Ezrin在肿瘤转移中的作用

如何预防和控制肿瘤转移是提高肿瘤患者生存率的关键。Ezrin,作为连接膜和细胞骨架的蛋白,通过组成膜细胞骨架相关复合体和形成特殊膜结构对细胞活动进行调节,如细胞存活、粘附和运动,而细胞的这一切活动都与肿瘤的发生、发展和转移有重要关系。Ezrin的高表达可以促进肿瘤细胞的转移。本文就Ezrin在肿瘤转移中的作用及其可能的分子机制作一综述。     

Ezrin蛋白与肿瘤转移

众所周知,转移是恶性肿瘤患者死亡的主要原因,如何预防和控制肿瘤转移是提高肿瘤患者生存率的关键,Ezrin作为连接使者,将细胞的膜与细胞骨架连接起来,调节诸如细胞存活、黏附和运动等活动,促进肿瘤的发生与发展。Ezrin的高表达促进肿瘤细胞的转移。本文就Ezrin的作用机制作一综述。     

Ezrin与肿瘤发生及发展关系的研究进展

Ezrin是一种膜－细胞骨架连接蛋白,在多种肿瘤中表达上调或亚细胞定位改变,通过与细胞粘附分子相互作用、参与Rho信号传导以及受体酪氨酸激酶信号传导途径等多种机制,参与肿瘤的发生及发展。     

乳腺与女性生殖系统恶性肿瘤中Ezrin的表达及意义

Ezrin是ERM(Ezrin-Radixin-Moesin)蛋白家族成员之一,是一种膜-细胞骨架连接蛋白.上世纪80年代初,Bretscher等学者首次在鸡小肠黏膜细胞刷状缘微绒毛的细胞骨架中发现了Ezrin蛋白.最初的10年间并未受到重视,只认定为细胞骨架的组成成分.2004年,Yu等和Khanna等在Nature Medicine同一期分别发表了Ezrin与小儿横纹肌肉瘤,Ezrin与小儿骨肉瘤关系的论文后才引起众多研究者的关注.近来越来越多的研究表明Ezrin在细胞形态形成、运动、黏附、细胞信号转导等多项细胞活动中发挥重要作用,而这些细胞活动与肿瘤的发生、发展及转移等密切相关.本文重点对其在乳腺与女性生殖系统恶性肿瘤中的表达及意义作一综述.     

Ezrin在炎症性疾病中的研究进展北大核心CSCD

Ezrin属于ezrin-radixin-moesin(ERM)家族成员,是连接质膜(PM)和细胞骨架的连接蛋白,在介导肿瘤的侵袭和转移过程中发挥主要作用。近年研究表明Ezrin参与调节免疫细胞功能,在T细胞中,Ezrin调节免疫突触的形成,通过控制B细胞信号传导和蛋白转运调节体液免疫。此外,Ezrin还可将囊性纤维化跨膜电导调节剂(CFTR)与TLR4信号联系起来,协调巨噬细胞的抗菌免疫反应,与L-选择素结合促使中性粒细胞功能转换和黏附。以上作用表明Ezrin在炎症性疾病中发挥作用。本文主要就Ezrin在炎症及炎症性疾病中的最新研究进展进行总结。     

Ezrin蛋白在软骨肉瘤中的表达及其意义

目的 探讨Ezrin蛋白在软骨肉瘤中的表达状况及其与相关临床病理因素的关系,以及可能的临床意义.方法 采用鼠抗人Ezrin单克隆抗体和免疫组化MaxVision法,检测42例软骨肉瘤和20例软骨瘤中Ezrin蛋白的表达.结果 (1)Ezrin在软骨肉瘤组和软骨瘤组中的阳性表达率分别为61.90%和25.00%(P<0.05).(2)Ezrin在普通型、透明细胞型和去分化型软骨肉瘤中的阳性表达率分别为60.61%、50%、71.43%.(3)Ezrin在普通型软骨肉瘤的Ⅰ-Ⅲ级中的阳性表达率分别为25%、64.29%、81.82%(P<0.05).结论 膜细胞骨架连接蛋白Ezrin在软骨肉瘤中高表达,提示可能参与软骨肉瘤的侵袭和转移;检测Ezrin蛋白可以辅助鉴别诊断软骨肉瘤与增生活跃之软骨瘤.     

siRNA干扰Ezrin基因对人脐静脉内皮细胞增殖的影响

目的探讨细胞膜与细胞骨架连接蛋白埃兹（Ezrin）对人脐静脉内皮细胞生长和转移能力的影响。方法培养人脐静脉内皮细胞,选择3对小干扰RNA（siRNA）序列下调Ezrin的表达,实时定量PCR和Western-blot印迹法分别检测Ezrin mRNA和蛋白表达水平的变化。BrdU ELISA法检测Ezrin siRNA干扰后细胞增殖能力的改变,伤口愈合实验检测Ezrin siRNA干扰后细胞迁移能力的变化,流式细胞术检测Ezrin siRNA干扰后细胞凋亡能力。结果实时定量PCR和Western-blot印迹结果显示,siRNA干扰后Ezrin的基因和蛋白水平均显著下调;BrdU法显示Ezrin siRNA干扰后细胞生长速率降低（P〈0.05）,划痕实验显示Ezrin siRNA干扰后细胞迁移率降低（P〈0.05）,流式细胞仪检测显示Ezrin siRNA干扰后细胞凋亡率升高。结论 Ezrin蛋白可影响脐静脉内皮细胞的增殖和迁移能力,推测其在血管功能和肿瘤研究中可能具有重要意义。     

Ezrin蛋白过表达对胰腺癌细胞系Panc-1生物学行为的影响

目的探讨Ezrin过表达对胰腺癌细胞系Panc-1生物学行为的影响。方法用过表达载体pcb6-Ezrin稳定转染Panc-1细胞,并用流式细胞仪检测细胞周期,CCK-8法检测细胞生长曲线,扫描电镜观察细胞表面形态及表面突起的变化,用未包被及包被Matrigel胶的Transwell小室分别检测细胞的运动和侵袭能力,并用免疫印迹法检测信号相关蛋白Erk1/2的变化。结果过表达Ezrin后其蛋白的表达明显升高,Panc-1细胞表面的细胞突起、微绒毛数量明显增加,运动及侵袭能力也明显增加,但对细胞的体外增殖和细胞周期无明显的影响。Ezrin的过表达能够激活Erk1/2的表达。结论 Ezrin蛋白对胰腺癌细胞的细胞突起、表面微绒毛的形成、细胞骨架及细胞的运动和侵袭发挥着重要的作用。因此,Ezrin可能在胰腺癌的进展中发挥着重要的作用,Erk1/2信号转导途径在这一过程中发挥着重要的作用。     

非小细胞肺癌患者埃兹蛋白、血管抑制蛋白1的表达与微血管密度的相关性研究

目的探讨非小细胞肺癌患者(non-small cell lung cancer,NSCLC)埃兹蛋白(Ezrin)和血管抑制蛋白1(vasohibin-1,VASH-1)的表达与肿瘤微血管密度(MVD)的相关性。方法选取2016年1月至2017年12月期间我院收治经手术切除的110例NSCLC患者临床资料进行研究,作为NSCLC组。选取同期肺良性病变组织标本80例作为对照组。比较两组间基本资料、Ezrin、VASH-1表达及MVD,并进行Spearman相关分析。结果 NSCLC组Ezrin、VASH-1阳性表达率(51. 8%、70.9%)均显著高于对照组(15.0%、16.3%)(P<0.05)。Ezrin和VASH-1阳性表达与性别、年龄、吸烟史、病理类型、分化程度、肿瘤直径均无关(P>0. 05),与TNM分期、淋巴结转移有关(P <0.05)。MVD与TNM分期、分化程度、淋巴结转移有关(P<0.05)。Ezrin、VASH-1及Ezrin+VASH-1阳性表达组的MVD值均明显高于Ezrin、VASH-1及Ezrin+VASH-1阴性表达组(P <0. 05),且以Ezrin+VASH-1均阳性表达组的MVD值最高(P <0.05)。经过Spearman相关性分析,Ezrin、VASH-1阳性表达与NSCLC患者MVD值呈正相关(P<0.05)。结论 Ezrin、VASH-1可能参与NSCLC患者肿瘤血管的形成机制,进而促进肺癌的生长、侵袭和转移。     

胃肠道间质瘤中Ezrin过表达的临床病理学意义

目的应用组织芯片技术检测Ezrin在胃肠道间质瘤(gastrointe stinals tromal tumors,GIST)中的过表达情况,并分析其临床病理学意义。方法采用免疫组化及原位杂交法检测组织芯片中42例GIST组织Ezrin蛋白和mRNA的过表达情况,并进行数据统计分析。结果在42例GIST组织中,21例有Ezrin蛋白的过表达(50%),16例有Ezrin mRNA的过表达(38%);Ezrin蛋白和mRNA在发生于非胃部位的GIST及出现浸润转移的患者中过表达更明显(P0.05);此外Ezrin蛋白的过表达在肿瘤大小分组及恶性潜能分级、临床分期中有差异,差异有统计学意义(P0.05);Ezrin蛋白和mRNA表达呈正相关(r=0.392,P0.05)。结论 Ezrin可能参与了GIST的浸润转移过程,并可能成为预测GIST转移的重要指标;免疫组化检测Ezrin蛋白的过表达可以作为评估GIST恶性潜能及肿瘤进展的指标。     

Ezrin in osteosarcoma: comparison between conventional high-grade and central low-grade osteosarcoma

Ezrin is a cytoskeleton linker protein that is actively involved in the regulation of growth and metastatic capacity of cancer cells. Recently, it has been demonstrated that a significant correlation exists between high ezrin expression levels and the poor outcome of pediatric osteosarcoma patients. The expression of ezrin was compared in conventional high-grade and central low-grade osteosarcoma lesions to investigate the role of ezrin overexpression in the metastasis of osteosarcoma. We compared the expression levels of the ezrin protein in 32 cases of high-grade osteosarcomas and 21 cases of low-grade osteosarcomas using immunohistochemistry. Ezrin protein expression levels were examined in three different human osteosarcoma cell lines by Western blotting. In addition, the mRNA expression levels of ezrin in these osteosarcoma cell lines and control fibroblasts were evaluated by real-time quantitative PCR. Ezrin immunoreactivity was present in 43.7% of high-grade osteosarcoma specimens. All low-grade osteosarcomas were negative for ezrin. The expression of ezrin was detected by Western blotting in all three osteosarcoma cell lines. The tested osteosarcoma cell lines showed marked amplification of ezrin mRNA compared to control cells. Taken together, ezrin appears to play a role in the progression of tumors, such as the metastasis of osteosarcoma. However, further data are needed before ezrin can be considered in clinical decision-making about osteosarcoma patients.     

Ezrin and BCAR1/p130Cas mediate breast cancer growth as 3-D spheroids

CAS proteins and Ezrin, Radixin, Moesin (ERM) family members act as intracellular scaffolds and are involved in interactions with the cytoskeleton, respectively. Both protein families have previously been associated with metastasis and poor prognosis in cancer. Our group recently reported on the overexpression of EZR/VIL2 and BCAR1 and their protein products in breast carcinoma effusions compared to primary breast carcinoma. In the present study, the role of these two proteins was studied in semi-normal MCF10A cells and metastatic MDA-MB-231 breast carcinoma cells cultured in tri-dimensional (3-D) conditions that were hypothesized to reproduce the in vivo conditions of breast cancer metastasis. MCF10A cells formed spheroid-shaped colonies without any Matrigel invasion, while MDA-MB-231 cells displayed an invasive phenotype and showed satellite projections that bridged multiple cell colonies in 3-D culture. E-cadherin was expressed in MCF10A, but not in MDA-MB-231 cells. The temporal expression of ezrin and BCAR1/p130Cas at the mRNA and protein level differed in the two cell lines upon 3-D culturing on Matrigel. Upregulation of BCAR1/p130cas was observed in the transition of MDA-MB-231 from attached to detached culture. Silencing of Ezrin and p130Cas in MDA-MB-231 cells by short hairpin RNA resulted in decreased invasive potential, and p130Cas silencing further resulted in smaller spheroid/colony formation. Our data show that MCF10A and MDA-MB-231 cells differ in their ability to form spheroids, in expression of E-cadherin and in the expression of Ezrin and BCAR1/p130Cas in 3-D cultures on Matrigel, suggesting a role in tumor progression in breast carcinoma.     

Merlin/ERM proteins establish cortical asymmetry and centrosome position

The ability to generate asymmetry at the cell cortex underlies cell polarization and asymmetric cell division. Here we demonstrate a novel role for the tumor suppressor Merlin and closely related ERM proteins (Ezrin, Radixin, and Moesin) in generating cortical asymmetry in the absence of external cues. Our data reveal that Merlin functions to restrict the cortical distribution of the actin regulator Ezrin, which in turn positions the interphase centrosome in single epithelial cells and three-dimensional organotypic cultures. In the absence of Merlin, ectopic cortical Ezrin yields mispositioned centrosomes, misoriented spindles, and aberrant epithelial architecture. Furthermore, in tumor cells with centrosome amplification, the failure to restrict cortical Ezrin abolishes centrosome clustering, yielding multipolar mitoses. These data uncover fundamental roles for Merlin/ERM proteins in spatiotemporally organizing the cell cortex and suggest that Merlin''s role in restricting cortical Ezrin may contribute to tumorigenesis by disrupting cell polarity, spindle orientation, and, potentially, genome stability.     

Ezrin in primary cutaneous melanoma.

Ezrin is a member of the ezrin-radixin-moesin family of proteins that link the actin-containing cytoskeleton to the plasma membrane. Ezrin is also connected to signaling molecules involved in the regulation of cell survival, proliferation and migration. Here, we examined the expression of ezrin in 95 primary cutaneous melanomas and correlated ezrin expression with conventional prognostic factors and biomarkers. From 12 patients metastatic tissue samples were also examined. In addition to ezrin staining, Mib-1 proliferation antigen, p53 and Bcl-2 were evaluated. Ezrin immunoreactivity was seen in most tumors; only 19 (20%) melanomas were negative. A total of 48 (51%) tumors had weak immunoreactivity and 28 (29%) strong immunoreactivity. The intensity of ezrin immunoreactivity was associated with tumor thickness (Breslow, P=0.0008) and with tumor invasion level (Clark, P=0.004), thicker tumors having stronger immunoreactivity. Also, there was a correlation between higher Mib-1 index in tumors and strong ezrin expression. All metastatic samples (n=12) showed positive ezrin immunoreactivity. In univariate analysis of survival, patients (n=76) with positive ezrin immunoreactivity had worse clinical disease behavior than those (n=19) without ezrin immunoreactivity, but the difference was not significant (P=0.19). In multivariate analysis of survival, the ezrin immunoreactivity was not a significant marker. The results indicate that ezrin is expressed in most primary melanomas of the skin and in all metastatic tumors. Ezrin expression correlates with tumor thickness and level of invasion suggesting an association between ezrin expression and tumor progression.     

Ezrin-dependent regulation of the actin cytoskeleton by beta-dystroglycan

Dystroglycan is part of an adhesion receptor complex linking the extracellular matrix to the actin cytoskeleton. Previous studies have implicated dystroglycan in basement membrane formation and as a crucial link between dystrophin and laminin in muscle. We report here a further novel function for dystroglycan which appears to be in addition to its role as an adhesion molecule. beta-dystroglycan has been localized to microvilli structures in a number of cell types where it associates with the cytoskeletal adaptor ezrin, through which it is able to modulate the actin cytoskeleton and induce peripheral filopodia and microvilli. Ezrin is able to interact with dystroglycan through a cluster of basic residues in the juxtamembrane region of dystroglycan, and mutation of these residues both prevents ezrin binding and the induction of actin-rich surface protrusions. These studies reveal novel functions and additional signalling roles for dystroglycan, raising the possibility of new avenues for therapeutic intervention in diseases such as Duchenne muscular dystrophy.     

Ezrin,actin and cytoskeleton in apoptosis of esophageal epithelial cells induced by arsenic trioxide

Ezrin is a key protein in membrane-cytoskeleton interaction. Expression of ezrin in actin-rich cell surfaces may play a role in the modulation of cell shape and adhesion. The aim of this study was to detect ezrin, actin and cytoskeleton and to explore their relationship in the apoptosis of esophageal epithelial cells (SHEE) induced by arsenic trioxide (As2O3). The SHEE is an immortalized human fetal esophageal epithelial cell line, and the cells were treated by administering 5, 10 and 20 micromol of As2O3. the proliferation and apoptosis of SHEE cells were examined by flow cytometry with propidium iodide staining. Ezrin expression was detected by immunocytochemistry and Western blotting. Actin filament was stained by FITC-labeled phalloidin and detected quantitatively by fluorescent microscopy. Cell morphology and microfilaments were examined by electron microscopy. The results revealed that As2O3 induced an inhibition of proliferation and the promotion of apoptosis in SHEE cells. The ezrin, actin and cytoskeleton were decreased after As2O3 treatment and the cellular morphology of apoptosis developed. Our results suggested that the morphological changes of arsenic-induced apoptosis of human esophageal epithelial cells were initiated by ezrin and actin-cytoskeletal aberrance.     

Ezrin、MMP-2及TIMP-2在子宫颈癌中的表达与侵袭转移的关系

目的 通过观察埃兹蛋白(Ezrin)、金属蛋白酶-2(MMP-2)及金属蛋白细胞组织抑制因子-2(TIMP-2)蛋白水平在子宫颈癌组织中的表达情况,探讨它们与子宫颈癌侵袭转移的关系. 方法 采用免疫组织化学方法对40例子宫颈鳞癌,20例腺癌,29例子宫颈上皮内瘤样病变和16例正常子宫颈组织进行标记及分析. 结果 Ezrin、MMP-2及TIMP-2蛋白主要表达在子宫颈鳞癌、腺癌、上皮内瘤变的异型细胞质内,各实验组中的表达量与正常组比,差异均有统计学意义(P<0.01).Ezrin和MMP-2蛋白在有淋巴结转移组中的表达量较无淋巴结转移组明显高(P<0.01), 而TIMP-2蛋白水平的表达结果却相反.同时发现Ezrin、MMP-2及TIMP-2蛋白水平在宫颈病变组织表达有正相关性. 结论 Ezrin、MMP-2及TIMP-2 蛋白在子宫颈鳞癌、腺癌的表达量较对照组高. Ezrin和MMP-2在有淋巴结转移的子宫颈癌中高表达,而TIMP-2为低表达,提示它们在子宫颈癌的侵袭转移中起重要的作用.Ezrin、MMP-2及TIMP-2蛋白水平在宫颈病变组织表达有正相关性,这三者在子宫颈癌的侵袭转移中可能起协同作用.