炎症对上皮间质转化的调控机制

炎症在肿瘤发生发展中发挥重要作用.上皮间质转化（EMT）是肿瘤增殖、侵袭及转移过程中的重要分子机制.越来越多的研究表明,炎症与EMT密切相关.在炎症微环境中,细胞因子和炎症微生物都参与EMT的调控.     

The transition of benign to malignant in epithelial and mesenchymal tumours

Following publication in this journal of a 4 mutation-model of oncogenesis some points of controversy emerged which are discussed. In particular an explanation is offered for the differences in histogenesis of epithelial and non-epithelial tumours. Some clinical features of benign tumours are also clarified.     

恶性间叶肿瘤的间叶-上皮表型转化研究进展

相对于上皮性肿瘤的上皮-间叶表型转化（epithelial to mesenchymal transition,EMT）及间叶-上皮表型转化（mesenchymal to epithelial transition,MET）的研究,恶性间叶性肿瘤中MET相关研究较少。MET在分子水平上反映为上皮性标志物如E-钙粘素E-cadherin的上调和间叶性标志物如波形蛋白Vimentin的下调,其过程涉及始动信号、转录因子调节、表面标志物的改变、信号通路改变等多个环节。本文概述了恶性间叶肿瘤中与MET紧密相关的TGF-β等始动因素、SNAI等关键转录因子、miRNA调节因素对重要细胞信号通路等影响及MET对肿瘤的演进及转归的影响等方面的研究,为针对MET的临床应用奠定基础。      

间叶上皮表型转化在肿瘤发生及演进中的作用

间叶上皮表型转化是指“间叶”向“上皮”细胞表型的可逆性转化,而非不同组织来源细胞间的转变.体内外实验证明,间叶上皮表型转化在恶性肿瘤侵袭和转移中发挥重要作用,现本文就其发展过程、研究现状进行综述.     

与肿瘤转移相关的上皮间质转化信号通路研究进展

恶性肿瘤细胞的侵袭和转移是患者死亡的主要原因,而上皮间质转化（epithelial　mesenchymal　transition,EMT）是肿瘤细胞侵袭和迁移的关键步骤。肿瘤细胞发生上皮间质转化可通过多种信号通路介导产生,深入了解与EMT相关的信号通路,可在信号通路中设立靶点,中止EMT的发生,进而阻止肿瘤侵袭、转移。本文就与肿瘤转移相关的EMT信号通路研究进展作一综述。     

脂肪间充质干细胞分泌的Exosome促进结肠癌细胞系上皮间质转化

目的：研究间充质干细胞（mesenchymal stem cell,MSC）来源的Exosome对结肠癌细胞系HCT8上皮间质转化（epithelial mesenchymal transition,EMT）的影响。方法从人脂肪组织中分离出MSC后,对MSC进行培养并传代,并对MSC的分化能力进行鉴定。在人脂肪来源的MSC中提取Exosome后,用透射电子显微镜观察并拍照,并用蛋白质印迹法检测其抗原表达情况。在HCT8培养体系中加入人脂肪来源的MSC分泌的Exosome ,定量PCR和蛋白质印迹法检测上皮和间质转化相关标志物的表达,细胞侵袭和迁移实验检测人脂肪来源的MSC分泌的Exosome对HCT8迁移和侵袭的影响。结果人脂肪来源的MSC具有多系分化能力,人脂肪来源的Exosome直径为40～100 nm ,表达CD63、HSP70和HSP90,下调HCT8上皮相关标志E-cadherin和ZO-1的表达,上调间质相关标志Fibronectin的表达,促进HCT8的迁移和侵袭。结论人脂肪来源的MSC分泌的Exosome可促进结肠癌细胞系HCT8的EMT。     

上皮间质转化与肿瘤干细胞的关系

目前越来越多的研究显示上皮间质转化(EMT)参与了肿瘤干细胞的形成以及肿瘤细胞的浸润、迁移和转移,不仅增强了癌细胞的侵袭和转移能力,还可使细胞获得自我更新等干细胞特性,促进肿瘤干细胞的产生.因此,研究EMT与常见干细胞之间的关系对于寻找控制肿瘤侵袭和转移的有效途径有非常重要的意义,亦可为肿瘤的治疗提供新的靶点.     

上皮间质细胞转化的分子机制及其在肿瘤转移中的作用

上皮细胞间质转化(epithelialmesenchymal transition,EMT)是具有极性的上皮细胞转换成为具有移行能力的间质细胞并获得侵袭和迁移能力的过程,它存在于人体多个生理和病理过程中。EMT与肿瘤细胞的侵袭和转移有着密切的关系。E钙黏蛋白（Ecadherin,Ecad）用于维持正常细胞间连接的稳定性,其表达水平与EMT的发生以及肿瘤的侵袭能力呈负相关,是EMT的关键分子。转录因子如锌指蛋白Snaill、SIP1等可下调Ecad的表达而促进EMT;Slug、Twist也可诱导EMT的发生。多种生长因子如HGF、TGFβ等可通过细胞内多个不同信号转导途径调控EMT的发生,促进肿瘤的转移。细胞外基质（ECM）对EMT的发生起着重要的作用,整合素介导的细胞与基质之间的黏附作用改变可引起EMT,基质金属蛋白酶（MMPs）通过影响ECM诱导EMT的发生。不同的MicroRNA如microRNA 10b或microRNA 200对EMT发生有促进或抑制作用。发生EMT的肿瘤细胞可获得某些类似于干细胞的能力如自我更新等,而胚胎干细胞在分化时伴有类似EMT过程的分子生物学事件。EMT的分子生物学过程、信号转导通路还有待更深入地研究完善。     

肿瘤细胞上皮间质转化表观遗传调控机制的研究进展

上皮间质转化(epithelial to mesenchymal transition,EMT)指上皮细胞向间质细胞转变的现象,其在组织损伤修复等生命过程中是必需的.研究发现,EMT在肿瘤细胞侵袭和转移中发挥至关重要的作用,EMT不仅使肿瘤细胞获得迁移、侵袭、转移能力,同时还与肿瘤细胞抑制衰老和凋亡、抵抗放化疗和形成肿瘤干细胞(cancer stem cells,CSCs)密切相关,因此抑制EMT成为抑制肿瘤转移的新策略.肿瘤细胞EMT受到表观遗传的复杂调控,DNA甲基化、组蛋白修饰、非编码RNA在EMT发生中扮演十分重要的角色,因此肿瘤细胞EMT的表观遗传调控已经成为国内外的研究热点.本文就肿瘤细胞EMT表观遗传调控机制的研究进展予以综述.     

Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer

BackgroundThe present study is aimed to identify genetic pathways correlated with chemoresistance in epithelial ovarian cancer (EOC).MethodsWe compared the molecular profiles of 23 tumour biopsies of stage III–IV (training set) at primary surgery, before chemotherapy, to the profile from the same patients at second surgery, after several lines of platinum (Pt)-based chemotherapy when the tumours were resistant. In the hypothesis that identified markers were related to Pt-resistance and to prognosis, we validated this signature in 52 EOC taken at primary surgery (validation set) selected to be either very sensitive to the first line therapy, i.e. not relapsing before one year from the end of therapy, or resistant, i.e. relapsing within 6 months from the end of therapy.ResultsIn the training set, we identified a resistance signature indicative of the activation of epithelial to mesenchymal transition (EMT) by transforming growth factor (TGF)-beta pathway. We then validated this signature in 52 EOC taken at primary surgery (validation set). Some genes involved in EMT, such as BMP and activin membrane-bound inhibitor (BAMBI), and mir-141 resulted in association with overall or progression free survival.ConclusionSome genes involved in EMT were associated to overall or progression free survival, suggesting EMT as vital to the resistance mechanisms.     

阿托伐他汀调控上皮间质转化抑制结肠癌细胞生长的机制研究

目的:探讨阿托伐他汀调控上皮间质转化（EMT）对人结肠癌SW480细胞侵袭和迁移的影响。方法:0.1、1、10、100 μmol/L的阿托伐他汀处理SW480细胞24 h、48 h和72 h,MTT检测细胞活力。100 μmol/L的阿托伐他汀处理细胞48 h,Transwell小室检测细胞侵袭能力及迁移能力,Western blotting检测EMT相关蛋白E-cadherin、β-catenin和Twist及PI3K/AKT信号通路PI3K、AKT和p-AKT蛋白表达。结果:随着阿托伐他汀浓度升高,作用时间延长,对SW480细胞活力抑制越明显,各浓度阿托伐他汀组与对照组比较差异具有统计学意义（P<0.05）,同一实验组不同时间点间比较差异具有统计学意义（P<0.05）。与对照组比较,阿托伐他汀组细胞侵袭及迁移能力均明显降低,E-cadherin蛋白表达明显升高,β-catenin、Twist、PI3K和p-AKT蛋白表达明显降低（P<0.05）。结论:阿托伐他汀可抑制结肠癌细胞的侵袭和迁移能力,机制可能与抑制EMT及PI3K/AKT信号通路有关。     

Numb与上皮间质转化关系的研究进展

目的:总结Numb与上皮间质转化(epithelial mesenchymal transitions,EMT)的研究进展,并讨论Numb在EMT中的可能作用机制。方法:应用PubMed及CNKI期刊全文数据库检索系统以"Numb、肿瘤和EMT"等为关键词,检索1990-01-2012-10的相关文献。共检索到英文文献815篇,中文文献285篇。纳入标准:1)以肿瘤中的Numb与EMT的关系;2)Numb在上皮间质转化中的作用机制研究。根据纳入标准分析文献38篇。结果:Numb是参与肿瘤信号转导途径的重要成分,新的研究表明,Numb表达下调或缺失,EMT的发生加剧。作用机制可能是其通过影响肿瘤细胞E-钙黏蛋白的定位、调控Notch等信号通路在肿瘤EMT过程中起关键作用,研究发现,10%的癌组织中伴有Notch1基因变异。通过参与EMT而诱导肿瘤形成和发展可能为Numb影响肿瘤发生、发展的又一重要机制。结论:肿瘤中Numb的表达水平及其相关信号通路在EMT中可能起重要作用,但具体作用方式和机制仍未阐明。     

Relationship between epithelial to mesenchymal transition and chemoresistance of lung cancer

Objective： The aim of this study was to explore the correlation between epithelial to mesenchymal transition （EMT） and chemoresistance of non-small-cell lung cancer （NSCLC）. Methods： In vitro, the drug resistance index of cisplatin resistant lung adenocarcinoma cell line （A549/DDP） was detected by CCK-8 assay; the morphological change between A549/ DDP cells and lung adenocarcinoma cells （A549） was observed by phase contrast microscope; expression of EMT markers （including E-cadherin and vimentin） and resistance protein, excision repair cross-complementing 1 （ERCC1） was detected by immunocytochemistry. The expression of E-cadherin, vimentin and ERCC1 was investigated by immunohistochemistry in 120 cases of NSCLC, half of that were treated with pre-operative neoadjuvant chemotherapy （neoadjuvant chemotherapy group）, and the other underwent surgery alone （simple surgery group）. Results： There was a significant difference between the ICso （half maximal inhibitory concentration） of A549/DDP cells （5.20） and A549 cells （1.88） （P 〈 0.05）, and the drug resistance index of A549/DDP cells was 2.77. Compared with A549 cells, A549/DDP cells increased expression of ERCC1 （P 〈 0.05）. Moreover, A549/DDP cells showed morphological and phenotypic changes consistent with EMT： with spindle-shaped morphology, and decreased expression of E-cadherin and increased expression of vimentin. Immunohistochemistry showed significant positive correlation between the expression of ERCCI and vimentin （r = 0.496, 0.332, P 〈 0.05）, and significant negative correlation between the ERCCI and E-cadherin （r = -0.403, -0.295, P 〈 0.05） in neoadjuvant chemotherapy group and simple surgery group. In addition, compared with simple surgery group, the expression of ERCC1 （P = 0.003） and vimentin （P = 0.004） was significantly increased, and the expression of E-cadherin was decreased in neoadjuvant chemotherapy group （P = 0.032）. Cenclusion： A549/DDP cells acquired cisplatin-resistance and occurred EMT simultaneously; the phenomenon of chemoresistance and EMT was caused more easily in neoadjuvant chemotherapy group. As such, we further confirmed the close correlation between chemoresistance and EMT of NSCLC, and provided theoretical basis for the targeting therapy with EMT regulatory factor for chemoresistant NSCLC patients.     

Ezrin蛋白与大肠癌上皮间质转化及侵袭转移的关系

目的探讨Ezrin蛋白与大肠癌上皮问质转化及其与大肠癌侵袭转移的关系。方法采用免疫组化Maxvision法检测大肠癌组织及正常大肠黏膜上皮组织中Ezrin蛋白、上皮性标志物E—cad和间质性标志物Vimentin的表达以及它们之间的关系。结果Ezrin蛋白过度表达与大肠癌患者的年龄和分化程度有关（P〈0．05）,与癌组织的大小、淋巴转移、部位和性别无关（P〉0．05）。Ezrin蛋白在大肠癌组织的阳性表达率较正常大肠黏膜上皮组织高（73．4％vs15．0％,P〈0．01）。E—cad在大肠癌中的阳性表达率明显低于正常大肠黏膜组织（48．4％vs80．0％,P=0．028）。Vimentin在癌组织中阳性表达率高于正常大肠黏膜组织（20．3％vs0．00％P=0．032）。相关分析表明Ezrin蛋白与E—cad的表达呈负相关,与Vimentin的表达无相关性。结论Ezrin蛋白在蛋白水平与大肠癌上皮问质转化没有直接关系,但在大肠癌侵袭转移过程中发挥重要作用。     

lncRNA-ATB介导的上皮间质转化在胃癌进展中的机制研究

目的 探讨lncRNA-ATB介导的上皮间质转化在胃癌进展中的可能机制。方法 采用生物信息学分析预测lncRNA-ATB的下游结合分子并采用荧光素酶报告基因验证。收集联勤保障部队第九八〇医院2017年1月—2019年12月胃癌及癌旁组织标本56例,采用qRT-PCR分析lncRNA-ATB及下游结合分子在胃癌及癌旁组织中的表达水平及二者之间的相关性,并分析二者与胃癌临床病理特征的相关性;在敲降lncRNA-ATB前后的胃癌BGC-823细胞系中,采用qRT-PCR及Western blot实验验证miR-200a、β-catenin、vimentin、E-cadherin表达水平的变化。结果 生物信息学分析发现lncRNA-ATB与miR-200a有直接结合位点,miR-200a与β-catenin能直接结合并采用荧光素酶报告基因验证。lncRNA-ATB在胃癌组织中较癌旁组织中明显高表达(P＜0.001),miR-200a在胃癌组织中较癌旁组织中明显低表达,差异有统计学意义(P＜0.001)。在胃癌组织中lncRNA-ATB与miR-200a表达水平呈负相关(r=-0.317,P=0.017)。lncRNA-ATB在Ⅲ、Ⅳ期胃癌较Ⅰ、Ⅱ期表达水平明显升高,淋巴结转移阳性组、脉管内癌栓阳性及肿瘤低分化组lncRNA-ATB表达水平更高,差异有统计学意义(P＜0.001)。miR-200a在Ⅲ、Ⅳ期胃癌患者较Ⅰ、Ⅱ期患者表达水平明显降低,淋巴结转移阳性组、脉管内癌栓阳性及肿瘤低分化组miR-200a表达水平明显降低,差异有统计学意义(P＜0.05)。在胃癌BGC-823细胞系中敲降lncRNA-ATB后β-catenin和vimentin表达降低、E-cadherin表达升高,差异有统计学意义(P＜0.05)。结论 lncRNA-ATB通过与miR-200a结合,影响β-catenin的表达促进上皮间质转化进程从而影响胃癌进展。     

Thymic epithelial neoplasia

Primary thymic epithelial neoplasms (PTENs) are uncommon tumors of anterior mediastinum with a broad range of biological characteristics. We retrospectively reviewed 58 consecutive patients with a diagnosis of PTENs that were confirmed pathologically during 28 yr. There were 58 patients, 31 males (53.4%) and 27 females (46.6%), with a mean age of 43.6 +/-13.8 yr (range, 17-73 yr). Twenty-one (36.2%) patients presented at the Masaoka stage I, 13 (22.4%) patient at stage II, 18 (31.0%) patient at stage III, and 6 (10.4%) patients at stage IV. Forty-five (77.7%) patients had myasthenia gravis, 1 (1.7%) immune deficiency, 1 (1.7%) pancytopenia, and 1 (1.7%) nephrotic syndrome. No paraneoplastic syndrome was associated in 10 (17.2%) patients. Complete resection was accomplished in 41 (70.7%) patients, while incomplete resection was performed in 8 (13.8%) patients. In nine (15.5%) patients only biopsy was carried out. Radiotherapy was administered to 19 (32.8%) patients. Eleven (19.0%) out of 58 who presented at advanced stages (at least III) received chemotherapy. Median follow-up period was 59 mo (range, 1-278 mo). During the follow-up period, 17 deaths occurred. Five patients (29.4%) died of tumor-related causes, and the remaining 12 patients died of other causes (cardiovascular diseases [n = 1, 5.9%], sepsis [n = 4, 23.5%], and MG-related respiratory insufficiency [n = 7, 41.2%]). The overall survival rates at 5 yr and 10 yr were 63.9% and 54.2%, respectively. Tumor-related survival rates at 5 yr and 10 yr were 89.0% and 83.2%, respectively. In our series, disease stage, presence or absence of myasthenia gravis, and tumor size did not affect survival (p> 0.05), either. Complete resection of the tumor seems to be the best predictive factor for long-term survival.     

Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition

Background  

Epithelial to mesenchymal transition (EMT), implicated as a mechanism for tumor dissemination, is marked by loss of E-cadherin, disruption of cell adhesion, and induction of cell motility and invasion. In most intraductal breast carcinomas E-cadherin is regulated epigenetically via methylation of the promoter. E-cadherin expression is therefore dynamic and open to modulation by the microenvironment. In addition, it has been observed that metastatic foci commonly appear more differentiated than the primary tumor, suggesting that cancer cells may further undergo a mesenchymal to epithelial reverting transition (MErT) in the secondary organ environment following the EMT that allows for escape.     

An in vivo model of epithelial to mesenchymal transition reveals a mitogenic switch

The epithelial to mesenchymal transition (EMT) is a process by which differentiated epithelial cells transition to a mesenchymal phenotype. EMT enables the escape of epithelial cells from the rigid structural constraints of the tissue architecture to a phenotype more amenable to cell migration and, therefore, invasion and metastasis. We characterized an in vivo model of EMT and discovered that marked changes in mitogenic signaling occurred during this process. DNA microarray analysis revealed that the expression of a number of genes varied significantly between post-EMT and pre-EMT breast cancer cells. Post-EMT cancer cells upregulated mRNA encoding c-Met and the PDGF and LPA receptors, and acquired increased responsiveness to HGF, PDGF, and LPA. This rendered the post-EMT cells responsive to the growth inhibitory effects of HGF, PDGF, and LPA receptor inhibitors/antagonists. Furthermore, post-EMT cells exhibited decreased basal Raf and Erk phosphorylation, and in comparison to pre-EMT cells, their proliferation was poorly inhibited by a MEK inhibitor. These studies suggest that therapies need to be designed to target both pre-EMT and post-EMT cancer cells and that signaling changes in post-EMT cells may allow them to take advantage of paracrine signaling from the stroma in vivo.