抑癌基因PTEN与食管鳞癌血管新生及预后相关性研究

[目的]探讨食管鳞状细胞癌（ESCC）抑癌基因PTEN蛋白表达及其对血管新生和预后的影响。[方法]免疫组化SP法检测102例ESCC组织及其相应的30例癌旁正常组织中PTEN蛋白表达，检测ESCC组织微血管密度（MVD），Kaplan—Meier法分析与预后的关系．[结果]ESCC中PTEN阳性表达率为63．7％（65／102），在癌旁正常食管组织中达到96．7％（29／30）（P〈0．01）。PTEN表达强度与浸润深度及是否伴淋巴结转移明显相关（P〈0．05），与MVD呈负相关（P〈0．01），而与ESCC预后呈正相关。[结论]PTEN表达下调可能参与ESCC发生及肿瘤血管生成，有望成为评价ESCC患者预后的较好指标。     

PTEN 表达与胃癌预后因素分析

目的：探讨胃癌组织中PTEN（张力蛋白和辅助蛋白同源、第10号染色体丢失的磷酸酶基因）和MMP-2（基质金属蛋白酶-2）蛋白表达与患者预后的关系。方法：用免疫组织化学S—P法检测64例胃癌组织PTEN和MMP-2蛋白表达，并对随访的33例胃癌患者进行单因素及多因素生存分析，选用Cox比例风险模型进行多因素生存分析。结果：PTEN蛋白在胃癌组织表达缺失率为21．98％，其表达缺失与淋巴结转移正相关，与患者生存期负相关（P〈0．05），Cox回归多因素生存分析显示PTEN蛋白表达缺失的患者生存的相对危险度是PTEN表达阳性的0．273倍（P〈0．05）；MMP-2蛋白在胃癌组织表达阳性率为68．75％，其高表达与癌细胞浸润深度、淋巴结转移呈正相关，与生存期呈负相关（P〈0．05）。另外，根治手术与患者的生存期呈正相关（P〈0．05），非根治术患者生存的相对危险度是根治术患者的1．104倍（P〈0．05）。结论：PTEN蛋白可作为胃癌患者预后的独立预测因子，PTEN蛋白表达缺失的胃癌患者预后不良。     

尿纤溶酶原激活物及血管内皮生长因子在食管癌中的表达及对肿瘤血管形成的影响

目的探讨尿纤溶酶原激活物（uPA）、血管内皮生长因子（VEGF）在食管癌中的表达及对肿瘤血管生成的影响。方法采用免疫组织化学sP法检测正常食管黏膜上皮组织（18例）及食管癌组织（68例）中uPA、VEGF的表达,检测CD。用以标记肿瘤微血管密度（MVD）,根据MVD均值分为高、低MVD组,分析食管癌uPA、VEGF的表达和临床病理特征的关系及对肿瘤血管形成的影响。结果uPA蛋白在正常食管黏膜上皮组织、食管癌组织中的阳性率分别为27．8％（5／18）和70．6％（48／68）,差异有统计学意义（X^2=11．63,P〈0．05）;VEGF蛋白在正常食管黏膜上皮组织、食管癌组织中的阳性率分别为22．2％（4／18）和63．2％（43／68）,差异有统计学意义（X^2=9．78,P〈0．05）。食管癌组织中uPA与VEGF表达有一致性（X^2=9．72,P〈0．05）。MVD平均为42．38±11．62,高MVD组uPA、VEGF蛋白表达显著高于低MVD组（X^2值分别为6．13和10．12,均P〈0．05）。uPA、VEGF蛋白表达与年龄、性别、病理类型无关（均P〉0．05）,均与临床病理分期、分化程度和淋巴结转移相关（P〈0．05）。结论食管癌组织中uPA、VEGF蛋白高表达,可能促进肿瘤血管形成,提示预后不良。     

PTEN、VEGF在胃癌组织中表达的相关性

[目的]探讨胃癌组织中PTEN和VEGF的表达及相互关系。[方法]应用免疫组化EnVision法检测65例胃癌组织中PTEN和VEGF的表达。[结果]胃癌组织中PTEN高表达率和VEGF阳性表达率分别为43．1％（28／65）和60．0％（39／65），与肿瘤的分化程度、浸润深度、淋巴结转移显著相关（P〈0．05）；Spearman等级相关分析显示PTEN与VEGF表达显著负相关（r=-0．368，P〈0．05）。[结论]胃癌组织中PTEN表达减少，VEGF表达增高，PTEN可能通过调控胃癌组织中的VEGF来抑制血管生成,从而抑制肿瘤的浸润和转移,影响病人的预后。     

微小RNA-126和微小RNA-7在食管鳞状细胞癌中的表达及临床意义

目的探讨微小RNA-126（miR-126）和微小RNA-7（miR-7）在食管鳞状细胞癌（ESCC）中的表达情况及其与ESCC临床病理特征、预后之间的关系。方法采用实时荧光定量聚合酶链反应法检测116例ESCC组织和癌旁正常组织中miR-126和miR-7的表达差异,并对miR-126和miR-7表达情况与ESCC患者临床病理特征、预后的相关性进行统计学分析。结果miR-126不同程度低表达病例数为73（62．9％）,正常表达病例数为35（30．2％）,高表达病例数为8（6．9％）;miR-7不同程度低表达病例数为52（44．8％）,正常表达病例数为35（30．2％）,高表达病例数为29（25．0％）。miR-126和miR-7表达降低组无瘤生存期均较非降低组短（r=4．268,P〈0．05;x2=4．993,P〈0．05）;miR-126低表达与ESCC肿瘤位置、家族史和饮酒相关（Xz=14．564,P〈0．05,x2=5．691,P〈0．05;X2=4．971,P〈0．05）,与性别、年龄、分化程度、浸润程度、淋巴转移、吸烟不相关（均P〉0．05）;miR-7低表达与ESCC的临床病理特征均不相关（均P〉O．05）。结论miR-126和miR-7的低表达可能与ESCC患者预后相关,具有一定的临床检测意义。     

PTEN在食管鳞状细胞癌中的表达和临床意义

目的：研究抑癌基因PTEN蛋白表达与食管鳞状细胞癌临床病理特征的关系,探讨其在食管癌变中的可能作用。方法：应用免疫组织化学SP法检测60例食管鳞状细胞癌及20例癌旁正常组织中PTEN蛋白的表达,结合临床资料进行分析。结果：PTEN蛋白阳性反应主要定位于胞浆。食管鳞状细胞癌组织中PTEN蛋白表达阳性率56．7％明显低于正常组织阳性率90．0％（P〈0．05）。PTEN蛋白在低分化、中分化、高分化鳞癌组的阳性表达率分别是21．4％、55．0％、76．9％,三组之间相互比较有极显著统计学差异（P〈0．01）,肿瘤分化程度越低PTEN蛋白表达越低。有淋巴细胞转移的食管癌组织中VrEN表达的阳性率42．9％明显低于无淋巴细胞转移的食管癌组织阳性率76．0％（P〈0．05）。有外膜浸润的食管癌组织中PTEN表达的阳性率26．1％明显低于无外膜浸润的食管癌组织阳性率75．7％（P〈0．05）。PTEN蛋白在食管癌早期表达高于晚期（P〈0．01）。结论：PTEN蛋白在食管鳞状细胞癌组织中的低表达可能与食管鳞癌的发生发展有重要关系。     

PTEN,P-AKT,P-ERK蛋白在胃癌组织中的表达及意义

目的：检测PTEN和P—AKT，P—ERK蛋白在胃癌中的表达，并探讨其相互关系。方法：应用免疫组织化学方法检测65例胃癌及癌旁组织中PTEN和P—AKT，P—ERK蛋白的表达情况。结果：PTEN蛋白在胃癌中表达的阳性率（58．46％）明显低于相应正常组织（100％）（P〈0．01），其表达水平与组织分化程度、浸润深度、淋巴结转移及TNM分期有关（P〈0．05）。P—AKT蛋白在胃癌中表达的阳性率（67．69％）明显高于相应正常组织（26．15％）（P〈0．01），其表达与淋巴结转移有关（P〈0．01），与浸润深度、分化程度和TNM分期无关（P〉0．05）。P—ERK蛋白在胃癌中表达的阳性率（86．15％）明显高于相应正常组织（16．92％）（P〈0．01），其表达水平与浸润深度、淋巴结转移及TNM分期有关（P〈0．05），与分化程度无关（P〉0．05）。胃癌组织中PTEN和P—AKT、PTEN和P—ERK蛋白表达之间呈明显负相关（P〈0．01）。结论：PTEN的低表达或失表达，可能与P—AKT、P—ERK的异常激活有一定联系，从而对胃癌的发生、发展起重要作用。     

PTEN，P—AKT，P—ERK蛋白在胃癌组织中的表达及意义

目的：检测PTEN和P—AKT，P—ERK蛋白在胃癌中的表达，并探讨其相互关系。方法：应用免疫组织化学方法检测65例胃癌及癌旁组织中PTEN和P—AKT，P—ERK蛋白的表达情况。结果：PTEN蛋白在胃癌中表达的阳性率（58．46％）明显低于相应正常组织（100％）（P〈0．01），其表达水平与组织分化程度、浸润深度、淋巴结转移及TNM分期有关（P〈0．05）。P—AKT蛋白在胃癌中表达的阳性率（67．69％）明显高于相应正常组织（26．15％）（P〈0．01），其表达与淋巴结转移有关（P〈0．01），与浸润深度、分化程度和TNM分期无关（P〉0．05）。P—ERK蛋白在胃癌中表达的阳性率（86．15％）明显高于相应正常组织（16．92％）（P〈0．01），其表达水平与浸润深度、淋巴结转移及TNM分期有关（P〈0．05），与分化程度无关（P〉0．05）。胃癌组织中PTEN和P—AKT、PTEN和P—ERK蛋白表达之间呈明显负相关（P〈0．01）。结论：PTEN的低表达或失表达，可能与P—AKT、P—ERK的异常激活有一定联系，从而对胃癌的发生、发展起重要作用。     

乳腺癌组织中核转录因子NF-κB和抑癌基因PTEN的表达及其意义

目的：探讨乳腺癌中核转录因子NF—κB和抑癌基因PTEN的表达及意义。方法：用免疫组织化学方法检测58例乳腺癌、20例乳腺增生症组织中NF—κB和抑癌基因PTEN的表达。结果：乳腺癌中NF—κB表达明显高于乳腺增生症组织，NF—κB表达强度与组织学分级和腋淋巴结转移有关（P〈0．05）。与患者年龄、肿瘤大小、组织学分型无关。乳腺癌中PTEN蛋白阳性率低于乳腺增生症组织，乳腺癌PTEN蛋白的表达与乳腺癌组织学分级有关（P〈0．05），与患者年龄、肿瘤大小、组织学分型、腋淋巴结无明显相关性（P〉0．05）。NF—κB p65与PTEN蛋白在乳腺癌组织中表达呈负相关（r=-0．355，P〈0．05）。结论：提示乳腺癌中NF—κB的高表达及PTEN缺失表达与乳腺癌的发生发展有关。     

乳腺癌组织中核转录因子NF—κB和抑癌基因PTEN的表达及其意义

目的：探讨乳腺癌中核转录因子NF—κB和抑癌基因PTEN的表达及意义。方法：用免疫组织化学方法检测58例乳腺癌、20例乳腺增生症组织中NF—κB和抑癌基因PTEN的表达。结果：乳腺癌中NF—κB表达明显高于乳腺增生症组织，NF—κB表达强度与组织学分级和腋淋巴结转移有关（P〈0．05）。与患者年龄、肿瘤大小、组织学分型无关。乳腺癌中PTEN蛋白阳性率低于乳腺增生症组织，乳腺癌PTEN蛋白的表达与乳腺癌组织学分级有关（P〈0．05），与患者年龄、肿瘤大小、组织学分型、腋淋巴结无明显相关性（P〉0．05）。NF—κB p65与PTEN蛋白在乳腺癌组织中表达呈负相关（r=-0．355，P〈0．05）。结论：提示乳腺癌中NF—κB的高表达及PTEN缺失表达与乳腺癌的发生发展有关。     

淋巴管生长因子对食管鳞癌血管生成、肿瘤转移及预后的影响

目的：探讨淋巴管生长因子与食管鳞癌临床病理参数、血管生成及预后的关系。方法：采用Elivision二步免疫组化法检测51例食管鳞癌手术切除标本中VEGF—C的表达，应用CD34标记肿瘤内微血管，计数微血管密度，对VEGF—C与临床病理参数、肿瘤内MVD以及预后间的关系进行回顾性分析。结果：食管鳞癌淋巴结转移组VEGF—C阳性率和MVD明显增高；VEGF—C阳性组和高MVD组患者的中位生存时间以及3年、5年生存率均明显低于阴性组。VEGF—C与MVD呈正相关。结论：淋巴管生长因子VEGF—C可促进肿瘤微血管生成。VEGF—C阳性、MVD增高可作为食管鳞癌淋巴转移增加以及预后差的指标。     

Overexpression of Id-1 is significantly associated with tumour angiogenesis in human pancreas cancers

It has been suggested that Id-1 has a critical role in the tumour progression and aggressiveness of several human cancers. However, the clinicopathological and biological significance of Id-1 overexpression remains unclear in human primary cancer. To investigate the association between Id-1 expression and cell proliferation or tumour angiogenesis, we examined the cell cycle kinetic indices (the proliferation and apoptotic indices, PI and AI) and intratumoral microvessel density (MVD) in 65 human pancreatic cancers. We also investigated the relationship between its expression and various clinicopathological factors to determine the clinical significance of Id-1 overexpression. Out of a total 65 cases, 32 (49.3%) showed overexpression of Id-1 vs normal tissues. Id-1 expression was found to be significantly associated with MVD (P=0.002). In further analysis of subgroups with higher and lower Id-1 expression, tumours with higher Id-1 expression (scores 4 and 5) showed significantly higher MVD than tumours with lower expression of Id-1 (scores 2 and 3) (111.18+/-57.14 vs 64.13+/-28.19, P<0.001). However, no significant association was found between Id-1 overexpression and patient survival rate. No significant association was also found between Id-1 expression and cell cycle kinetic indices (PI or AI) in pancreatic cancer. Moreover, the overexpression of Id-1 protein was not correlated with any significant clinicopathologic factors. These findings indicate that Id-1 overexpression is closely related with tumour angiogenesis and a higher density of intratumoral vessel, but that it is not associated with a poorer prognosis of survival or a higher cell proliferative potential in human pancreatic cancer.     

VEGF and Id-1 in pancreatic adenocarcinoma: Prognostic significance and impact on angiogenesis

Objectives

The significance of vascular endothelial growth factor (VEGF) and inhibitor of differentiation/DNA synthesis (Id-1) in tumor neoangiogenesis and tumor progression in pancreatic ductal adenocarcinoma (PDAC) is still unclear. Given the central role of VEGF in cancer angiogenesis and the inconclusive results on Id-1 expression in PDAC, it is of great interest to investigate whether Id-1 and VEGF expression are associated with angiogenesis and prognosis in PDAC.

Methods

Paraffin-embedded specimens from 60 consecutive patients with PDAC were immunostained for VEGF, Id-1 and CD34 and staining quantification was assessed by Image analysis system. The correlations among the expression of individual angiogenic factors and microvessel density (MVD), clinicopathologic features and clinical prognosis were analyzed.

Results

Id-1 and VEGF Positive Activity Indices (PAIs) closely correlated with each other. MVD positively correlated with both Id-1 and VEGF expression. More advanced T and N status correlated with more intense expression of Id-1, VEGF and higher MVD. With regard to prognostic significance higher Id-1 PAI (adjusted HR = 1.69, 95%CI: 1.10–2.59, p = 0.017), higher VEGF PAI (adjusted HR = 2.66, 95%CI: 1.09–6.50, p = 0.032), and MVD (adjusted HR = 1.55, 95%CI: 1.27–1.88, p < 0.001) were associated with poorer survival.

Conclusions

VEGF and Id-1 overexpression were found to be associated with high MVD and emerged as adverse prognostic factors in terms of patient survival in PDAC. The potential of selective anti-angiogenic targeting therapy for pancreatic malignancies should prompt further validation of the present findings in studies encompassing larger samples and more elaborate techniques.     

腋淋巴结阴性乳腺癌中基因表达PTEN和微血管密度的关系及意义

目的:研究腋淋巴结阴性(ph node negative,LN N)乳腺癌中PTEN蛋白的表达,探讨与微血管密度lym(VD)及患者预后的关系。方法:应用免疫组化S-P法检测81例LN N乳腺癌及20例癌旁乳腺组织中PTEN和MCD34蛋白的表达,分析与各临床病理因素和预后的关系。结果:32.6%的患者PTEN蛋白表达减低或完全阴性表达,PTEN与乳腺癌病理分级,ER状态和复发转移显著相关;PTEN阳性表达组的5年生存率(83.7%)明显高于阴性表达组(66.7%)(P<0.05);PTEN的表达与M VD呈显著的负相关关系(r=-0.552,P<0.01)。结论:PTEN缺失是乳腺癌发生过程中的多发事件,并有抑制血管生成的作用,PTEN缺失和高M V D的LNN乳腺癌患者5年生存率低,两者的检测有助于提高评估LN N乳腺癌患者术后生存的准确性。     

Identification of differentially expressed genes in esophageal squamous cell carcinoma (ESCC) by cDNA expression array: overexpression of Fra-1, Neogenin, Id-1, and CDC25B genes in ESCC.

PURPOSE: This study aims to identify differentially expressed genes in esophageal squamous cell carcinoma (ESCC) through the use of a membrane-based cDNA array. EXPERIMENTAL DESIGN: Two newly established human ESCC cell lines (HKESC-1 and HKESC-2) and one corresponding to a morphologically normal, esophageal epithelium tissue specimen, prospectively collected from the HKESC-2-related patient, were screened in parallel using a cDNA expression array containing gene-specific fragments for 588 human genes spotted onto nylon membranes. RESULTS: The results of cDNA expression array showed that 53 genes were up-regulated 2-fold or higher and 8 genes were down-regulated 2-fold or higher in both ESCC cell lines at the mRNA level. Semiquantitative RT-PCR analysis of a subset of these differentially expressed genes gave results consistent with cDNA array findings. Four of the differentially expressed genes that belong to the categories of oncogenes/tumor suppressor genes (Fra-1 and Neogenin) and cell cycle-related genes (Id-1 and CDC25B) were studied more extensively for their protein expression by immunohistochemistry. The two ESCC cell lines and their corresponding primary tissues, 61 primary ESCC resected specimens and 16 matching, morphologically normal, esophageal epithelium tissues were analyzed. The immunostaining results showed that Fra-1, Neogenin, Id-1, and CDC25B were overexpressed in both ESCC cell lines and their corresponding primary tumors at the protein level, validating the microarray findings. The results of the clinical specimens showed that the Fra-1 gene was overexpressed in ESCC compared with normal esophageal epithelium in 53 of 61 cases (87%), Neogenin in 57 of 61 cases (93%), Id-1 in 57 of 61 cases (93%), and CDC25B in 48 of 61 cases (79%). Furthermore, the expression of Fra-1, Neogenin, and Id-1 in ESCC correlated with tumor differentiation. CONCLUSIONS: Overall, this study demonstrates that multiple genes are differentially expressed in ESCC and provides the first evidence that oncogenes Fra-1 and Neogenin and cell cycle-related genes Id-1 and CDC25B are overexpressed in ESCC.     

食管癌中FHIT PTEN基因蛋白表达与预后相关性分析

目的:探讨食管小细胞癌与鳞状细胞癌中 FHIT、PIEN基因蛋白表达及其生物学特性对预后的影响.方法:选取食管小细胞癌60例,鳞状细胞癌100例进行FHIT、PTEN基因蛋白的检测和临床资料综合分析.结果:FHIT、PTEN基因蛋白在小细胞癌与鳞状细胞癌中阳性表达比较有显著性差异(P＜0.01),且有相关性.在小细胞癌中,FHIT、PIEN阳性表达与淋巴结转移、瘤栓及预后有相关性.FHIT、PTEN基因蛋白在食管癌中的表达,小细胞癌属于低表达型,其生物学行为呈现出高恶性度,5年生存率低;鳞状细胞癌则属高表达型,其生物学行为所表现的恶性度远不如小细胞癌高,5年生存率明显提高.结论:两种基因在食管癌中表达的高低,与组织学类型、分化程度及预后相关,可作为临床治疗和判断预后的依据.     

Id-1 overexpression in invasive ductal carcinoma cells is significantly associated with intratumoral microvessel density in ER-negative/node-positive breast cancer

The aim of this study is to investigate the possible role of inhibitor of DNA binding (Id-1) overexpression in human breast cancer. We examined Id-1 expression by immunohistochemistry in 263 human breast cancers, 15 in situ lesions and 248 invasive cancers to investigate the relationship between its expression and various clinicopathological factors. Id-1 expression was significantly higher in invasive ductal carcinoma than in in situ ductal carcinoma or other invasive cancer subtypes (P=0.029 and 0.006, respectively). We also examined the association between Id-1 expression and tumor angiogenesis by measuring microvessel densities (MVD). Regarding the endothelial cells of microvessels showed negative or very weak Id-1 expression, Id-1 overexpression was found to be significantly related to MVD (P=0.014). Furthermore, Id-1 overexpression was found to be significantly associated with higher MVD in the ER-negative and node-involved subgroups of breast cancer (P=0.040 and 0.046, respectively). These data indicate that Id-1 overexpression is significantly associated with tumor angiogenesis, especially in the ER-negative and node-positive subtypes of invasive breast cancer. Thus, Id-1 presents a possible therapeutic antitumor target molecule in ER-negative and node-positive breast cancer.     

食管鳞状细胞癌中微血管密度的研究

目的　探讨食管鳞状细胞癌中微血管密度与其分级、分期及临床预后的关系。方法　 1994年收集 63例食管鳞癌标本 ,利用LSAB免疫组化技术检测肿块内微血管密度 ,研究微血管表达与食管鳞癌病理分级、临床分期及生存率的关系。结果　微血管密度与食管鳞癌病理分级、临床分期、生存率呈负相关性 ,与年龄、性别、肿块大小、病理分型无关。结论　微血管密度与食管鳞癌的分级、分期、预后呈负相关 ,其可以作为评价食管鳞癌预后的可靠指标