正常肺组织中的表达．探讨MMP-26在NSCLC发生发展中的作用及与预后的关系。方法：采用免疫组织化学（SP）法,分别检测72例NSCLC、14例非典型增生和10例正常肺组织中MMP-26蛋白的表达。结果：MMP-26蛋白高表达率在正常肺组织中为0（0／10）,在非典型增生巾为14．3％（2／14）,在NSCLC中为59．7％（43／72）。MMP-26蛋白在NSCLC中的表达高于在非典型增生及正常肺组织中（P〈0．01）,在非典型增生中高于正常肺组织中,但二者差异无统计学意义（P〉0．05）。MMP-26蛋白表达与NSCLC分期（P〈0．05）和淋巴结转移有关（P〈0．05）,而与患者年龄、性别以及肿瘤大小、分化无关（P〉0．05）。Cox比例风险模型进行多因素生存分析显示：MMP-26表达和临床分期是有意义的NSCLC预后指标（P〈0．05）。MMP-26蛋白高表达的NSCLC患者无复发生存期和总生存期低于阴性表达的患者（分别为log-rank=19．34、23．2,P〈0．001、0．001）。结论：MMP-26蛋白高表达与NSCLC发生、淋巴结转移、临床分期及预后相关,有可能作为判断NSCLC进展和预测预后的一项指标。     

Elevated activities of MMP-2 in the non-tumorous lung tissues of curatively resected stage I NSCLC patients are associated with tumor recurrence and a poor survival

BACKGROUND AND OBJECTIVES: We wanted to assess whether the level of enzyme activity for a particular matrix metalloproteinase (MMP), and not the amount of expressed protein, in lung tissue could be used as a reliable prognostic biomarker for tumor recurrence leading to poorer survival in a certain subgroup of patients who have undergone curative resection for stage I human NSCLC. METHODS: We determined what type of MMP was significant for tumor recurrence by using a mouse model of pulmonary metastasis with inoculating the footpad with H460 human cancer cells. We then looked for any association between tumor recurrence and the level of enzyme activities for the selected MMP in the tumor and also in the pathologically non-tumorous tissues from 34 stage I lung cancer patients. RESULTS: We obtained H460/PM6 cells having a highly metastatic potential after six repeated cycles of pulmonary metastasis by using the mouse footpad inoculated with the metastasized cancer cells in the previous cycle. We started with human lung cancer cells, H460, and we found that among the tested MMPs we tested for, the level of MMP-2 mRNA was elevated. No significant difference was seen in the level of enzyme activity of the MMP-2 cells from the curatively resected tumor tissues of the stage I NSCLC patients who were later found with or without recurrence. However, the level of MMP-2 enzyme activity was found to be significantly different between the non-tumorous lung tissues from patients later found with and without recurrence, and it was associated with the 5-year survival rate. CONCLUSIONS: This observation suggests that the higher level of MMP-2 enzyme activity in the non-tumorous tissues from the patients could be used as a prognostic biomarker to predict post-operative tumor recurrence and survival for patients with stage I NSCLC. The elevated enzyme activity of MMP-2 in the non-tumorous tissue resected from stage I NSCLC could be used as a prognostic indicator for post-operative tumor recurrence and the patients' poor survival. Further, this could be an important aid for physicians' making decision on whether to subject particular patients to post-operative adjunct chemotherapy.     

非小细胞肺癌组织中AKT2、Cyclin D1、MMP-9表达及其与临床病理因素的关系

背景与目的：AKT2是一种丝氨酸／苏氨酸激酶,已被确定为癌基因,在多种肿瘤组织中都存存AKT2的异常表达和活化,AKT2与肿瘤的增殖和侵袭转移密切相关。本研究旨在探讨AKT2、Cyclin D1、MMP-9存非小细胞肺癌（nonsmall cell lung cancer,NSCLC）中的表达及与临床病理因素的关系。方法：应用免疫组化的方法检测68例NSCLC组织、38例相应的癌旁组织和14例非肿瘤性肺组织标本中AKT2蛋白、Cyclin D1、MMP-9的表达,采用X^2检验分析临床病理因素与上述指标的相关性。结果：AKT2、Cyclin D1、MMP-9在NSCLC组织中阳性率分别为91．2％、76．5％、72．1％,显著高于癌旁及非肿瘤性肺组织中阳性率（3．8％、0％、13．5％）（P〈0．05）。AKT2的表达与患者年龄、性别、肿瘤类型及分化程度、TNM分期无关（P〉0．05）,与淋巴结转移有关（P〈0．05）。Cyclin D1、MMP-9表达与淋巴结转移、鳞癌的分化程度有关（P〈0．05）,MMP-9还与TNM分期有关（P〈0．05）。AKT2的表达与Cyclin D1、MMP-9呈正相关。结论：AKT2、Cyclin D1、MMP-9均与肺癌的发展有关,Cyclin D1、MMP-9的高表达可能与AKT2的调节有关。     

Membrane type matrix metalloproteinases (MMPs) show differential expression in non-small cell lung cancer (NSCLC) compared to normal lung: correlation of MMP-14 mRNA expression and proteolytic activity

Improved understanding of the involvement of matrix metalloproteinases (MMPs), including membrane-type MMPs (MT-MMPs), in human tumours has potential diagnostic, prognostic and therapeutic implications. We assessed the relationship between MT-MMP expression and clinicopathological parameters in human non-small cell lung cancer (NSCLC) and histologically normal lung tissue by quantitative Real Time PCR (qRT-PCR). All MT-MMPs (MMPs 14-17, 24 and 25) were detected by qRT-PCR with significantly higher MMP-14, -15 and -17 expression observed in tumour relative to normal lung specimens. MMP-16 was undetectable in normal lung but expressed in 8% tumours. MMP-15 demonstrated significant overexpression in adenocarcinomas relative to squamous cell carcinomas and normal lung tissue. MMP-14 mRNA expression strongly correlated to MMP-14 proteolytic activity in preclinical tumour models, indicating that qRT-PCR may predict MMP-14 activity levels in NSCLC. These data suggest that MMP-14, -15 and -17 may be good markers of disease, or therapeutic targets for treatment of human NSCLC.     

MMP-2和MMP-3在非小细胞肺癌组织中的表达及意义

目的探讨基质金属蛋白酶(matrixmetalloproteinases,MMPs)MMP-2和MMP-3在肺癌组织中的表达及与患者临床病理特征的关系。方法用免疫组化S-P染色技术对45例非小细胞肺癌标本及20例癌旁正常肺组织标本中MMP-2和MMP-3的表达水平进行检测,并结合患者的临床病理资料对其结果进行对比分析。结果MMP-2和MMP-3在肺癌组织中的阳性表达率明显高于癌旁正常肺组织(P<0.05),MMP-2的表达与肺癌临床分期、组织分化程度、淋巴结转移有密切关系(P<0.05〉,而MMP-3的表达与上述临床病理特征无明显关系(P>0.05)。结论MMP-2、MMP-3均是良好的肺瘤标记物,MMP-2与肺癌侵袭转移关系密切,MMP-3可能在肺癌侵袭转移中作用不显著。     

Expression of MMP-13 and its correlation with prognosis in non-small cell-lung cancer

Objective： To investigate the expression of MMP-13 in non-small cell lung cancer （NSCLC）, so as to analyze its correlation with prognosis of NSCLC. Methods： MMP-13 expression was detected in 99 NSCLC tissues and 32 normal lung tissues by immunohistochemical method. Results： （1） Expression of MMP-13 （51.5%, 51/99） in cancer tissues was significantly higher than that in normal tissues 0% （P 〈 0.05）. Expression level of MMP-13 was significantly related to lymph node metastasis and clinical stage （P 〈 0.01）. （2） Kaplan-Meier analysis showed that expression level of MMP-13 was closely cor- relate with the prognosis of NSCLC. Multivariate Cox model analysis suggested that the survival time was significantly related to clinical stage and the expression of MMP-13. Conclusion： MMP-13 is an independent factor that affect prognosis.     

非小细胞肺癌组织中白细胞介素17、基质金属蛋白酶9表达与pTNM分期的关系

目的 探讨白细胞介素17 (IL-17)、基质金属蛋白酶9(MMP-9)在非小细胞肺癌(NSCLC)组织中的表达及其与pTNM分期的关系.方法 应用免疫组织化学法检测102例NSCLC组织和癌旁组织中IL-17、MMP-9的表达,并对其与pTNM分期的关系进行统计学分析.结果 IL-17、MMP-9 在NSCLC组织中阳性表达率分别为73.53％(75/102)和60.78％(62/102),癌旁组织中分别为71.57％(73/102)、7.84％(8/ 102);二者在不同pTNM分期癌组织中表达差异均有统计学意义(P＜0.05),癌组织中IL-17与MMP-9的表达有相关性(P＜0.05),在癌旁组织中二者表达无相关性(P＞0.05).结论 IL-17和MMP-9在NSCLC中表达上调,两者在癌组织中的表达呈正相关,可能共同参与了NSCLC的浸润和转移.     

Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the processes of extracellular matrix degradation. Changes in their expression levels have been observed in various tumor types, including lung carcinoma. However, their clinical significance and their prognostic importance in the progression of nonsmall cell lung carcinoma (NSCLC) remain to be specified. In this study, mRNA expression levels of MMP-1, MMP-9, TIMP-1, and TIMP-2 were evaluated in patients with resected NSCLC, and their associations with disease progression and prognosis were determined. METHODS: Between June 1996 and December 1999, 116 patients underwent resection for NSCLC. Expression levels of MMPs and TIMPs were evaluated using Northern blot analysis in these NSCLC tissue samples and in 39 matched samples of normal lung tissue. RESULTS: MMP-1, MMP-9, and TIMP-1 expression levels were increased in tumor samples compared with matched, corresponding normal tissues. In contrast, TIMP-2 expression was decreased in tumor samples. MMP-1 tumor expression was correlated significantly with the evolution of lymph node status and tumor-lymph node-metastasis (TNM) stage. In contrast, MMP-9 tumor expression was correlated significantly with increased T stage. TIMP-1 overexpression was an independent predictor of worse survival in patients with NSCLC that was not associated with other prognosis factors, such as TNM stage. CONCLUSIONS: The overexpression of TIMP-1 was an independent prognostic marker in patients with NSCLC, and evaluating TIMP-1 may be important for identifying patients who are at greater risk of disease recurrence.     

长链非编码RNA BC200在非小细胞肺癌患者组织中的表达及作用

  目的  分析长链非编码RNA（long non-coding RNA，lncRNA）BC200在非小细胞肺癌（non-small cell lung cancer，NSCLC）组织中的表达情况，并探讨其临床意义及其与上皮-间质转化（epithelial-mesenchymal transition，EMT）相关蛋白E-cadherin、N-cadherin及Snail之间的关系。  方法  采用实时荧光定量PCR（QPCR）法检测2014年1月至2018年6月天津市胸科医院60例癌组织及60例对应的正常肺组织中BC200表达情况，40例癌组织及40例正常肺组织中E-cadherin、N-cadherin及Snail mRNA表达水平，统计分析NSCLC中BC200与E-cadherin、N-cadherin及Snail mRNA表达水平以及两者的相关性，分析BC200与临床病理特征（性别、年龄、TNM分期、肿瘤大小、淋巴结转移及病理类型水平）的关系，应用受试者工作特征（receiver operating characteristic curve，ROC）曲线鉴别诊断NSCLC的效能；采用免疫组织化学法检测E-cadherin、N-cadherin及Snail蛋白在40例NSCLC组织及20例正常肺组织中表达情况，分析其与BC200表达情况的关系。  结果  1）肺癌组织中的BC200、N-cadherin及Snail mRNA的表达水平显著高于正常肺组织中的表达水平（P < 0.05），E-cadherin mRNA的表达量低于正常肺组织（P < 0.05）；2）E-cadherin、N-cadherin及Snail在NSCLC组织中阳性表达率分别为40.0%（16/40）、57.5%（23/40）、57.5%（23/40），在正常肺组织中的阳性表达率为95%（19/20）、5%（1/20）、10%（2/20），表达差异具有统计学意义（P < 0.05）；3）肺癌组织中BC200的高表达与淋巴结转移、临床分期、E-cadherin、N-cadherin及Snail阳性率相关（P < 0.05），BC200的表达与E-cadherin mRNA的表达呈负相关（r=-0.31，P < 0.05），与Snail、N-cadherin mRNA的表达呈正相关（r=0.305、r=0.257，P < 0.05）；4）ROC曲线分析表明，组织lncRNA表达水平对NSCLC的诊断敏感度和特异度均较满意。  结论  BC200在NSCLC组织中高表达，且与淋巴结转移、临床分期、E-cadherin、N-cadherin及Snail阳性率相关，BC200的表达与E-cadherin mRNA的表达呈负相关，与Snail、N-cadherin mRNA的表达呈正相关，提示BC200可能通过上皮间质转化调节肺癌细胞侵袭和迁移能力。在NSCLC诊断上，lncRNA BC200水平有较高的价值，可考虑作为NSCLC诊断的潜在标记物。      

端粒酶活性在非小细胞肺癌中的表达及其临床意义

探讨端粒酶活性在非小细胞肺癌中的表达及其作用为ＮＳＣＬＣ肿瘤标记物和治疗靶点的可能性。方法：采用端粒重复扩增法研究了７４例ＮＳＣＬＣ组织及周围百癌组织、１０例肺良性病变组织端粒酶活性表达。结果７４例ＮＳＣＬＣ组织６９例（９３．２４％）有端粒酶活性表达,７４例周围非癌组织有９例。     

MMP-2和E-cadherin在肺癌中的表达及临床意义

目的：观察肺癌发生过程中基质金属蛋白酶-2（MMP-2）和上皮性钙黏附素（E-cadherin）的表达,探讨二者临床应用价值。方法收集肺癌患者肺组织石蜡标本78例、良性病变肺组织石蜡标本28例及正常肺组织石蜡标本10例,采用流式细胞免疫法定量检测肺组织MMP-2和E-cadherin的表达。比较三组差异并分析MMP-2与E-cadherin的相关性。结果肺癌组织中的MMP-2的表达显著高于良性病变组织和正常肺组织,良性病变组织中的MMP-2的表达高于正常肺组织,Ⅲ、Ⅳ期肺癌组织中MMP-2的表达高于Ⅰ、Ⅱ期,低分化肺癌组织中MMP-2的表达高于高中分化,差异均有统计学意义（P＜0.05）。肺癌组中E-cadherin的表达显著低于良性病变组和正常组,Ⅲ、Ⅳ期肺癌组织中E-cadherin的表达低于Ⅰ、Ⅱ期,低分化肺癌组织中E-cadherin的表达低于高中分化,差异均有统计学意义（P＜0.05）。肺癌组织中MMP-2和E-cadherin表达呈负相关（r=-0.763,P＜0.01）。结论MMP-2高表达和E-cadherin低表达可能与肺癌的发生、发展、分化及转移过程有关,联合检测可以作为肺癌治疗、预后的判断指标。     

非小细胞肺癌中基质金属蛋白酶-13表达及与预后的关系研究

Objective: To investigate the expression of MMP-13 in non-small cell lung cancer (NSCLC), so as to analyze its correlation with prognosis of NSCLC. Methods: MMP-13 expression was detected in 99 NSCLC tissues and 32 normal lung tissues by immunohistochemical method. Results: (1) Expression of MMP-13 (51.5%, 51/99) in cancer tissues was significantly higher than that in normal tissues 0% (P ＜ 0.05). Expression level of MMP-13 was significantly related to lymph node metastasis and clinical stage (P＜0.01). (2) Kaplan-Meier analysis showed that expression level of MMP-13 was closely correlate with the prognosis of NSCLC. Multivariate Cox model analysis suggested that the survival time was significantly related to clinical stage and the expression of MMP-13. Conclusion: MMP-13 is an independent factor that affect prognosis.     

EphA2、E-钙黏蛋白在非小细胞肺癌中的表达及意义

目的:探讨非小细胞肺癌（NSCLC）中EphA2、E-钙黏蛋白（E-cadherin）的表达及意义。方法:采用免疫组织化学SP法,检测60例NSCLC及10例正常肺组织（对照组）中EphA2、E-cadherin的表达。结果:EphA2在NSCLC中的阳性表达率为80.00%,明显高于癌旁正常肺组织20.00％（P=0.001）。E-cadherin在NSCLC中的阳性表达率为58.33%,明显低于癌旁正常肺组织100.00％（P=0.000）。EphA2、E-cadherin蛋白在NSCLC中的表达差异与患者性别、年龄、病变部位无关(均P>0.05),但与NSCLC的分化程度、临床分期、有无淋巴结转移相关（P<0.05）。结论:EphA2可促进肿瘤细胞的转化、增殖、迁移,E-cadherin可促进肿瘤细胞的迁移,两者在NSCLC中的共同作用导致了NSCLC的恶性进展,可作为临床评估肺癌恶性程度的指标。     

Prognostic significance of telomerase activity and some tumor markers in non-small cell lung cancer

The prognosis of non small cell lung cancer (NSCLC) has remained disappointing over the last decades even in localized stages. Numerous prognostic factors have been investigated which might select patients for additional treatment. The objective of the current study was to assess the prognostic significance of telomerase activity, serum anti-p53 antibodies (anti-p53a), c-erbB-2 and CEA in patients with NSCLC. The study included 60 patients with histological proven NSCLC besides 60 controls (30 smokers and 30 nonsmokers). Patients were divided into four stages according to their histopathology. All patients were subjected to; determination of telomerase activity by telomeric repeat amplification protocol (TRAP) assay in tumor tissue specimens and adjacent normal lung tissues, also, determination of preoperative serum anti-p53a, c-erbB-2 and CEA. Telomerase activity was detected in 40 of 60 (66.6%) of NSCLC tissue specimens using the TRAP assay. As regard the stages, telomerase activity was positive in 5 of 15 patients (33.3%) with stage I NSCLC, in 11 of 20 patients (55%) with stage II NSCLC, in 9 of 10 patients (90%) with stage III NSCLC and in all patients (100%) with stage IV NSCLC. More cases of positive telomerase activity were observed in the group with advanced disease and in the group with poorly differentiated tumors. Telomerase activity was not detected in any normal lung tissue. The concentrations of serum anti-p53a, c-erbB-2, CEA were significantly higher in patients with NSCLC in comparison to the smoker and nonsmoker controls and their levels increased according to the stage of disease. Logistic regression test showed a relation between telomerase positivity and anti- p53a but no relation with c-erbB2, CEA. Telomerase activity was detected in most of NSCLC tissues; it was detected more frequently in advanced disease than early-stage disease. Anti-p53, c-erbB-2 and CEA were significantly higher in patients with NSCLC than controls and this increment was more evident in late stages of the disease. So, these biological markers might be useful predictors of prognosis. They may be helpful in defining groups of patients with NSCLC who could benefit from adjuvant treatments, also these markers can be used as therapeutic targets.     

S100A4蛋白在非小细胞肺癌中的表达与侵袭和转移的关系

背景与目的:实验证明S100A4在多种恶性肿瘤细胞中高表达,它可能在恶性肿瘤细胞的侵袭和转移等过程中发挥重要作用。本研究探讨S100A4在人非小细胞肺癌中的表达及其与侵袭和转移的关系。方法:采用免疫组化SP法检测41例非小细胞肺癌及6例正常肺组织中S100A4蛋白的表达水平。结果:S100A4在非小细胞肺癌中的阳性率(70.7%)显著高于正常肺组织(16.7%)(P<0.05);在肺腺癌中的阳性率(90.0%)明显高于肺鳞癌(52.4%)(P<0.01)。在TNM分期中,S100A4在Ⅲ Ⅳ期、Ⅱ期和Ⅰ期的阳性率分别为100.0%、66.7%和30.0%,Ⅲ Ⅳ期明显高于Ⅱ期和Ⅰ期(P<0.01),但是Ⅱ期和Ⅰ期间无显著性差异(P>0.05)。S100A4的阳性率在有淋巴结转移的非小细胞肺癌中(90.0%)明显高于无淋巴结转移组(52.4%)(P<0.01),且S100A4的表达与淋巴结转移密切相关(r=0.480,P=0.001)。肿瘤体积增大(<3cm,≥3cm),S100A4的阳性率明显升高(44.4%,91.3%)(P<0.001),且相关性显著(r=0.288,P=0.017)。S100A4的阳性率与非小细胞肺癌的病理分级无明显相关性(P>0.05)。结论:S100A4在非小细胞肺癌中的表达上调,且与淋巴结转移、TNM分期和肿瘤大小密切相关,提示S100A4与非小细胞肺癌的侵袭和转移有关。     

Increased phospho-AKT (Ser(473)) expression in bronchial dysplasia: implications for lung cancer prevention studies.

AKT, a downstream mediator of phosphatidylinositol 3'-kinase, is activated in non-small cell lung cancer (NSCLC), but we have not yet defined the stage of malignant transformation at which AKT is activated in the bronchial epithelium. We performed immunohistochemical analysis of activated AKT [phosphorylated (p)-AKT Ser(473)] in tissue specimens of normal bronchial epithelium, bronchial hyperplasia and squamous metaplasia ("reactive" epithelium), bronchial dysplasia, and NSCLC. Among NSCLC specimens, immunohistochemical findings were correlated with patient demographics, tumor stage, histology, and survival. We observed p-AKT expression in 12 of 44 (27.3%) normal bronchial biopsy specimens, 4 of 9 (44.4%) reactive epithelium specimens, 22 of 25 (88%) dysplastic specimens, and 25 of 76 (33%) NSCLC specimens. Among patients with resected early-stage or locally advanced NSCLC, p-AKT expression had no effect on tumor stage, histology, or survival. Of the histological groups examined, bronchial dysplasia specimens expressed p-AKT most frequently, supporting AKT activation as an early event in lung cancer progression. Given its role as a mediator of malignant transformation, p-AKT should be investigated as a potential target in future lung cancer prevention studies.     

MMP-9及TIMP-1在非小细胞肺癌中的表达及意义

目的：研究组织基质金属蛋白酶MMP-9及其抑制剂-1（TIMP-1）在非小细胞肺癌组织中的表达及意义.方法：通过免疫组织化学方法检测非小细胞肺癌组织和癌周组织中MMP-9和TIMP-1的表达,并分析其表达与肺癌临床病理特征的关系.结果：MMP-9、TIMP-1在肺癌组织中的阳性表达率明显高于癌旁正常组织（P＜0.05）,表达强度与肿瘤分化程度、临床分期、淋巴结转移密切相关（P＜0.05）.结论：检测非小细胞肺癌组织中MMP-9及TIMP-1的表达对判断肿瘤的恶性程度和预后评估有一定的意义,为临床诊断和治疗提供依据.