EZRIN蛋白与妇科肿瘤侵袭转移关系研究进展

Ezrin (埃兹蛋白)是ERM (ezrin∕radixin∕moesin,埃兹蛋白/根蛋白/膜突蛋白)蛋白家族成员之一,是膜细胞骨架连接蛋白,通过介导膜与细胞骨架的连接,Ezrin调节细胞形态形成、运动、黏附以及细胞信号转导等多项细胞活动,而这些细胞活动与肿瘤的发生、发展及浸润转移等密切相关.多项研究表明Ezrin的表达水平与多种肿瘤的侵袭力、转移、临床预后有密切关系.Ezrin可能与妇科肿瘤病程进展密切相关,但相关研究较少.     

Ezrin 蛋白与肿瘤转移关系的研究进展

Ezriil蛋白是ERM（Ezfin／Radixin／Moesin）家族的重要成员，是细胞骨架与细胞膜之间的连接蚤白，对细胞膜区域的整合和稳定性起到结构和功能调控的作用Ezrin蛋白参与了微绒毛的形成及细胞形态的维持、细胞运动及黏附、细胞骨架的重塑及细胞信号转导过程．且可以作为膜的有机体和连接体连接细胞膜与细胞骨架，如：与细胞膜分子CD43、CD44、E-cadherin、ICAM-1等及细胞骨架成员F-型肌动蛋白（F-aetin）的连接，并且有令人注目的临床证据显示：Ezrin蛋白家族和黏附分子在控制癌细胞具有的如粘附性的细胞功能及浸润转移的生物学特性上显得尤为重要目前许多研究表明Ezrin蛋白与多种肿瘤的发生、转移和预后相关，如：妇科肘’瘤、消化道肿瘤、黑色素瘤及鼻咽癌、成人软组织肿瘤、儿童骨肉瘤和横纹肌肉瘤等Ezrin蚤白在肿痛细胞中的表达异常，提示其在肿痈的浸润、转移机制中发挥重要作用.有研究显示：Ezrin蛋白的异常表达可赋予肿瘤细胞高转移活性，影响并参与到肿瘤转移的多个环节．如：从原发灶脱落并具有运动性、侵入周围组织及脉管系统、穿透基底膜、选择性的在靶器官增殖形成转移灶等。对Ezrin蛋白在肿瘤中的全面研究，可以为肿瘤的诊断、治疗和预后评价提供新的思路和标准。     

细胞骨架蛋白Ezrin的生物学特性

埃兹蛋白(Ezrin)是连接细胞膜和细胞骨架之间的膜细胞骨架连接蛋白,由于Ezrin细胞中的特殊位置,不仅在细胞的运动、黏附和信号转导等正常生理活动中起重要作用,其在肿瘤细胞转移过程中的作用也逐渐受到重视.     

Ezrin、RhoA与肿瘤浸润转移

肿瘤浸润转移的各阶段有很多相关因子参与,寻找肿瘤浸润转移过程中的关键分子,对肿瘤防治具有重要意义.膜细胞骨架链接蛋白Ezrin和RhoGTP酶超家族成员RhoA与肿瘤浸润转移密切相关,尤其是在影响肿瘤细胞运动能力、调节细胞间及细胞与基质间黏附、促进基质降解等方面有重要作用.本文综述Ezrin和RhoA与肿瘤浸润转移的关系.     

Ezrin蛋白与消化系统恶性肿瘤关系的研究进展

Ezrin蛋白作为ERM(Ezrin,Radixin, Moesin)家族的重要成员,其主要作用是参与细胞膜信号转导,维持细胞形态、运动和黏附,重塑细胞骨架等,还起到连接细胞膜和细胞骨架的作用。Ezrin蛋白在肿瘤细胞中的异常表达会影响肿瘤细胞的浸润及转移活性,说明Ezrin蛋白与肿瘤的发生、转移与预后密切相关。伴随着消化系统恶性肿瘤发病率的不断升高,严重影响到了人类的生活质量,探究Ezrin蛋白在肿瘤中的表达及其作用机制对于消化系统恶性肿瘤（如食管癌、结直肠癌、胃癌、肝癌、胰腺癌和胆道肿瘤）的早期诊断、治疗及预后评价等方面具有重要意义,同时也可为寻找新的基因治疗靶点及诊断用生物标志物提供新的依据。     

Ezrin在散发性结直肠癌中的表达及意义

背景与目的：细胞骨架和细胞浆膜的连接蛋白Ezrin（埃兹蛋白）被认为可能参与肿瘤的发生发展，是近年来肿瘤转移的研究热点，但Ezrin与结直肠癌发生发展的关系尚不明确。本研究探讨Ezrin在散发性结直肠癌中的表达情况及其临床病理意义。方法：应用EnVision免疫组织化学的方法检测132例散发性结直肠癌及43例癌旁正常肠粘膜中Ezrin的表达情况，并对其有无转移（转移组74例，未转移组58例）进行分组比较。结果：①Ezrin在结直肠癌中的阳性率（79．5％）显著高于癌旁正常肠粘膜的阳性率（11．6％）（P〈0．001）；②Ezrin总阳性率在转移组（86．5％）高于未转移组（70．7％）（P=0．026），其中在膜的表达率转移组（31．1％）显著高于未转移组（6．9％）（P〈0．001）；③Ezrin在结直肠癌中的表达与年龄、性别、肿瘤大小、发生部位、分化程度、浸润深度等临床病理参数均无关（P〉0．05）。结论：Ezrin的表达增高与结直肠癌转移密切相关，其从胞质表达到胞膜表达在肿瘤细胞转移过程中可能起着至关重要的作用，并可作为临床判断散发性结直肠癌转移及预后等生物学行为的重要参考指标。     

埃兹蛋白与肿瘤转移

埃兹（Ezrin）蛋白是埃兹蛋白、根蛋白、膜突蛋白（ezrin—radixin—moesin,ERM）家族重要成员之一,连接于细胞膜与细胞骨架之间,在维持细胞的形状、极性、运动以及信号转导方面发挥着重要作用。近年研究发现,埃兹蛋白在多数肿瘤细胞中异常高表达,在肿瘤癌变、肿瘤细胞浸润和转移中起重要作用。     

埃兹蛋白与肿瘤转移相关信号通路的研究进展

埃兹蛋白（Ezrin）不仅参与细胞形态的维持、细胞运动及黏附过程,而且参与肿瘤侵袭和转移的多个环节。Ezrin蛋白在肿瘤转移中参与多个肿瘤相关信号通路如Rho介导的信号转导通路、肝细胞生长因子（HGF）通路、Fas介导的细胞凋亡信号通路、磷脂酰肌醇-3激酶（P13K）-蛋白激酶C（Akt）通路等,并在其中发挥不同的调节作用。     

Ezrin与骨巨细胞瘤侵袭转移机制的关系

0 引言 Ezrin蛋白又称细胞绒毛蛋白(cytovillin),是一种胞质内细胞骨架蛋白,在胞质中起交叉连接胞膜与肌动蛋白骨架的作用,能够影响细胞的迁移和形态发生,调节细胞黏附,参与细胞信号转导和细胞凋亡.Ezrin在许多肿瘤组织中都存在异常表达[1],在肿瘤的浸润和转移机制中发挥重要作用.     

埃兹蛋白相关信号通路与肿瘤侵袭转移

埃兹蛋白(Ezrin)是一种重要的膜-细胞骨架连接分子,在骨肉瘤、乳腺癌等常见的恶性肿瘤中异常表达,并与肿瘤侵袭转移和预后有关,其作用机制复杂,根据组织细胞类型不同,涉及黏附分子信号途径、Rho、Akt等多条肿瘤相关的信号途径.因此,研究埃兹蛋白相关的肿瘤信号转导对认识肿瘤的进展有重要意义,埃兹蛋白可能成为新的肿瘤治疗...     

ezrin和E-cadherin在非小细胞肺癌中的表达及意义

背景与目的 有研究表明埃兹蛋白(ezrin)可与上皮钙黏素(E-cadherin)相互作用,参与肿瘤细胞的转移过程.本研究的目的是利用组织芯片技术探讨ezrin和E-cadherin在非小细胞肺癌(NSCLC)组织和淋巴结转移灶中的表达及其意义.方法 应用免疫组织化学LSAB法检测25例良性病变肺组织、287例NSCLC原发灶及120例淋巴结转移灶中ezrin和E-cadherin蛋白的表达.结果 NSCLC原发灶及淋巴结转移灶中ezrin过度表达率分别为57.8%(166/287)和83.3%(100/120),E-cadherin异常表达率分别为82.6%(237/287)和98.3%(118/120),差异均有统计学意义(P=0.000).ezrin过度表达率与病理分级(P=0.005)、转移(P=0.032)有密切关系.E-cadherin异常表达率与病理分级(P=0.024)、转移(P=0.015)、TNM分期(P=0.037)有密切关系.ezrin与E-cadherin表达呈负相关(P=0.029).COX多因素分析显示病理分级、转移、TNM分期、ezrin表达和E-cadherin表达是影响肺癌患者预后的危险因素(P＜0.05).结论 ezrin和E-cadherin可能与肺癌的转移有关;二者有可能作为NSCLC患者临床预后判断的指标.     

Roles of ezrin in the growth and invasiveness of esophageal squamous carcinoma cells

Ezrin, which crosslinks the cytoskeleton and plasma membrane, is involved in the growth and metastatic potential of cancer cells. Ezrin expression in esophageal squamous cell carcinoma (ESCC) was described recently, but its roles and the underlying mechanism(s) remain unclear. In our study, we first showed that ezrin in ESCC cell is expressed in the nucleus as well as in the cytoplasm and plasma membrane. Then, by using RNAi, we revealed that interference of ezrin expression suppressed the growth, adhesion and invasiveness of ESCC cells. Tumorigenesis experiments revealed that ezrin may directly regulate tumor formation in vivo. To explore the molecular mechanisms through which ezrin contributes to the proliferation and invasiveness of ESCC cells, we used cDNA microarrays to analyze ezrin knockdown cells and the control cells; of 39,000 genes examined, 297 were differentially expressed upon ezrin knockdown, including some proliferation‐ and invasiveness‐related genes such as ATF3, CTGF and CYR61. Furthermore, pathway analysis showed that ezrin knockdown led to decreased activation of the TGF‐β and MAPK pathways, and ezrin‐mediated cell invasiveness alteration was dependent on the activation of these pathways. Finally, immunohistochemical staining on 80 ESCC specimens and 50 normal esophageal mucosae revealed that the expression levels of 3 altered genes involved in the regulation of cell proliferation and tumor metastasis, including CTGF, CYR61 and ATF3, were altered in ESCCs, and their expression pattern correlated with ezrin expression. Taken together, we propose that ezrin might function in the growth and invasiveness of ESCC cells through the MAPK and TGF‐β pathways. © 2008 Wiley‐Liss, Inc.     

Abnormal ezrin localization is associated with clinicopathological features in invasive breast carcinomas

Summary The membrane-cytoskeleton crosslinker ezrin is associated with malignant progression and metastasis in human neoplasias. To study the role of ezrin in breast cancer, we first assessed ezrin expression in a panel of breast cancer cell lines by western blot and confocal microscopy. Western blot revealed no differences in total ezrin levels among these breast cell lines. However, immunofluorescence staining revealed that Estrogen receptor (ER)-positive, noninvasive and nontumorigenic cell lines concentrated ezrin at the apical surface, whereas invasive cell lines localized ezrin in motile structures (membrane ruffles and filopodia) but also had more diffuse cytoplasmic staining. We next studied ezrin expression in 509 breast carcinomas using tissue microarrays. Immunohistochemical staining for ezrin, p53, Ki-67, phospho-Akt, HER2, and hormonal receptors was performed. Ezrin staining in normal breast epithelium localized at the apical, but not lateral, cell surface, whereas, in most breast tumor cases (331, 70.3%), it localized in the cytoplasm. Complete membranous staining occurred in 89 (18.9%) samples, and apical staining was seen in 51 (10.8%) cases. There were significant positive associations between cytoplasmic ezrin localization and adverse tumor characteristics such as high grade, high level of Ki-67 expression, hormonal-receptor negativity, and lymph-node metastases. Apical ezrin staining was associated with favorable clinicopathological features and node-negative tumors. Membranous ezrin staining was associated with high grade, strong HER2 and p-Akt expression. In conclusion, the switch of ezrin localization from the apical membrane to either the complete membrane or to the cytoplasm is correlated with dedifferentiation and adverse features in invasive breast tumors and cancer cell lines.     

Ezrin在肺癌中的表达及临床意义

背景与目的Ezrin蛋白为膜细胞骨架连接蛋白,近年来研究发现ezrin蛋白在多种肿瘤的发展、浸润和转移过程中扮演重要角色。本研究目的是探讨ezrin在肺癌组织及肺癌细胞系中的作用及其临床意义。方法采用免疫组化二步法检测75例肺癌及16例正常肺组织标本中ezrin蛋白的表达,结合肺癌的临床病理特点进行分析。同时应用RT-PCR及激光扫描共聚焦显微镜检测肺癌细胞系的ezrin基因及蛋白水平的表达情况。结果肺癌组织中ezrin的阳性表达率(77.3%)较正常肺组织(100%)有所降低,两者比较差异有统计学意义(P<0.05)。ezrin表达下降与肺癌患者性别、年龄、肿瘤大小、病理类型、组织分化程度、临床分期等无关,与有无区域淋巴结及远处转移有关。另外,ezrin表达在肺癌有从胞膜向胞浆移位倾向,这与体外实验结果一致。结论肺癌组织及肺癌细胞系中ezrin的表达下降,其从胞膜向胞浆的移位可能参与肺癌的发生发展。     

散发性结直肠癌组织中ezrin mRNA的表达及临床意义

目的研究散发性结直肠癌（SCRC）组织中ezrin mRNA的表达，探讨其在SCRC发生发展中的作用以及与ezrin蛋白表达部位、临床病理参数之间的关系。方法运用TaqMan实时逆转录-聚合酶链反应（real—time RT—PCR）技术检测132例SCRC患者的肿瘤组织及43例患者的癌旁正常组织中ezrinmRNA的表达；免疫组化法检测相应组织中ezrin蛋白的表达。结果SCRC组织中ezrinmRNA含量和ezrin蛋白表达阳性率均显著高于癌旁正常组织（P〈0．05）；转移组ezrinmRNA含量和ezrin蛋白表达阳性率均高于未转移组（P〈0．05）。转移组胞膜为主型ezrin蛋白表达阳性率（31．1％）显著高于未转移组（6．9％，P=0．0006）；转移组胞浆为主型ezrin蛋白表达阳性率（55．4％）与未转移组（63．8％）的差异无统计学意义（P〉0．05）；胞膜为主型组ezrinmRNA含量与胞浆为主型组的差异无统计学意义（P〉0．05）。年龄〈50岁组ezrinmRNA含量高于年龄≥50岁组（P=0．016）；右半结肠组胞膜为主型ezrin蛋白表达阳性率显著高于左半结肠和直肠（P=0．0003），左半结肠组胞浆为主型ezrin蛋白表达阳性率显著高于右半结肠和直肠（P=0．004）。ezrinmRNA、ezrin蛋自在SCRC中的表达与性别、肿瘤大小、侵袭程度、分化程度均无关（P〉0．05）。结论ezrinmRNA和ezrin蛋白表达的增高与SCRC的发生发展密切相关；ezrin蛋白表达从胞浆到胞膜的移位在肿瘤转移中可能起着重要作用；ezrinmRNA含量可能与患者年龄相关，ezrin表达部位可能与SCRC发生部位相关。ezrinmRNA、ezrin蛋白水平及表达部位可能成为临床判断SCRC预后的重要参考指标。     

Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells

Ezrin is a multifunctional protein that connects the actin cytoskeleton to the extracellular matrix through transmembrane proteins. High ezrin expression is associated with lung metastasis and poor survival in cancer. We screened small molecule libraries for compounds that directly interact with ezrin protein using surface plasmon resonance to identify lead compounds. The secondary functional assays used for lead compound selection included ezrin phosphorylation as measured by immunoprecipitation and in vitro kinase assays, actin binding, chemotaxis, invasion into an endothelial cell monolayer, zebrafish and Xenopus embryonic development, mouse lung organ culture and an in vivo lung metastasis model. Two molecules, NSC305787 and NSC668394, that directly bind to ezrin with low micromolar affinity were selected based on inhibition of ezrin function in multiple assays. They inhibited ezrin phosphorylation, ezrin-actin interaction and ezrin-mediated motility of osteosarcoma (OS) cells in culture. NSC305787 mimicked the ezrin morpholino phenotype, and NSC668394 caused a unique developmental defect consistent with reduced cell motility in zebrafish. Following tail vein injection of OS cells into mice, both molecules inhibited lung metastasis of ezrin-sensitive cells, but not ezrin-resistant cells. The small molecule inhibitors NSC305787 and NSC668394 demonstrate a novel targeted therapy that directly inhibits ezrin protein as an approach to prevent tumor metastasis.     

Ezrin蛋白在肿瘤转移中的作用及机制研究

肿瘤转移是肿瘤恶化及死亡的主要原因,近年来研究发现,许多microRNA(miR)、蛋白分子、细胞信号转导通路等均可介导肿瘤迁移侵袭.Ezrin蛋白又称细胞绒毛蛋白,属埃兹蛋白/根蛋白/膜突蛋白(Ezrin/Radixin/Moesin,ERM)家族最早发现的一员,广泛分布于人体细胞内,是细胞骨架与细胞膜之间的连接蛋白...     

Osteosarcoma metastasis: prospective role of ezrin

Osteosarcoma is the most commonly diagnosed primary malignant bone tumor, with similar global incidence rate across childhood and adolescence. Patients with localized disease have a 5-year survival period of 80 %; however, the prognosis is poor in those with metastatic osteosarcoma. The origin of the primary tumor is most frequently the metaphyseal (actively growing) regions of the distal femur, proximal tibia, and proximal humerus, although the tumor can develop in any bone, and the most likely sites for metastasis are the lungs and bone. Ezrin is a member of the ezrin-radixin-moesin (ERM) family of proteins that functions as a cross-linker between the actin cytoskeleton and the plasma membrane, and ezrin also plays a positive role in maintaining cell shape and polarity and facilitates membrane-trafficking pathways, cell migration, cell signaling, growth regulation, and differentiation. There is strong evidence to suggest that ezrin is necessary for osteosarcoma metastasis. The objective of the current review is to summarize the know-how about metastatic progression in osteosarcoma, with a focus on ezrin. Despite the promise that preliminary studies on ezrin have shown, there is a great need to further analyze the role of ezrin in osteosarcoma metastasis and to determine its usefulness as a biomarker for the disease.     

Ezrin pAkt在肺癌组织中的表达及相关性研究*

目的:探讨肺癌组织中Ezrin 与pAkt 表达的临床病理学意义及二者相关关系。方法:采用免疫组化二步法检测75例肺癌及16例正常肺组织中Ezrin与pAkt 的表达,并分析两种蛋白表达与临床病理特征的关系以及二者的相关性。结果:1）Ezrin蛋白在肺癌组织中阳性表达率（77.3%）低于正常肺组织（100%）,二者比较差异具有统计学意义（χ2=4.460,P=0.036）;Ezrin蛋白表达水平与肺癌患者年龄、性别、吸烟史、原发肿瘤大小,病理类型、分化程度等均无关,与有无区域淋巴结转移及远处转移有关。2）pAkt 蛋白在正常肺组织中全部阴性表达,而在肺癌组织中阳性表达率为68.0% ,二者比较差异具有统计学意义（χ2=6.954,P=0.005）。 pAkt 蛋白表达水平与肺癌患者年龄、性别、吸烟史、原发肿瘤大小、病理类型、有无区域淋巴结转移及远处转移等无关与分化程度及肺癌分期有关。3）使用Spearman 相关分析显示Ezrin与pAkt 的表达无显著相关（r=-0.137,P=0.236）。 结论:Ezrin在肿瘤肺癌组织表达下调,在肺癌的侵袭转移过程中可能发挥重要作用,有可能成为肿瘤治疗的良好靶点。pAkt 在肺癌组织表达上调,可能在肺癌晚期发挥更强的作用。Ezrin低表达的肿瘤,Ezrin可能通过pAkt 以外路径参与肿瘤的进展,也可能在pAkt 上游或间接通过pAkt 路径发挥作用。