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TES functions as a mena-dependent tumor suppressor in gastric cancer carcinogenesis and metastasis

Cancer Communications 2019年第1期39卷 14-27页

作者： Dan-dan Wang Yi-bing Chen Jing-jing Zhao Xiao-fei Zhang Guang-chao Zhu De-sheng Weng Ke Pan Lin Lv Qiu-zhong Pan Shan-shan Jiang Lei-lei Wang Jian-chuan Xia Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangzhou 510060GuangdongP.R.China Department of Biotherapy Sun Yat-sen University Cancer Center651 Dongfeng Road EastGuangzhou 510060GuangdongP.R.China Shandong Medicinal Biotechnology Centre Back and Neck Pain HospitalShandong Academy of Medical SciencesJinan 250062ShandongP.R.China Genetic and Prenatal Diagnosis Center Department of Gynecology and ObstetricsFirst Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052HenanP.R.China Key Laboratory for Applied Microbiology of Shandong Province Ecology Institute of Shandong Academy of SciencesJinan 250014ShandongP.R.China

Background: In our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with mena. This study aimed to investigate the tumor suppressive functions of TES in GC. Methods: We explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prog-nostic significance of TES and mena in GC. Results: TES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with mena, and inhibited the interaction of mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a mena-dependent fashion. In GC patients with high mena expression, the expression of TES was associated with tumor infiltration (P = 0.005), lymph node metastasis (P = 0.003), TNM stage (P = 0.003), and prognosis (P = 0.010). However, no significant association was observed in GC patients with low mena expression. Conclusions: We believe that TES functions as a mena-dependent tumor suppressor. TES represents a valuable prog-nostic marker and potential target for GC

关键词： Gastric cancer TES Tumor suppressor mena Lamellipodin

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Renewable Energy Technologies Penetration in mena Region （2010-2030）

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Journal of Electrical Engineering 2016年第2期4卷 100-107页

作者： Marc Anthony Mannah Loren Makki Ahmad Haddad Hassan Bazzi Ali Hammoud School of Engineering Department of Electrical Engineering Lebanese International University Beirut Lebanon

This paper focuses on quantifying the renewable energy mix in the mena （Middle East and North Africa） region and underlines its impact in terms of economic aspects. The installed and targeted capacities of solar, wind and other technologies will be revealed. In addition, distinguished present and on-going projects as well as prominent funding organizations are discussed. The overall strategy as well as the evolution of the renewable energy plan is resumed.

关键词： mena renewable energy solar energy wind energy funding organizations.

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Comparison of WRF Model Physics Parameterizations over the mena-CORDEX Domain

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American Journal of Climate Change 2014年第5期3卷 490-511页

作者： George Zittis Panos Hadjinicolaou Jos Lelieveld Energy Environment and Water Research Center The Cyprus Institute Nicosia Cyprus Department of Atmospheric Chemistry Max Plank Institute for Chemistry Mainz Germany

We investigated the performance of 12 different physics configurations of the climate version of the Weather, Research and Forecasting (WRF) Model over the Middle East and North Africa (mena) domain. Possible combinations among two Planetary Boundary Layer (PBL), three Cumulus (CUM) and two Microphysics (MIC) schemes were tested. The 2-year simulations (December 1988-November 1990) have been compared with gridded observational data and station measurements for several variables, including total precipitation and maximum and minimum 2-meter air temperature. An objective ranking method of the 12 different simulations and the selection procedure of the best performing configuration for the mena domain are based on several statistical metrics and carried out for relevant sub-domains and individual stations. The setup for cloud microphysics is found to have the strongest impact on temperature biases while precipitation is most sensitive to the cumulus parameterization scheme and mainly in the tropics.

关键词： WRF Physics Parameterizations Regional Climate Modeling Sensitivity mena CORDEX

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Water Shortage in mena Region: An Interdisciplinary Overview and a Suite of Practical Solutions

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Journal of Water Resource and Protection 2013年第4期5卷 49-58页

作者： Anas Zyadin University of Eastern Finland Joensuu Finland

The chronic water shortage in the Middle East North Africa (mena) region is a perplexing issue, undoubtedly because various operational sectors, multi-institutions and stakeholders are inextricably interconnected. In the light of climate variability and the unprecedented population growth rate, the per capita water resources and biocapacity will continue plummeting, and the demand-gap will seriously expand. Existing water quantification agreements have been deemed inefficient to solve the problem of naturally diminishing water resources and thus require immediate re-assembling. Most scholarly endeavors, including key international organizations, NGOs, and “Think Tank” policy briefs have limitedly addressed water shortage in contexts of regional politics, mass media, and, importantly, from social psychology perspectives. Therefore, a thorough analysis and interdisciplinary approach is required to find a feasible and suitable framework of solutions and from a multi-perspective podium. A synthesis of cross-sectorial bottlenecks that are crucial to water management is presented, and a suite of practical recommendations are introduced to water authorities and governments. This study argues that in the shadow of the region’s political instability, the clash of ideologies and its repercussions, and issues of national security and sovereignty, regional cooperation on water issues remain prognostications. In this essence, governments of mena countries are urged to develop measures to substantially increase the water supply through innovative approaches. Such measures include enhancing the capacities of water harvesting, maximizing the storage capacities of the built dams, and deploying groundwater recharge techniques. Furthermore, seawater and brackish water desalination through clean energy technologies is a contemporary solution with socio-economic and multiple benefits. Multi-billion water projects might not be suitable approach in the absence of external funding and the

关键词： Water Conflicts Renewable Energy mena Region Interdisciplinary Approach

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Water Demand Management Is a Must in mena Countries…But Is It Enough?

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Journal of Geological Resource and Engineering 2018年第2期6卷 59-64页

作者： Wael Mualla The Department of Civil Engineering School of EnergyGeoscienceInfrastructure and SocietyHeriot-Watt UniversityDubai BranchUAE

The majority of Middle East and North Africa(mena)countries suffer from chronic imbalance between available water supply and rising water *** imbalance is expected to worsen even further in the future as a result of sharp population growth,rapid economic development and climate change,unless major positive measures are implemented to augment water supply and manage water *** supply management approach,on its own,practiced by many countries in the region for so many years has so far demonstrated its inability to bridge the“water gap”between available water resources and rising water demand,as most traditional water resourced in almost all mena countries have been exploited(or over exploited),and the cost of non-traditional water resources has become increasingly prohibitively high,apart from its environmental *** management is regarded by many water experts in the region as the answer or“panacea”for the water imbalance ***,is demand management approach alone able to solve the problem of water scarcity in the mena region?In other words,if all demand management measures have been fully implemented,would there still be gaps between supply and demand that need to be filled with supply augmentation,andwill supply management options still need to be part of the solution?This paper tries to answer this question by reviewing several works in this domain,particularly,recent studies by the World Bank[9-11].It was concluded that,although water demand management measures should be given the first priority,especially,in the agricultural sector where it has the maximum impact,demand management on its own will not be able to bridge the“water gap”,and supply management options,such as sea water desalination and the re-use of treated wastewater,will be part of the solution.

关键词： mena countries demand management water scarcity water gap

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Linking Environmental Water Scarcity and Options for Adaptation in the mena Region

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Journal of Water Resource and Protection 2017年第4期9卷 378-392页

作者： Bachar Ibrahim Henry Mensah Faculty of Economy Law and Society Department of Public Law with Reference to the Law of Environment and Planning Brandenburg University of Technology Cottbus-Senftenberg Cottbus Germany

Contamination of surface and underground water by sea level rise, surface runoff, and land use activities such as industrial and agricultural activities can lead to water scarcity. Water could be available and accessible but not suitable for human use. In the Middle East and North Africa (mena) region countries, the agriculture sector depends massively on water for farming activities, which consumes about 80% of the available water resources. In this context, the issue of environmental water scarcity is under highlighted, though the use of this term itself is still lacking in an international context (FAO). Meanwhile, the international goal of universal access to clean freshwater is included in global development targets (SDGs). This study provides some insights and deepens our understanding on environmental water scarcity, particularly MEN-A region countries. This review paper begins with an introduction to water scarcity and continues with a discussion of environmental issues associated with water scarcity in mena region countries. Finally, we suggest some adaptive measures in two distinct areas such as agriculture sectors and policy makers and conclude that the lack of implementation of this particular term is hindering sustainable development in mena region countries.

关键词： Adaptation mena Climate Change Water Scarcity Water Quality Environment

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TES通过mena依赖的方式抑制胃癌生长和转移

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癌症 2020年第7期39卷 321-334页

作者：王丹丹陈义兵赵靖靖张晓菲朱广超翁德胜潘科吕琳潘求忠江珊珊王磊磊夏建川中山大学肿瘤防治中心华南肿瘤学国家重点实验室肿瘤医学协同创新中心广东省鼻咽癌诊治研究重点实验室广东广州510060 中山大学肿瘤防治中心生物治疗科广东广州510060 山东省医药生物技术研究中心山东省医学科学院颈肩腰痛医院山东济南250062 郑州大学第一附属医院妇产科遗传与产前诊断中心河南郑州450052 山东省应用微生物学重点实验室山东省科学院生态研究所山东济南250014

背景与目的在前期研究中,我们在原发性胃癌(gastric cancer,GC)中发现了一个候选抑癌基因——TES(testin LIM domain protein)。TES包括3个LIM结构域,后者是与细胞黏附和细胞骨架调节蛋白发生特异性相互作用的区域。mena是一种已知的细... 详细信息

背景与目的在前期研究中,我们在原发性胃癌(gastric cancer,GC)中发现了一个候选抑癌基因——TES(testin LIM domain protein)。TES包括3个LIM结构域,后者是与细胞黏附和细胞骨架调节蛋白发生特异性相互作用的区域。mena是一种已知的细胞骨架调节因子,可通过与片状伪足(lamellipodin,Lpd)相互作用调节肌动蛋白丝的组装并调节细胞黏附与运动。因此,我们假设TES在胃癌中通过与mena相互作用发挥抑癌因子功能。本研究旨在探索TES在胃癌中的肿瘤抑制功能。方法我们通过体外细胞增殖实验、克隆形成实验、细胞周期分析、转移实验和体内肿瘤形成与转移试验来研究TES在胃癌中的抑癌作用。采用免疫沉淀–质谱法研究TES和mena的相互作用。我们采用免疫组化分析了172例胃癌样本中TES和mena的表达情况,并研究了胃癌中TES和mena的临床病理特征及预后意义。结果TES抑制胃癌细胞的增殖和克隆形成,导致细胞周期阻滞,并在裸鼠内抑制胃癌细胞的成瘤性。此外,TES还可以抑制胃癌细胞在体外的迁移和侵袭,同时抑制体内肿瘤转移。TES与mena相互作用,抑制了mena与Lpd之间的相互作用。Transewll实验表明,TES通过mena依赖方式抑制胃癌细胞的迁移和侵袭。在mena高表达的胃癌患者中,TES的表达与肿瘤浸润(P=0.005)、淋巴结转移(P=0.003)、TNM分期(P=0.003)及预后(P=0.010)相关。但在mena低表达的胃癌患者中无以上相关性。结论我们认为TES通过mena依赖的方式发挥抑癌作用。TES可作为一种有价值的胃癌预后标志物及潜在的治疗靶标。

关键词：胃癌 TES 抑癌因子 mena 片状伪足

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细胞骨架调节蛋白mena在食管鳞癌细胞增殖、迁移和侵袭中的作用及其机制

细胞骨架调节蛋白Mena在食管鳞癌细胞增殖、迁移和侵袭中的作用及...

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作者：李岳衡郑州大学

学位级别：硕士

背景与目的食管癌是最常见的消化道恶性肿瘤之一,河南是中国乃至世界上食管癌发病率和死亡率最高的地区。食管癌按组织学可分为食管鳞状细胞癌（Esophageal squamous cell carcinoma,ESCC）、食管腺癌（Esophageal adenocarcinoma,EAC... 详细信息

背景与目的食管癌是最常见的消化道恶性肿瘤之一,河南是中国乃至世界上食管癌发病率和死亡率最高的地区。食管癌按组织学可分为食管鳞状细胞癌（Esophageal squamous cell carcinoma,ESCC）、食管腺癌（Esophageal adenocarcinoma,EAC）、腺鳞癌和未分化小细胞癌等,我国食管癌患者中90%以上是ESCC,而EAC及其他类型的食管癌不足10%,这与欧美国家以EAC为常见病症的特点有所不同。迄今,ESCC的病因尚未完全明确,因其发病隐匿,大多数患者确诊时已属中晚期,且ESCC发病后进展快速,易发生肿瘤的转移和化疗耐受,因此ESCC患者的5年生存率只有不到20%。而得益于过去几十年医学技术上的进步与发展,曾经致死率很高的肿瘤如恶性黑色素瘤和白血病,其五年生存率也已超过50%,因此食管鳞癌目前仍然是全球最致命的癌症之一。mena是由ENAH基因转录翻译得到的细胞骨架调节蛋白,属于Ena/VASP蛋白家族的一员。Ena/VASP蛋白家族成员均具有两个特殊结构域,分别是在其N端的EVH1结构域和C端的EVH2结构域,而mena除了具有EVH1和EVH2结构域之外还存在一个mena特异性的LERER结构域,并且不同于其他Ena/VASP蛋白成员,mena的mRNA存在着丰富的可变剪接,这导致mena蛋白存在诸多亚型。多项研究显示mena在多种人类肿瘤中高表达,如乳腺癌、非小细胞肺癌、恶性黑色素瘤、胰腺癌等,其肿瘤组织相较于癌旁组织均有着高表达的mena蛋白,同时也有研究显示mena的高表达与肿瘤的转移及恶性程度高度相关。尤其是在针对乳腺癌的研究当中,已明确证实了 mena具有促进肿瘤侵袭转移的作用。在食管鳞癌中,肿瘤的转移是导致绝大部分ESCC患者死亡的原因,但到目前为止,仍没有关于mena在食管鳞癌中的研究。为了探究mena这一促进肿瘤侵袭转移的蛋白在ESCC中所起到的作用,本实验通过（1）比较27对ESCC肿瘤组织和相应的癌旁组织中menamRNA的表达情况;（2）检测ESCC细胞系和食管上皮细胞中mena蛋白的表达差异,并比较mena表达水平不同的ESCC细胞的生物学特性,具体包括细胞的增殖能力、克隆形成能力、侵袭及迁移能力;（3）通过构建mena特异性siRNA和mena表达质粒来分别下调和升高mena的表达水平从而明确mena对ESCC细胞增殖能力、克隆形成能力、侵袭及迁移的影响;（4）mena-siRNA和过表达质粒干预mena的表达后检测EMT相关分子标志物（E-cadherin、N-cadherin、Snail和Slug）、基质金属蛋白酶（Matrix metalloproteinas,MMP-2、MMP-9）和PI3K/AKT信号通路中关键分子（Akt、p-Akt）的表达,共四个部分来探究mena对ESCC细胞增殖能力、克隆形成能力、侵袭及迁移能力的影响及其分子机制,以此来明确mena在ESCC的发生发展中所起到的功能,同时也为发现ESCC肿瘤转移及其预后评价的分子标志物提供新思路。方法1食管鳞癌病人肿瘤组织和癌旁组织中mena mRNA表达水平的比较于2015年-2016年在安阳市肿瘤医院收取食管鳞癌病人的肿瘤组织及癌旁组织并提取组织总mRNA,通过实时荧光定量PCR（Quantitative Real-Time PCR,qPCR）检测肿瘤组织和癌旁组织中menamRNA的表达水平。2 ESCC细胞系和食管上皮细胞中mena蛋白表达水平的比较Western blot检测不同ESCC细胞和食管上皮细胞中mena蛋白的表达情况。并选择mena表达水平不同的ESCC细胞来进行后续实验。3 mena表达水平不同的ESCC细胞生物学特性的比较分别采用CCK-8实验、平板克隆形成实验、划痕实验和Transwell实验检测高表达mena的ESCC细胞系（TE13）和低表达mena的ESCC细胞系（TE1）在增殖能力、克隆形成能力、迁移和侵袭能力上的差异。4 mena-siRNA下调TE13细胞中mena的表达通过将mena-siRNA转染进TE13细胞来敲低mena的表达。CCK-8法比较siNC组和simena组细胞增殖能力的变化并绘制生长曲线;平板克隆形成实验比较二者的克隆形成能力;划痕实验和Transwell实验比较二者的迁移和侵袭能力;Western blot 检测二者 EMT 标志物 E-cadherin、N-cadherin、Snail、Slug、基质金属蛋白酶MMP-2和MMP-9以及Akt和磷酸化Akt的表达变化。5表达质粒上调TE1细胞中mena的表达构建mena表达质粒,空载质粒为对照。转染TE1细胞来升高其mena的表达水平,CCK-8法比较转染了空载质粒（Contr

关键词： mena 食管鳞癌侵袭迁移基质金属蛋白酶 PI3K/Akt信号通路

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乳腺癌组织中mena和Her-2的表达及意义

乳腺癌组织中Mena和Her-2的表达及意义

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作者：张青山河南科技大学

学位级别：硕士

目的乳腺癌是一种最常见的严重危害女性身心健康的恶性肿瘤之一,其发病率呈现逐年上升的趋势,并且已经跃居女性恶性肿瘤第一位。据世界卫生组织统计:全球每年有120万妇女罹患乳腺癌,有50万妇女死于乳腺癌,平均每分钟就有一名妇女死于乳... 详细信息

目的乳腺癌是一种最常见的严重危害女性身心健康的恶性肿瘤之一,其发病率呈现逐年上升的趋势,并且已经跃居女性恶性肿瘤第一位。据世界卫生组织统计:全球每年有120万妇女罹患乳腺癌,有50万妇女死于乳腺癌,平均每分钟就有一名妇女死于乳腺癌,而浸润和转移是导致乳腺癌病人死亡的最主要的原因。本课题通过检测乳腺癌组织中mena(mammalian enabled)和人表皮生长因子受体2(human epidermal growth factor receptor2,Her-2)蛋白的表达情况,分析mena和Her-2蛋白在乳腺癌组织中的表达及其与临床病理特征的关系,探讨二者在乳腺癌浸润和转移中的作用及其意义,以及二者之间的相关性。方法采用免疫组化SP法检测60例乳腺癌组织和15例正常乳腺组织中mena和Her-2蛋白的表达,同时分析其与临床病理资料的关系。采用SPSS17.0统计软件对数据进行分析,并用χ2检验及Spearman相关性分析进行统计学处理,以Pmena蛋白在乳腺癌组织中的阳性表达率为73.3%(44/60) ,Her-2蛋白在乳腺癌组织中的阳性表达率为38.3% (23/60),均显著高于在正常乳腺组织中的表达(Pmena蛋白阳性表达率在腋淋巴结转移组为85.7%(36/42),在无腋淋巴结转移组为44.4%(8/18)二者比较有统计学意义(P0.05)。***蛋白在Her-2蛋白阳性组的表达率为95.7%(22∕23),在Her-2蛋白阴性组的表达率为59.5%(22/37),统计分析显示二者间差别具有统计学意义(Pmena和Her-2可能均参与了乳腺癌细胞的扩散,在肿瘤的浸润转移过程中起协同作用,联合检测mena和Her-2蛋白的表达有可能对判断乳腺癌的恶性程度、浸润转移潜能及预后判断有重要的参考价值。

关键词：乳腺癌 mena Her-2 免疫组织化学

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肝癌中mena蛋白的表达及其临床意义

肝癌中Mena蛋白的表达及其临床意义

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作者：牟林大连医科大学

学位级别：硕士

目的:通过间接免疫组化,证明肝癌组织中骨架调节蛋白mena的存在,进一步探讨骨架调节蛋白mena在肝癌中的表达,及其可能的临床意义。方法:选择并收集大连医科大学附属第一医院及大连中心医院2006-2009年经手术治疗的肝癌标本54例。首... 详细信息

目的:通过间接免疫组化,证明肝癌组织中骨架调节蛋白mena的存在,进一步探讨骨架调节蛋白mena在肝癌中的表达,及其可能的临床意义。方法:选择并收集大连医科大学附属第一医院及大连中心医院2006-2009年经手术治疗的肝癌标本54例。首先经间接免疫组化检测样本肝癌中mena蛋白的表达阳性率;并以此为基础,以患者性别、年龄,肿瘤的平均直径,肿瘤中的癌灶数目的多少,是否伴有肝脏门静脉癌栓形成,患者血清中AFP的含量,患者HBsAg的情况以及肝癌的临床分期（TNM）的不同进行分组,后经统计学分析来判定不同分组因素中肝癌mena蛋白的表达的差异是否存在统计学意义,从而得到可能影响肝癌组织中mena蛋白的表达情况因素。结果:经过间接免疫组化染色的肝癌组织,阳性染色均表现胞浆为黄色或褐色。以免疫组化中常用的染色得分为标准:无阳性肿瘤细胞的肝癌切片得0分;以此类推阳性肿瘤细胞＜33%的肝癌切片得1分;阳性肿瘤细胞33%—66%的肝癌切片得2分;阳性肿瘤细胞＞66%肝癌切片得3分。显色度计分:以接近肿瘤细胞的正常细胞染色为0分,浅黄染色1分,棕黄染色2分,棕褐染色3分。将两项分数相加除以2,按积分高低分为0分:阴性（—）,0-2分:弱阳性（+）,2-3分:阳性（++）,3分以上:强阳（+++）。1,54例肝癌标本中,阴性6例,弱阳性（+）9例,阳性（++）20例,强阳性（+++）19例。阳性表达率为89%。2,在肿瘤超过5厘米的肿瘤组,伴有门静脉癌栓组,以及临床早晚分期组mena蛋白的表达经统计学分析差异具有统计学意义（P＜0.05）。在直径超过5厘米的肿瘤组,伴有门静脉癌栓组及晚期临床分期组,mena蛋白过度表达。这预示着随着肿瘤的进展,mena蛋白的表达是增加的。3,而性别,年龄,癌灶数目,AFP以及HBsAg组,未得出mena蛋白的表达有组间差别。结论:mena蛋白在绝大多数（89%）肝癌中表达阳性,阳性结果定位于细胞质中。在恶性程度较高的晚期肝癌中,mena蛋白出现近膜染色增强的特点。同时mena蛋白的表达随着肝癌肿瘤分期增加而表达增强,表明mena蛋白与肝癌的发生发展密不可分。mena蛋白的过量表达也许可以作为肿瘤标记物而对肿瘤的发生、发展和预后起到重要作用。

关键词：肝癌 mena 免疫组化

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