中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 陆金健, 陈修平
, LU Jinjian, CHEN Xiuping,
上皮间质转化(EMT)是上皮细胞失去上皮特征,获得间质表型的生物学现象,参与了多种生理病理过程,尤其是肿瘤转移和器官纤维化。EMT及其信号通路蕴含着抗肿瘤转移和器官纤维化的潜在药物靶点。从中药中发现了一些具有抑制EMT作用的化合物、提取物及中药复方。该文简述了EMT这一生物现象,并通过查阅Web of science、PubMed等数据库,对中药抑制EMT的药理作用与分子机制进行综述,以期为基于EMT的创新中药研究提供参考。
Epithelial-mesenchymal transition (EMT), a biological phenomenon, refers to the loss of epithelial characteristics and gain of mesenchymal phenotype.EMT actively participates in several physiological and pathological processes, especially in tumor metastasis and organ fibrosis.The EMT signaling pathways provide many potential drug targets for drug discovery.Recent studies showed that a large number of pure compounds, extracts, and formations from traditoinal Chinese medicine (TCM) are able to inhibit the EMT process.In this review, we briefly introduce the EMT phenomenon and then discuss the inhibitory effects and the underlying mechanisms of EMT inhibitors isolated from TCM using references obtained from literature database such as Web of Science and PubMed.This review will provide more information for the study of Traditional Chinese Medicine in the field of EMT.
编者按 中药作为中华民族的传统瑰宝,在我国有2000多年的应用历史。中药在防治重大慢性疾病如心血管疾病、糖尿病、肿瘤等方面积累了大量的临床治疗经验,其药效作用也被越来越多的循证医学研究所证实。然一直以来,中药作用物质基础不清,药效机制不明两个关键问题成为制约中药现代发展的主要瓶颈。如何结合当代生物医药学领域的最近研究进展,利用现代科学技术和策略方法,阐释中药作用基础与分子机制,以实现"继承不泥古、创新不离宗",是实现现代中药研究从"量变"到"质变" 的关键。上皮间质转化(epithelial-mesenchymal transition,EMT)是器官纤维化和肿瘤转移的共同病理基础之一,也是目前药物研发的热点通路之一。《靶向上皮间质转化: 中药抗肿瘤转移和器官纤维化新策略》总结了目前报道的可抑制EMT的中药小分子、提取物和复方的作用和机制,以期为中药药效机制研究提供新的策略参考。
恶性肿瘤已经超越心血管疾病,成为人类死亡的第一大杀手。肿瘤患者死亡的主要原因是远处转移。
据统计,90%以上的肿瘤患者死于肿瘤转移。因此,抑制肿瘤转移是提高肿瘤患者生存率的关键环节,然而目前尚缺乏抑制肿瘤转移的有效药物。肿瘤转移过程异常复杂,主要包括肿瘤细胞局部浸润、渗入血管、随循环系统转移、远处器官定居并增殖等一系列生物过程和多条信号通路。靶向这些通路将有助于实现对肿瘤转移的抑制。器官纤维化是多种因素导致的器官组织内纤维结缔组织增多、胶原沉积的复杂过程,可发生于肺脏、肝脏、心脏、肾脏、眼等多个器官,是多种慢性疾病的最后结局。器官纤维化虽发病率较低,但临床治疗药物有限。一些器官的纤维化,如特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)死亡率很高,被称为“类肿瘤疾病”,亦亟待有效的防治药物。上皮间质转化(epithelial-mesenchymal transition,EMT)是上皮细胞向间质细胞转变的过程,同时参与了肿瘤转移和器官纤维化。EMT相关信号通路蕴含了一些潜在药物靶点,其抑制剂有望成为抗肿瘤转移和(或)器官纤维化的药物。中药在防治肿瘤转移、肺纤维化方面积累了相当丰富的临床经验,笔者综述了中药中发现的具有抑制EMT作用的中药单体、提取物和复方,以期为创新中药研发提供参考。
1982年,Greenberg和Hay在研究小鸡胚胎原条时首次发现并提出 EMT的概念[1]。EMT是指极化的上皮细胞失去上皮特性(如细胞间粘附、细胞极性等)、同时获得间质表型、向间质细胞转化的生物学过程[2]。EMT有3种类型:Ⅰ型EMT是指器官移植、胚胎和器官发育时发生的EMT现象;Ⅱ型EMT是指组织再生和器官纤维化时发生的EMT现象; Ⅲ型EMT是指与肿瘤演进及转移相关的EMT现象[3]。Ⅰ型EMT是基于生命发展的需要—形成不同类型及功能的组织器官,主要参与胚胎器官发育[4]。Ⅱ型EMT主要始于炎症诱导的损伤,伴随着炎症反应而持续,参与组织再生和器官纤维化[2]。Ⅲ型EMT主要是肿瘤细胞为实现远处转移,通过EMT获得一个更具侵入性的间质表型,促进肿瘤细胞自肿瘤组织的脱落、侵入细胞外基质等[5]。上皮细胞发生EMT后,形态上,细胞变为细长、细胞间间隙增大、细胞间链接变得松散;功能上,细胞运动能力增加、对凋亡抵抗增加、侵袭和迁移能力增强;分子水平上,上皮细胞标志分子,如E-钙粘蛋白(E-cadherin)、闭锁连接蛋白(zonula occludens-1, ZO-1)、紧密连接蛋白(claudins)、角蛋白(cytokeratins)、IV型胶原(collagen-IV)等表达降低;同时,间质细胞标志分子如波形蛋白(vimentin)、成纤维细胞特异性蛋白1(fibroblast-specific protein 1,FSP1)、α-平滑肌肌动蛋白(alpha-smooth muscle actin,α-SMA)、纤连蛋白(fibronectin)、N-钙粘蛋白(N-cadherin)、Ⅰ和Ⅲ型胶原等表达增加[2-3, 6]。细胞形态和分子标志的变化被广泛用于鉴定EMT。多种因素包括生长因子如转化生长因子β(transforming growth factor-β,TGF-β)、肝细胞生长因子(hepatocyte growth factor,HGF)、胰岛素样生长因子-1(insulin-like growth factor 1,IGF-1)、骨形态发生蛋白(bone morphogenetic protein,BMP);炎症因子如白细胞介素(IL-1β、IL-6、IL-8)、肿瘤坏死因子-α(TNF-α);病理因素如高葡萄糖、末端糖基化终产物、氧化型低密度脂蛋白、血管紧张素Ⅱ(AngⅡ)和某些 microRNA等均能诱导EMT发生[6,7]。其中,TGF-β是诱导EMT的高效生长因子,是建立EMT模型最为常用工具药。TGF-β主要有3种亚型,TGF-β1、TGF-β2、TGF-β3。TGF-β1主要调节肿瘤和纤维化过程中的EMT;TGF-β2主要调节心脏发育过程中内皮细胞的EMT(endothelial-mesenchymal transition,EndMT); 而TGF-β3主要介导颚发生中的EMT。因此,目前多以TGF-β1为诱导EMT之模型药物。TGF-β通过结合细胞表面的TGF-β受体(TGF-βR)发挥作用。TGF-βR也有3种:TGF-βRⅠ、TGF-βRⅡ、TGF-βRⅡ。Ⅰ型和Ⅱ型受体是跨膜丝氨酸/苏氨酸激酶, 二者同时进行信息转导; Ⅲ型受体直接转导信息,主要功能是将 TGF-β 传递给 TGF-βRⅡ。 TGF-β1诱导EMT的主要机制:TGF-β1首先结合并启动细胞膜表面的异源二聚体TGF-βR(TGF-βRⅠ/TGF-βRⅡ),受体启动后主要通过Smad依赖性(经典通路)和smad非依赖性通路(非经典通路)介导EMT。前者主要通过smad2和(或)smad3,与smad4形成三聚体并发生核转位,调节相关基因表达;后者主要通过Akt、NF-κB、Rho、Rac、Cdc42 GTPase、PI3K、MAPKs(JNK、p38MAPK、ERK1/2等)等信号通路[8,9,10]。转录因子是EMT发生过程中主要调节因子,对上皮和间质表型的基因表达的调节起关键作用。其中,转录因子家族E 盒结合锌指蛋白(zincfingerE-box-bindinghomeobox,ZEB)、锌指转录因子(Snail)、Twist、碱性螺旋-环-螺旋转录因子(basic Helix-Loop-Helix,bHLH)、叉头框转录因子(forkhead box,FOX)、SOX(SRY-relatedHMG-box)等在介导EMT过程中起主要作用[11,12]。EMT的主要信号转导通路概括如
姜黄素是广泛研究的天然明星分子,可抑制肝、肠、肾纤维化。在氯化亚钴(CoCl2)诱导的人LO2肝细胞EMT模型中,姜黄素可通过下调TGF-βRⅠ的表达,抑制smad2和smad3的磷酸化逆转EMT[13]。在肠纤维化大鼠模型,姜黄素处理后IEC-6大鼠肠上皮细胞α-SMA和氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor-γ,PPAR-γ)蛋白表达上调,PPAR-γ核转位增多。该作用可以被PPAR-γ抑制剂GW9662所逆转,提示姜黄素可通过上调PPAR-γ表达抑制大鼠肠纤维化[14]。在单侧输尿管梗阻诱导的大鼠肾小管间质纤维化模型中,姜黄素处理可逆转模型组大鼠α-SMA表达的增多、E-cadherin表达的降低,并通过抑制p-smad2、p-smad3、TGF-β1、TGF-βRI、Collagen-Ⅰ和Collagen-Ⅲ的表达延缓大鼠肾小管间质纤维化[15]。丹酚酸B是丹参主要水溶性成分之一。在 TGF-β1诱导的HK-2细胞EMT模型,丹酚酸B部分逆转E-cadherin和肌酸激酶-18(CK-18)的表达,抑制α-SMA的表达和F-肌动蛋白(F-actin)的重组,下调基质金属蛋白酶(matrix metallopeptidase,MMP)-2/9活性。在氯化汞(HgCl2)诱导的大鼠肾间质纤维化模型,丹酚酸B可上调肾脏组织中E-cadherin的蛋白表达、下调α-SMA和TGF-β1的表达、抑制MMP-2活性[16]。TGF-β1诱导的NRK-52E细胞EMT模型,阿魏酸处理后E-cadherin表达增多,α-SMA、Snail、p-smad2/3和整合素连锁激酶(integrin linked kinase,ILK)的表达减少,提示阿魏酸或可通过调控smad/ILK/Snail信号通路抑制EMT[17]。在IL-1β诱导的NRK-49F和HK-2细胞EMT模型,黄芪甲苷 IV与阿魏酸合用可降低α-SMA和Fibronectin的表达,抑制JNK磷酸化,提示二者可通过JNK信号通路抑制EMT[18]。此外,在输尿管梗阻诱导的大鼠肾纤维化模型中,牛蒡子苷元通过下调TGF-β1及其受体的表达、抑制smad2/3磷酸化及核移位以及上调smad7的表达抑制EMT[19]。人参皂苷Rg1通过上调NRK-52E细胞的E-cadherin表达,下调α-SMA、Collagen I、Fibronectin和p-ERK1/2的表达,抑制TGF-β1诱导的EMT[20]。
2.2.1 肺癌 汉黄芩素是黄芩的主要活性成分之一。在THP-1条件培养基或IL-6诱导的A549细胞EMT模型中,汉黄芩素处理后 E-cadherin的表达上调,N-cadherin、Vimentin、Snail、Twist的表达下调。同时信号传导及转录激活因子3(signal transducers and activators of transcription3,STAT3)的磷酸化(p-STAT3)受到抑制,p-STAT3二聚体核转位减少。这提示汉黄芩素可抑制炎症微环境诱导的EMT[21]。淫羊藿次苷Ⅱ是淫羊藿中提取的一种黄酮醇苷。在利用LPS刺激THP-1细胞所得的条件培养基或TNF-α诱导A549和H1299细胞建立的EMT模型中,淫羊藿次苷Ⅱ处理可增加E-cadherin表达,降低N-cadherin、Vimentin、Snail和Slug(Snail2)表达,同时抑制TNF-α诱导的NF-κB的核转移及IκBα的磷酸化[22]。蛇床子素是蛇床子的主要成分之一。笔者研究发现,在TGF-β1诱导的A549细胞EMT模型中,蛇床子素明显改善细胞的梭形形态,上调E-cadherin表达,下调N-cadherin、Vimentin、NF-κB p65、Snail蛋白表达,抑制TGF-β1诱导的细胞侵袭和迁移。SiRNA沉默Snail和NF-κB抑制剂PDTC具有类似的作用。这显示蛇床子素可通过抑制NF-κB介导的Snail的活化从而抑制EMT[23]。此外,在TGF-β1诱导的A549细胞EMT模型中,芝麻素和蟾毒灵可通过分别抑制Fibronectin、Vimentin的表达及smad3的磷酸化[24]以及TGF-β受体和Twist2、ZEB2、p-smad2和p-smad3的表达[25]抑制EMT。人参皂苷Rg3可以通过抑制A549,H1299和H358细胞的岩藻糖基转移酶Ⅳ(fucosyltransferase Ⅳ,FUT4)基因的表达使细胞内E-cadherin表达增多,Snail、N-cadherin和Vimentin表达降低,从而缓解EMT进程[26]。肉桂醛通过调控Wnt/β-连环蛋白(β-catenin)信号通路抑制CoCl2诱导的A549、YTLMC-90和NCL-H1299细胞的EMT[27]。
2.2.2 卵巢癌 在缺氧诱导的卵巢癌SKOV3和3AO细胞EMT模型,人参皂苷Rb1处理抑制EMT,降低细胞内miR-25表达,提示Rb1或可通过抑制miR-25表达抑制EMT[28]。20
2.2.3 乳腺癌 黄芩素可显著抑制人乳腺癌细胞MDA-MB-231的迁移和侵袭。黄芩素诱导细胞内E-cadherin表达增多,特异富含AT序列结合蛋白1(special AT-richsequence binding protein1,SATB1)、Snail、Wnt1和β-catenin表达下降,Wnt/β-catenin信号通路基因表达下降。这提示黄芩素可通过调控SATB1和Wnt/β-catenin通路抑制MDA-MB-231细胞EMT[31]。马钱子碱可显著抑制MDA-MB-231和Hs578-T细胞的EMT,上调细胞内 E-cadherin和β-catenin的蛋白和mRNA表达,下调Vimentin和Fibronectin的蛋白和mRNA表达[32]。
2.2.4 胰腺癌 冬凌草素可以抑制胰腺癌细胞SW1990的EMT,降低Vimentin、Snail和Slug的表达,增加E-cadherin表达,同时抑制细胞Wnt/β-catenin信号通路[33]。川楝素可以逆转TGF-β诱导的PANC-1和AsPC-1细胞的E-cadherin的下调和Vimentin、ZEB1、Snail的上调,缓解胰腺癌细胞的EMT及病理形态[34]。
2.2.5 肝癌 蟾毒灵和Hedgehog信号通路抑制剂(GANT61)均可抑制高转移性肝癌细胞HCC-LM3的EMT并降解细胞外基质,提示蟾毒灵可能通过抑制Hedgehog信号通路抑制EMT[35]。在TGF-β诱导的人肝癌细胞株SMMC7721中,蟾毒灵可通过PI3K/AKT/mTOR通路上调细胞内E-cadherin表达,降低HIF-1α、N-cadherin、Vimentin和Snail表达[36]。虫草素是冬虫夏草和蛹虫草中(尤其是核苷类)主要活性成分。虫草素处理后肝癌细胞SK-Hep-1内E-cadherin表达升高,FAK的磷酸化、整合素(Integrin)α3、Integrin α6和Integrin β1的表达等均降低,提示虫草素通过抑制Integrin/FAK信号通路抑制SK-Hep-1的EMT[37]。此外,人参皂苷Rg1可以有效抑制TGF-β诱导的HepG2的EMT[38]。
2.2.6 其他肿瘤 姜黄素可通过抑制NKD2/Wnt/CXCR4信号通路调节E-cadherin和Vimentin表达,抑制直肠癌细胞SW620细胞EMT[39]。毛蕊异黄酮可抑制TGF-β诱导的胶质瘤U87和U251细胞的间质细胞相关基因和MMP-2、MMP-9蛋白的表达[40]。在IGF-1诱导的胶质瘤GBM8401 细胞EMT模型中,蛇床子素通过抑制PI3K/Akt通路抑制EMT[41]。和厚朴酚可以通过上调miR-141(miR141以ZEB2为作用靶点,调控ZEB2的表达)的表达逆转肾癌细胞A498的EMT[42]。吴茱萸碱通过调控Wnt/β-catenin信号通路抑制胃癌干细胞AGS和SGC7901的EMT[43]。氯化两面针碱通过抑制Akt/GSK-3β/Snail信号通路改善骨肉瘤细胞U2OS的EMT[44]。木犀草素可抑制缺氧诱导的黑色素瘤B16F10细胞的EMT[45]。丹参酮ⅡA可以抑制膀胱癌细胞株(5637、BFTC、T24)的趋化因子配基2(CCL2)的表达和STAT3的磷酸化抑制MMP-9/-2的表达及酶活性,升高E-cadherin、降低N-cadherin和Vimentin的表达,抑制Snail和Slug的转录[46]。蛇床子素通过抑制TGF-β/Akt/MAPK通路抑制Snail 和miR-23a-3p,降低E-cadherin表达,抑制前列腺癌Du145细胞EMT[47]。中药成分抑制EMT作用与机制总结见
糖尿病肾病是慢性肾衰竭的主要原因,主要表现为肾小球和间质纤维化。EMT过程是其重要的病理基础。五味子提取物可以抑制糖尿病肾病小鼠的足状突细胞的EMT,调节E-cadherin表达,下调α-SMA和Snail表达[48]。垂盆草具有抗炎、抗氧化的作用。在马兜铃酸诱导的NRK-52E细胞EMT模型中,垂盆草提取物显著改善细胞的纤维样表型及其EMT,抑制间质细胞标记和细胞外基质(ECM)成分的表达,调节MMP-2和组织金属蛋白酶抑制剂-2(TIMP-2)之间的失衡,下调 TGF-β1及其受体的表达[49,50]。在单侧输尿管结扎所诱导的大鼠肾纤维化模型中,垂盆草提取物保护肾脏功能,降低血清肌酐和TGF-β1的表达,缓解肾小球损伤和间质纤维化[50]。郁金提取物可以有效抑制TGF-β1诱导的NRK-52E向肌成纤维细胞转化,上调E-cadherin,下调α-SMA的表达,改善细胞病理形态[51]。
龙葵水提物处理乳腺癌细胞MCF-7后,细胞内E-cadherin表达增多,ZEB1、N-cadherin、Vimentin的表达下降,同时发生线粒体分裂。这提示龙葵水提物抑制EMT的作用可能是通过抑制线粒体功能[52]。当归多糖是可抑制胶质瘤细胞U251的TGF-β信号通路,刺激细胞表达E-cadherin[53]。南蛇藤乙酸乙酯提取物可通过抑制NF-κB/Snail信号通路抑制TGF-β诱导的人胃腺癌SGC-7901细胞的EMT,显著缓解细胞的间质样形态变化,上调E-cadherin 的表达,下调Vimentin、N-cadherin的表达[54,55]。温郁金正丁醇提取物具有抑制幽门螺杆菌诱导的人胃癌AGS细胞侵袭的作用,可降低AGS的ZEB1转录水平和细胞内尾型同源框转录因子(CDX-2)、Claudin-2的表达[56]。
通心络胶囊(人参、水蛭、全蝎等组成)具有益气活血、通络止痛之功效。可显著抑制高糖诱导的肾小管上皮细胞HKCs中TGF-β1及其下游蛋白smad3/p-smad3的表达,下调Collagen-Ⅳ和Fibronectin的表达[57]。在miRNA-21诱导的糖尿病肾病模型,通心络胶囊上调E-cadherin和smad7表达,下调α-SMA、smad3/p-smad3、Collagen-Ⅳ和Fibronectin表达[58]。糖尿病大鼠连续灌胃糖脂清颗粒(桑叶、荷叶、丹参等组成)8周,大鼠足状突细胞的EMT分子标记如结蛋白(Desmin)和α-SMA蛋白表达下降,TGF-β和p-smad2/3的表达降低[59]。在单侧输尿管结扎诱导的大鼠EMT模型,尿毒清胶囊(大黄、黄芪、桑白皮等组成)上调E-cadherin表达,下调Vimentin和α-SMA表达,改善细胞纤维样表型[60]。在腺嘌呤诱导的慢性肾衰竭大鼠模型中,黄葵胶囊(主要含黄蜀葵花)抑制α-SMA、p-ERK1/2、NADPH 氧化酶 1、NADPH 氧化酶 2和NADPH 氧化酶 4表达,改善肾小管间质纤维化[61]。在HgCl2诱导的大鼠肾间质纤维化模型中,扶正化瘀方(丹参、发酵虫草菌粉、桃仁等组成)可以抑制肾脏胶原沉积,显著降低羟脯氨酸含量,下调α-SMA、TGF-β1、p-smad2、p-smad3和TGF-βRI等蛋白的表达[62]。肾气丸(干地黄、山药、山茱萸等组成)处理后大鼠肾脏中E-cadherin表达增多,Vimentin表达降低,p-smad2/3下调,smad7上调[63]。玉屏风散(黄芪、白术、防风)的多糖可以显著缓解博来霉素诱导的大鼠肺纤维化,抑制肺组织中高迁移率族蛋白1(high mobility group box-1 protein,HMGB1)及间质细胞标记物如Vimentin和α-SMA的表达[64]。扶正化瘀方(桃仁、虫草菌丝、丹参等组成)可以上调肝星状细胞BMP-7水平,下调其TGF-β1水平,使细胞的TGF-β1/BMP-7的比例下降。同时,细胞内p38 MAPK和磷酸化的p38 MAPK表达下降,逆转EMT[65]。地五养肝方(熟地、茵陈、五味子等组成)可通过抑制Hedgehog信号通路下调TGF-β1/BMP-7的比值改善四氯化碳(CCl4)诱导所致的Wistar大鼠肝纤维化[66]。
表1 中药成分抑制EMT作用及其机制
Tab.1 Inhibitory of the components from traditional Chinese medicine on EMT and its mechanism
传统名方片仔癀可显著抑制CT-26细胞的肝转移率[67]、降低人结直肠癌腺癌细胞HCT-8的侵袭率和转移率。HCT-8细胞的TGF-β1、smad2/3、smad4、ZEB1、ZEB2、miR-200a、miR-200b和miR-200c的表达下降。表明片仔癀可通过调控TGF-β1/ZEB/miR-200通路抑制HCT-8细胞EMT[68]。在缺氧诱导HCT-8细胞EMT模型中,片仔癀显著改善细胞病理形态,下调间质细胞相关分子的表达。这提示HIF-1信号通路可能也是片仔癀抑制EMT的作用机制之一[69]。此外,在氟尿嘧啶(5-Fu)耐药的HCT-8细胞中,片仔癀既抑制EMT,也改善耐药[70]。益气除痰汤(党参、五爪龙、法半夏等组成)对A549细胞的EMT有显著抑制作用,可以上调细胞E-cadherin表达,下调Vimentin和Fibronectin表达。机制涉及抑制GRP78、smad2/3和SRC/MAPK信号通路[71]。补肺汤(黄芪、甘草、钟乳等组成)可以通过调控smad信号通路抑制A549细胞的EMT及 TGF-β1诱导的表型转变[72]。扶正抑癌汤(生晒参、生黄芪、莪术等组成)可通过调控STAT3/MMP9信号通路抑制肺癌细胞A549、PC9和H1650的EMT[73]。健脾解毒方(炒黄连、泽泻、山药等组成)可通过调控TGF-β/smad信号通路调节Snail/E-Cadherin 表达[74]。在氧化偶氮甲烷/右旋糖酐硫酸酯钠诱导的结肠炎相关的结肠直肠癌模型,参苓白术散(白扁豆、白术、茯苓等组成)和芍药汤(芍药、槟榔、大黄等组成)上调E-cadherin、下调N-cadherin、Vimentin、Fibronectin和Snail,降低Wnt5a的活性,抑制EMT[75,76]。此外,在接种胃癌细胞MGC-803的裸鼠,益气化瘀解毒汤(生黄芪、当归、骨碎补等组成)上调的E-cadherin,下调N-cadherin、TGF-β、p-smad2、p-smad3、Snail和Slug[77]。健脾化瘀汤(党参、黄芪、炒白术等组成)通过调控smad3/smad7级联抑制肝癌SMMC7221细胞EMT[78]。
越来越多的证据表明EMT在器官纤维化和肿瘤转移中扮演了重要角色。随着对EMT信号通路中发现了一些潜在的药物作用靶点,一些可以抑制EMT的化合物也已经开展临床试验研究[79]。多年的中药抗肿瘤显示,中药直接杀伤肿瘤细胞作用较弱,在抑制肿瘤转移过程中或有优势。中药抑制EMT的研究取得了一些进展,发现了多个具有抑制EMT作用的单体、提取物、复方等。但总体的研究尚不够深入,尤其缺乏中药抑制EMT作用靶点的鉴定。中医治疗学上有“同病异治、异病同治”的理论,EMT不仅参与了肿瘤转移,也参与了器官纤维化,通过中药对EMT抑制作用与机制的研究,或有助于揭示和阐明中药“异病同治”的指导理论,有助于促进中药现代化和国际化。
The authors have declared that no competing interests exist.
| [1] |
Epithelium is the tissue phenotype of early embryos and primitive adults of the chordate phylum. A second tissue type, however, is produced by epithelial-mesenchymal transformation (EMT) in higher chordates, such as vertebrata. Mesenchymal cells have the ability, which true epithelia do not, to invade and migrate through the extracellular matrix (ECM) to create dramatic cell transpositions. The first-formed or primary mesenchymal cells in amniote vertebrates migrate from the primitive streak to differentiate into the mesodermal and endodermal epithelia. Definitive mesenchyme with connective tissue and muscle potentials arises from the epithelial mesoderm at about the same time as the neural crest mesenchyme forms from the ectoderm. Later on in embryogenesis. EMT is used to remodel unwanted epithelia, such as that of the palate medial edges. We discuss the mechanisms by which epithelial cells transform into mesenchyme and vice versa. On the one hand, cells activate putative mesenchymal master genes, turn off epithelial genes, and acquire motility machinery that allows them to interact in 3 dimensions (3D) with ECM via actin cortex while sliding their endoplasm into their new front ends. On the other hand, primary mesenchymal cells can reactivate epithelial regulatory genes, such as E-cadherin, turn off the motility machinery for invading ECM, and reexpress apical-basal polarity. We review the genes, such as FSPI, src, ras, andfos, that are activated in cells transforming to mesenchyme and the genes their neighbors activate to induce EMT, such as those for TGFβ, NT-3, and sonic hedgehog. Suspension in 3D collagen gels can induce adult epithelium to undergo EMT; α5βl integrin is activated on surfaces in contact with collagen, including apical surfaces that do not normally express integrins. In vivo, it is possible that pathological manipulations of a cell’s environment likewise induce EMT. Of the examples we give, the creation of invasive metastatic carcinoma cells by EMT is the most fearful. Interestingly, transfection of either metastatic cells or normal embryonic fibroblasts with the E-cadherin gene converts them to the epithelial phenotype. It may be possible in the future to manipulate the tissue phenotype of diseased cells to the advantage of the animal.
[本文引用:1]
|
| [2] |
Abstract The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
[本文引用:3]
|
| [3] |
Abstract Somatic cells that change from one mature phenotype to another exhibit the property of plasticity. It is increasingly clear that epithelial and endothelial cells enjoy some of this plasticity, which is easily demonstrated by studying the process of epithelial-mesenchymal transition (EMT). Published reports from the literature typically rely on ad hoc criteria for determining EMT events; consequently, there is some uncertainty as to whether the same process occurs under different experimental conditions. As we discuss in this Personal Perspective, we believe that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon - namely, the transition of epithelial and endothelial cells to a motile phenotype.
[本文引用:2]
|
| [4] |
Embryo implantation in higher primates is mediated by trophoblast: in the earliest phases by syncytiotrophoblast, then by both cytotrophoblast and syncytiotrophoblast. In the course of placentation three main trophoblast populations can be identified: cytotrophoblast stem cells and two differentiated derivative cell types: the syncytiotrophoblast and the extravillous cytotrophoblast. The syncytiotrophoblast remains mainly epithelial while the extravillous cytotrophoblast undergoes an epithelial-mesenchymal transition (EMT), initially forming multi-layered cell columns and then, in human, infiltrating deeply the maternal decidual stroma and blood vessels. Finally, some infiltrating cells differentiate further to become giant cells of the placental bed and myometrium. During the course of these events the extravillous cytotrophoblast acquires a distinct phenotype, losing some typical epithelial components (e.g. E-cadherin, integrin a6(34), but retaining others (e.g. cytokeratins). The signals that trigger this EMT are not well understood but its realisation is of critical importance for pregnancy success.
[本文引用:1]
|
| [5] |
Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in02vitro. Genetic loss of Id1 in the host tissue (Id1(-/-) mice) impaired liver colonization and increased survival of Id1(-/-) animals. Histologically, the presence of Id1 in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor nodules from Id1(+/+) mice and Id1(-/-) mice injected with LLC control cells revealed that Id1 loss reduces the levels of EMT-related proteins, such as vimentin. In tissue microarrays containing 532 NSCLC patients' samples, we found that Id1 significantly correlated with vimentin and other EMT-related proteins. Id1 loss decreased the levels of vimentin, integrinβ1, TGFβ1 and snail, both in02vitro and in02vivo. Therefore, Id1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis.
[本文引用:1]
|
| [6] |
Abstract The epithelial-mesenchymal transition (EMT) is an essential mechanism in embryonic development and tissue repair. EMT also contributes to the progression of disease, including organ fibrosis and cancer. EMT, as well as a similar transition occurring in vascular endothelial cells called endothelial-mesenchymal transition (EndMT), results from the induction of transcription factors that alter gene expression to promote loss of cell-cell adhesion, leading to a shift in cytoskeletal dynamics and a change from epithelial morphology and physiology to the mesenchymal phenotype. Transcription program switching in EMT is induced by signaling pathways mediated by transforming growth factor 尾 (TGF-尾) and bone morphogenetic protein (BMP), Wnt-尾-catenin, Notch, Hedgehog, and receptor tyrosine kinases. These pathways are activated by various dynamic stimuli from the local microenvironment, including growth factors and cytokines, hypoxia, and contact with the surrounding extracellular matrix (ECM). We discuss how these pathways crosstalk and respond to signals from the microenvironment to regulate the expression and function of EMT-inducing transcription factors in development, physiology, and disease. Understanding these mechanisms will enable the therapeutic control of EMT to promote tissue regeneration, treat fibrosis, and prevent cancer metastasis. Copyright 漏 2014, American Association for the Advancement of Science.
[本文引用:2]
|
| [7] |
肿瘤生物学研究近年来取得长足进展,肿瘤免疫、肿瘤干细胞、细胞自噬、上皮-间质转化等已成为肿瘤学研究热点.对这些肿瘤生物过程的详尽阐明,为这种多因素导致细胞异常增殖,发病率和死亡率均居重大疾病之首肿瘤疾病治疗,也为抗肿瘤中药的药理评价、原理阐明和创新药研发提供了提供了新的靶标、新的契机与新的研究策略.
[本文引用:1]
|
| [8] |
react-text: 450 The matrix metalloprotease matrilysin is expressed in premalignant polyps and plays a key role in local invasion during the progression of digestive tumors. In the present work, we investigated the possible relationships between the activity of the mouse and human matrilysin promoters (Mp), endogenous matrilysin protein expression, and two early oncogenetic defects frequently observed in human... /react-text react-text: 451 /react-text [Show full abstract]
[本文引用:1]
|
| [9] |
|
| [10] |
System biology uses a range of experimental and statistical methods to dissect complex processes that results from alterations in biological models. Given the complexity of the epithelial鈥搈esenchymal transition (EMT) program, system biology represents a promising approach to understanding its fine molecular regulation by the interpretation of high-throughput datasets. Herein, we review recent contributions of system biology applied to the field of EMT physiology and illustrate the importance of these approaches to model biological networks that are perturbed during the transition. Together, these results allowed the definition of an EMT signature across different tumor types, the identification of dysregulated processes and new modules of regulation, making possible to reveal the EMT molecular visage underneath.
[本文引用:1]
|
| [11] |
DOI:10.1038/nrm3758
URL
[本文引用:1]
|
| [12] |
Abstract The plasticity of cancer cells underlies their capacity to adapt to the selective pressures they encounter during tumour development. Aberrant reactivation of epithelial-mesenchymal transition (EMT), an essential embryonic process, can promote cancer cell plasticity and fuel both tumour initiation and metastatic spread. Here we discuss the roles of EMT-inducing transcription factors in creating a pro-tumorigenic setting characterized by an intrinsic ability to withstand oncogenic insults through the mitigation of p53-dependent oncosuppressive functions and the gain of stemness-related properties.
[本文引用:1]
|
| [13] |
Abstract Epithelial-mesenchymal transition (EMT) occurs during adult tissue remodeling responses including carcinogenesis and fibrosis. Existing evidence reveals that hepatocytes can undergo EMT in adult liver, which is critically involved in chronic liver injury. We herein established a hypoxia-induced EMT model in human LO2 hepatocytes treated with cobalt chloride (CoCl2) in vitro, and evaluated the effects of curcumin, a natural antifibrotic compound, on hepatocyte EMT and explored the underlying molecular mechanisms. We found that CoCl2 at non-toxic doses induced a mesenchymal cell phenotype in hepatocytes and upregulated several mesenchymal markers including 02±-smooth muscle actin, vimentin, N-cadherin, fibronectin and Snail (an EMT-related transcription factor), but downregulated the epithelial marker E-cadherin in hepatocytes. However, curcumin reversed the morphological changes, abrogated the increased expression of mesenchymal markers, and rescued E-cadherin expression in CoCl2-treated hepatocytes, suggesting the inhibition of hepatocyte EMT in vitro. We further found that curcumin interfered with the transforming growth factor-0205 (TGF-0205) signaling by reducing the expression of TGF-0205 receptor I and inhibiting the expression and phosphorylation of Smad2 and Smad3. Use of SB431542, a specific inhibitor of TGF-0205 receptor I, demonstrated that interference with the TGF-0205/Smad pathway was associated with curcumin suppression of hepatocyte EMT. Our in vivo data showed that curcumin affected hepatic EMT in rat fibrotic liver caused by carbon tetrachloride, which was associated with the inhibition of TGF-0205/Smad signaling. These findings characterized a novel mechanism by which curcumin modulated hepatocyte EMT implicated in treatment of liver fibrosis.
[本文引用:1]
|
| [14] |
Intestinal fibrotic stricture is a major complication of Crohn???s disease (CD) and epithelial-to-mesenchymal transition (EMT) is considered as an important contributor to the formation of intestinal fibrosis by increasing extracellular matrix (ECM) proteins. Curcumin, a compound derived from rhizomes of Curcuma, has been demonstrated with a potent antifibrotic effect. However, its effect on intestinal fibrosis and the potential mechanism is not completely understood. Here we found that curcumin pretreatment significantly represses TGF-??1-induced Smad pathway and decreases its downstream ??-smooth muscle actin (??-SMA) gene expression in intestinal epithelial cells (IEC-6); in contrast, curcumin increases expression of E-cadherin and peroxisome proliferator-activated receptor ?? (PPAR??) in IEC-6. Moreover, curcumin promotes nuclear translocation of PPAR?? and the inhibitory effect of curcumin on EMT could be reversed by PPAR?? antagonist GW9662. Consistently, in the rat model of intestinal fibrosis induced by 2,4,5-trinitrobenzene sulphonic acid (TNBS), oral curcumin attenuates intestinal fibrosis by increasing the expression of PPAR?? and E-cadherin and decreasing the expression of ??-SMA, FN, and CTGF in colon tissue. Collectively, these results indicated that curcumin is able to prevent EMT progress in intestinal fibrosis by PPAR??-mediated repression of TGF-??1/Smad pathway.
[本文引用:1]
|
| [15] |
|
| [16] |
Background Salvianolic Acid B (Sal B) is a water-soluble component from Danshen (a traditional Chinese herb widely used for chronic renal diseases) with anti-oxidative and cell protective properties. Sal B also has potential protective effects on renal diseases. Tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT), which plays an important role in the pathogenesis of renal interstitial fibrosis (RIF) and is mainly regulated by TGF-??1/Smads pathway. The aims of the study are to investigate the effect of Sal B on tubular EMT in vivo and in vitro, and to elucidate its underlying mechanism against EMT related to TGF-??1/Smads pathway. Results For in vivo experiments, RIF was induced in rats by oral administration of HgCl2 and prophylaxised with Sal B and vitamin E. The protein expression of E-cadherin was down-regulated, while the expression of ??-SMA, TGF-??1, T??R-I, p-Smad2/3 and the activity of matrix metalloproteinase-2 (MMP-2) were up-regulated in kidneys of model rats when compared with those of normal rats. In contrast, Sal B and vitamin E significantly attenuated the expression of ??-SMA, TGF-??1, T??R-I, p-Smad2/3, and MMP-2 activity, but increased E-cadherin expression. For in vitro experiments, HK-2 cells were incubated with TGF-??1 to induce EMT, and the cells were co-cultured with 1 and 10 ??M Sal B or SB-431542 (a specific inhibitor of T??R-I kinase). TGF-??1 induced a typical EMT in HK-2 cells, while it was blocked by Sal B and SB-431542, as evidenced by blocking morphologic transformation, restoring E-cadherin and CK-18 expression, inhibiting ??-SMA expression and F-actin reorganization, and down-regulating MMP-2/9 activities in TGF-??1 mediated HK-2 cells. Furthermore, Sal B and SB-431542 profoundly down-regulated the expressions of T??R-I and p-Smad2/3 but prevented the decreased expression of Smad7 in TGF-??1 stimulated HK-2 cells. Conclusions Sal B can prevent tubular EMT in the fibrotic kidney induced by HgCl2 as well as HK-2 cells triggered by TGF-??1, the mechanism of Sal B is closely related to the regulation of TGF-??1/Smads pathway, manifested as the inhibition of TGF-??1 expression, suppression of T??R-I expression and function, down-regulation of Smad2/3 phosphorylation, and restoration of the down-regulation of Smad7, as well as inhibition of MMP-2 activity.
[本文引用:1]
|
| [17] |
Renal fibrosis is a common cause of renal dysfunction with chronic kidney disease. Central to this process is epithelial-mesenchymal transformation (EMT) of proximal tubular epithelial cells driven by transforming growth factor-??1 (TGF-??1) signaling. The present study aimed to investigate the effect of Ferulic acid (FA) on EMT of renal proximal tubular epithelial cell line (NRK-52E) induced by TGF-??1 and to elucidate its underlying mechanism against EMT related to TGF-??1/Smads pathway. The NRK-52E cells were treated for 48???h with TGF-??1 (5???ng/mL) in different concentrations of FA (0 to 200?????M). Fibronectin, a mesenchymal marker, was assessed by western blotting. Western blotting was also used to examine the EMT markers (E-cadherin, and ??-smooth muscle actin (??-SMA)), signal transducer (p-Smad2/3), and EMT initiator (Snail). ILK was also assayed by western blotting. The results showed that TGF-??1 induced spindle-like morphological transition in NRK-52E cells. Smad2/3 signaling pathway activation, increased fibronectin, ??-SMA, ILK, and Snail expression, and decreased E-cadherin expression in TGF-??1-treated NRK-52E cells. FA efficiently blocked P-Smad2/3 activation and attenuated all these EMT changes induced by TGF-??1. These findings suggest that FA may serve as a potential fibrosis antagonist for renal proximal tubule cells by inhibiting EMT process.
[本文引用:1]
|
| [18] |
BACKGROUND AND PURPOSE The combination of Chinese herbs, Astragali Radix and Angelicae Sinensis Radix, could alleviate renal interstitial fibrosis. Astragaloside IV (AS-IV) and ferulic acid (FA) are the two major active constituents in this combination. In this study, we employed rats with unilateral ureteral obstruction to determine whether AS-IV and FA have the same renoprotective effects and investigated the mechanisms of this action.EXPERIMENTAL APPROACH Renal pathological changes were evaluated after treatment with AS-IV, FA or AS-IV + FA (AF) for 10 days. Meanwhile, the expression of transforming growth factor 02051 (TGF-02051), fibronectin, -smooth muscle actin (-SMA), phosphorylation of c-Jun NH2-terminal kinase (p-JNK) and nitric oxide (NO) production in kidney were determined. The expressions of fibronectin, -SMA, mitogen-activated protein kinases [JNK, extracellular signal-regulated kinases (ERK), P38] in TGF-02051-treated NRK-49F cells or interleukin-1-treated HK-2 cells after AS-IV, FA or AF were assessed.KEY RESULTSAF alleviated the infiltration of mononuclear cells, tubular atrophy and interstitial fibrosis; reduced the expression of fibronectin, -SMA, TGF-02051 and p-JNK; and dramatically increased the production of NO in obstructed kidneys. Neither AS-IV nor FA alone improved renal damage, but both increased NO production. AF inhibited -SMA and fibronectin expression in NRK-49F or HK-2 cells. Furthermore, AF significantly inhibited IL-10205-induced JNK phosphorylation, without affecting ERK or P38 phosphorylation. Neither AS-IV nor FA alone had any effect on the cells.CONCLUSIONS AND IMPLICATIONS AS-IV synergizes with FA to alleviate renal tubulointerstitial fibrosis; this was associated with inhibition of tubular epithelial090009mesenchymal transdifferentiation (EMT) and fibroblast activation, as well as an increase in NO production in the kidney.
[本文引用:1]
|
| [19] |
: ATG could protect the kidney from UUO-induced injury and fibrogenesis by suppressing inflammation, oxidative stress, and tubular EMT, thus supporting the potential role of ATG in renal fibrosis treatment.
[本文引用:1]
|
| [20] |
The medicinal herb, Panax notoginseng , has been used for thousands of years in traditional Chinese medicine and possesses anti-fibrosis properties. Epithelial-myofibroblast transition (EMT) plays an important role in renal tubulointerstitial fibrosis. The present study was designed to examine whether ginsenoside Rg1, a major active component isolated from Panax notoginseng , has an ability to block this phenotypic transition in rat renal tubular epithelial cells (NRK-52E) induced by transforming growth factor-β1 (TGF-β1). The morphology of tubular epithelial-myofibroblast transition was observed through light microscope and transmission electron microscopy. α-SMA and E-cadherin are two markers of tubular epithelial-myofibroblast transition, their protein expressions were assessed by immunohistochemistry and western blot analysis. Gene expression of α-SMA as well as the two major extracellular matrix components collagen I and fibronectin was measured by real-time PCR analysis. Enzyme-linked immunosorbent assay was used to quantitatively detect collagen I and fibronectin in the supernatant. Our results revealed that ginsenoside Rg1 obviously blocked morphologic transformation in NRK-52E induced by TGF-β1. Meanwhile, ginsenoside Rg1 inhibited the expression of α-SMA and the loss of E-cadherin, subsequently decreased the levels of collagen I and fibronectin in a dose-dependent manner. In addition, western blot analysis indicated that ginsenoside Rg1 inhibited the expression of P-ERK1/2 in NRK-52E induced by TGF-β1. These results suggest that ginsenoside Rg1 can restrain the process of EMT maybe via suppressing the expression of P-ERK1/2 in vitro.
[本文引用:1]
|
| [21] |
Increasing evidence from various clinical and experimental studies has demonstrated that the inflammatory microenvironment facilitates tumor metastasis. Clinically, it will be a promising choice to suppress tumor metastasis by targeting inflammatory microenvironment. Our previous studies have demonstrated that wogonin (a bioflavonoid isolated from the traditional Chinese medicine of Huang-Qin) possesses the anti-metastatic and anti-inflammatory activity, but we have little idea about its efficacy on inflammatory-induced tumor metastasis and the mechanism underlying it. In this study, we focused on epithelial mesenchymal transition (EMT), the first step of tumor metastasis, to evaluate the effects of wogonin on tumor metastasis in inflammatory microenvironment. We found that wogonin inhibited THP-1 conditioned-medium- (CM-) and IL-6-induced EMT by inactivating STAT3 signal. And in wogonin-treated A549 cells which pretreated with THP-1 CM or IL-6, the expression level of E-cadherin, an EMT negative biomarker, increased while that of N-cadherin, Vimentin, and EMT-related transcription factors including Snail and Twist decreased. Moreover, wogonin inhibited IL-6-induced phosphorylation of STAT3, prevented p-STAT3 dimer translocation into the nucleus, and suppressed the DNA-binding activity of p-STAT3. Interestingly, similar results were obtained in the tumor xenografts mice, including downregulation of p-STAT3, N-cadherin, and Vimentin while up-regulation of E-cadherin. Wogonin also inhibit the metastasis of A549 cells in vivo. Taken all data together, we concluded that wogonin suppresses tumor cells migration in inflammatory microenvironment by inactivating STAT3 signal. 漏 2014 Wiley Periodicals, Inc.
[本文引用:1]
|
| [22] |
Abstract Inflammatory microenvironment created by immune cells is favorable for tumor metastasis. Epithelial-mesenchymal transition (EMT) is involved in the progression of cancer invasion and metastasis in inflammatory microenvironment. In this study, we sought to investigate the effects of Icariside II, a flavonol glycoside isolated from Epimedium koreanum Nakai, on A549 and H1299 cells migration in inflammatory microenvironment. At non-cytotoxic concentrations, Icariside II could inhibit invasion and EMT of A549 and H1299 cells induced by LPS-stimulated-THP-1 medium or by pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Exposure to Icariside II resulted in the increment of E-cadherin, accompanied with decrement of N-cadherin, vimentin, Slug, and Snail in A549 and H1299 cells stimulated by TNF1α. Furthermore, Icariside II suppressed TNF-α-triggered nuclear translocation of NF-κB and phosphorylation of IκBα, and repressed the DNA-binding activity of NF-κB. Further data demonstrated that Akt/GSK-3β, other than MAPK signaling pathway was taking a part in the inhibitory potential of Icariside II on NF-κB activation. Importantly, Icariside II also impeded lung metastasis of A549 cells and EMT in nude mice. In conclusion, Icariside II might prohibit invasion through inactivating Akt/NF-κB pathway. 08 2016 Wiley Periodicals, Inc.
[本文引用:1]
|
| [23] |
|
| [24] |
61Sesamin reduced TGF-β1-induced proliferation and activation of primary fibroblasts.61Sesamin suppressed TGF-β1-indeced EMT in A549 cells.61Sesamin inhibited subepithelial fibrosis in ovalbumin-challenged mice.61Sesamin protected against airway basement membrane thickening.
[本文引用:1]
|
| [25] |
The epithelial-to-mesenchymal transition (EMT) is a well-known prerequisite for cancer cells to acquire the migratory and invasive capacity, and to subsequently metastasize. Bufalin is one of the major active components of the traditional Chinese medicine Chan Su, and accumulating evidence has shown its anticancer effect in multipe types of cancer. However, the role of bufalin in transforming growth factor-β (TGF-β)-induced EMT and migration remains unclear. In the present study, the effect of bufalin on TGF-β-induced EMT and migration was investigated in human lung cancer A549 cells. TGF-β induced EMT in A549 cells and increased their migratory ability, which were markedly suppressed by bufalin. Additionally, TGF-β-induced upregulation of Twist2 and zinc finger E-box binding homeobox 2 (ZEB2), as well as the phosphorylation of Smad2 and Smad3 were also inhibited by bufalin. However, the Smad-independent signaling pathways were not affected. Further analysis showed that the TGF-β receptor I (TβRI) and TGF-β receptor II (TβRII) were downregulated in the presence of bufalin. Pretreatment with SB431542, a potent inhibitor of the phosphorylation of TβRI, significantly attenuated TGF-β-induced EMT, mimicking the effect of bufalin on A549 cells. Taken together, these results suggest that bufalin suppresses TGF-β-induced EMT and migration by downregulating TβRI and TβRII in A549 cells.
[本文引用:1]
|
| [26] |
The epithelial-mesenchymal transition (EMT) is an important factor in lung cancer metastasis, and targeting EMT is a potential therapeutic strategy. Fucosyltransferase IV (FUT4) and its synthetic cancer sugar antigen Lewis Y (LeY) was abnormally elevated in many cancers. In this study, a traditional Chinese medicine ginsenoside Rg3 was used to investigate whether its inhibition to EMT and invasion of lung cancer is by the glycobiology mechanism. We found that Rg3 treatment (25, 50, 100 渭g/ml) inhibited cell migration and invasion by wound-healing and transwell assays. Rg3 could significantly alter EMT marker proteins with increased E-cadherin, but decreased Snail, N-cadherin and Vimentin expression. Rg3 also down-regulated FUT4 gene and protein expression in lung cancer cells by qPCR, Western blot and immunofluorescence. After FUT4 down-regulated with shFUT4, EMT was obviously inhibited. Furthermore, the activation of EGFR through decreased LeY biosynthesis was inhibited, which blocked the downstream MAPK and NF-魏B signal pathways. In addition, Rg3 reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. In conclusion, Rg3 inhibits EMT and invasion of lung cancer by down-regulating FUT4 mediated EGFR inactivation and blocking MAPK and NF-魏B signal pathways. Rg3 may be a potentially effective agent for the treatment of lung cancer.
[本文引用:1]
|
| [27] |
Cinnamaldehyde, the main chemical component of the essential oil separated from the traditional herb Cinnamomum cassia, has been demonstrated to be an efficient cytotoxic agent against several human cancers. The present experiment showed that cinnamaldehyde dose-dependently depresses the proliferation of three types of NSCLC cells and induces cell apoptosis in vitro and in vivo. Moreover, cinnamaldehyde attenuated CoCl2-induced EMT and decreased matrix metalloprotease (MMP) family while the in vivo study showed the same trend. Mechanistically, cinnamaldehyde imitated the suppressive effect of XAV939 on cell motility and EMT which could be impaired by LiCl. Collectively, our research demonstrated for the first time that cinnamaldehyde is able to inhibit NSCLC cell growth by inducing apoptosis and reverse EMT through terminating Wnt/尾-catenin pathway, which might supply further insight into cinnamaldehyde-mediated anti-tumor effect against NSCLC for better prognosis.
[本文引用:1]
|
| [28] |
Abstract Metastasis frequently occurs in advanced ovarian cancer, which not only leads to substantial mortality but also becomes a major challenge to effective treatment. Epithelial-mesenchymal transition (EMT) is a key mechanism facilitating cancer metastasis. Targeting the EMT process with more efficacious and less toxic agents to prevent metastasis is of significant therapeutic value for ovarian cancer treatment. The anti-EMT function and mechanism of ginsenoside Rb1, a monomer composition extracted from the traditional Chinese herb Panax ginseng or P. notoginseng , was investigated in the present study. Western blotting demonstrated that treatment with ginsenoside Rb1 antagonized hypoxia-induced E-cadherin downregulation and vimentin upregulation in SKOV3 and 3AO human ovarian cancer cells. Wound healing assays and in vitro migration assays indicated that ginsenoside Rb1 weakened hypoxia-enhanced cell migration ability. Furthermore, it was demonstrated that microRNA (miR)-25 is upregulated by hypoxia in ovarian cancer cells, which was attenuated by ginsenoside Rb1 treatment. Additionally, forced expression of miR-25 in ovarian cancer cells was identified to not only trigger EMT, but also block the suppressive effects of ginsenoside Rb1 on hypoxia-induced EMT by negatively targeting the E-cadherin transactivator, EP300. In conclusion, ginsenoside Rb1 may reverse hypoxia-induced EMT by abrogating the suppression of miR-25 on EP300 and E-cadherin, which suggests that ginsenoside Rb1 may be a potential therapeutic candidate for the treatment of ovarian cancer.
[本文引用:1]
|
| [29] |
The prognosis of patients with ovarian cancer has remained poor mainly because of aggressive cancer progression. Since epithelial-mesenchymal transition (EMT) is an important mechanism mediating invasion and metastasis of cancer cells, targeting the EMT process with more efficacious and less toxic compounds to inhibit metastasis is of great therapeutic value for the treatment of ovarian cancer. We have found for the first time that the ginsenoside 20(S)-Rg3, a pharmacologically active component of the traditional Chinese herb Panax ginseng, potently blocks hypoxia-induced EMT of ovarian cancer cells in vitro and in vivo. Mechanistic studies confirm the mode of action of 20(S)-Rg3, which reduces the expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha) by activating the ubiquitin-proteasome pathway to promote HIF-1 alpha degradation. A decrease in HIF-1 alpha in turn leads to up-regulation, via transcriptional suppression of Snail, of the epithelial cell-specific marker E-cadherin and down-regulation of the mesenchymal cell-specific marker vimentin under hypoxic conditions. Importantly, 20(S)-Rg3 effectively inhibits EMT in nude mouse xenograft models of ovarian cancer, promising a novel therapeutic agent for anticancer therapy.
[本文引用:1]
|
| [30] |
Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in聽vitro and in聽vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in聽vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent.
[本文引用:1]
|
| [31] |
The flavonoid baicalein, a historically used Chinese herbal medicine, shows a wide range of biological and pharmaceutical effects, among which its potent antitumor activity has raised great interest in recent years. However, the molecular mechanism involved in the antimetastatic effect of baicalein remains poorly understood. This study aimed to verify the inhibitory effects of baicalein on metastasis of MDA-MB-231 human breast cancer cells both in vitro and in vivo, as well as to investigate the related mechanisms. MTT assay was used to examine the inhibition of baicalein on proliferation of MDA-MB-231 cells. Wound healing assay and the in vitro invasion assay was carried out to investigate the effects of baicalein on migration and invasion of MDA-MB-231 cells, respectively. In order to explore the effects of baicalein on tumor metastasis in vivo, xenograft nude mouse model of MDA-MB-231 cells was established. Animals were randomly divided into four groups (control, therapy group, and low-dose and high-dose prevention group, n=6), and treated with baicalein as designed. Following sacrifice, their lungs and livers were collected to examine the presence of metastases. qRT-PCR and Western blot were performed to study the effects of baicalein on expression of SATB1, EMT-related molecules, and Wnt/尾-catenin signaling components of MDA-MB-231 cells as well as the metastatic tissue. Effects of baicalein on the expression of target proteins in vivo were also analyzed by immunohistochemistry. Our results indicated that baicalein suppressed proliferation, migration, and invasion of MDA-MB-231 cells in a time- and dose-dependent manner. Based on assays carried out in xenograft nude mouse model, we found that baicalein inhibited tumor metastasis in vivo. Furthermore, baicalein significantly decreased the expression of SATB1 in MDA-MB-231 cells. It suppressed the expression of vimentin andSNAILwhile enhancing the expression of E-cadherin. Baicalein also downregulated the expression of Wnt1 and 尾-catenin proteins and transcription level of Wnt/尾-catenin-targeted genes. Our results demonstrate that baicalein has the potential to suppress breast cancer metastasis, possibly by inhibition of EMT, which may be attributed to downregulation of both SATB1 and the Wnt/尾-catenin pathway. Taken together, baicalein may serve as a promising drug for metastasis treatment of breast cancer.
[本文引用:1]
|
| [32] |
Abstract OBJECTIVE: To examine the effect of brucine on the migration, invasion, adhesion and expressions of epithelial-to-mesenchymal transition (EMT) markers and matrix metalloproteinases (MMPs) in the highly metastatic breast cancer cell lines MDA-MB-231 and Hs578-T. METHODS: MDA-MB-231 and Hs578-T cells were divided to 4 groups: the control group (0.1% DMSO), and 25, 50 and 100 0204mol/L brucine groups. The cell viability was determined using a CellTiter-Glo0003 luminescent cell viability. The scratch wound healing assay and tanswell migration assay were used to determine the migration ability of these cells treated by different concentrations of brucine. The proliferation rate, invasive potential and adhesive ability were respectively performed by colony formation assay, transwell invasion assay and adhension assay. The protein and mRNA expressions of EMT biomarkers, MMP-2 and MMP-9 were investigated by real-time reverse transcription polymerase chain reaction and Western blot. RESULTS: Compared with the control group, brucine had little effect on cell viability or proliferation (P>0.05), but led to a dose-dependent decrease on migration, invasion, adhension of MDA-MB-231 and Hs578-T cells (P<0.01). Furthermore, brucine increased the protein and mRNA levels of EMT markers such as E-cadherin and 0205-catenin in MDA-MB-231 and Hs578-T cells, and decreased the protein and mRNA levels of mesenychmal markers such as vimentin and fifibronectin, as well as the expressions of MMP-2 and MMP-9 (all P<0.01). CONCLUSION: Brucine inhibited triple negative breast cancer cells metastasis potentially through EMT reversion and MMP-2 and MMP-9 inhibition.
[本文引用:1]
|
| [33] |
Oridonin (ORI) can inhibit proliferation and migration in various types of cancer cell lines. However, the exact mechanism remains unclear. We investigated the migration inhibitory effect of ORI on human pancreatic cancer SW1990 cells and dissected the possible molecular mechanism(s). CCK-8 assay was used to observe the cell viability. Wound healing assay, transwell assay and spontaneous metastasis model were used to observe the migration activities. Real-time PCR, immunofluorescence, western blot analysis and immunohistochemistry methods were used to observe the expression of genes or proteins. ORI inhibited the migration of SW1990 cells. Real-time PCR and immuno-fluorescence analyses of epithelial-to-mesenchymal transition (EMT) markers were compared between control group and ORI group. The expression of mesenchymal molecular markers, such as vimentin, snail and slug decreased. The expression of epithelial-related marker E-cadherin increased. Wnt/β-catenin signalling was inhibited by ORI using luciferase reporter assay. ORI can decrease the β-catenin protein level not only in the nucleus, but also in the cytoplasm and the whole cell after the treatment with ORI and glycogen synthase kinase 3β (GSK3β) was increased in the ORI-treated group. CHIR could attenuate the effects of ORI in SW1990 cells. We established a mice model by injecting 102×02106SW1990 cells into nude mice intraperitoneally to test whether ORI affects tumour metastasis. Metastatic formation was inhibited by ORI (5 and 1002mg/kg) compared with the control group. Tumour sections stained with anti-E-cadherin, anti-vimentin and anti-β-catenin antibodies revealed that ORI inhibited EMT, as well as the Wnt/β-catenin pathway in vivo. ORI can inhibit pancreatic cancer cell SW1990 migration and EMT by down-regulating Wnt/β-catenin signal transduction in vitro and in vivo. Therefore, it can be potentially and effectively used in the clinical management of pancreatic cancer.
[本文引用:1]
|
| [34] |
Abstract The pancreatic cancer is among the most aggressive malignancies with strong proclivity to metastasis. The malignancy during pancreatic cancer progression is largely ascribed to epithelial-mesenchymal transition (EMT). Here we showed that toosendanin (TSN), which is an active component in traditional Chinese medicine, can strongly attenuate pancreatic cancer progression. TSN suppressed the viability and grow of pancreatic cancer cells in a dose-dependent manner. The migration and invasion of pancreatic cancer cells were also consistently inhibited dose-dependently. TSN can reverse the TGF-脦虏 induced EMT and morphological change in pancreatic cancer cells by increasing Ecadherin expression while reducing Vimentin, ZEB1 and SNAIL levels. Furthermore, TSN evidently repressed xenograft tumor growth in mouse pancreatic cancer models without significantly toxic side effects. Mechanistic studies suggested that TSN mediated pancreatic cancer inhibition by blocking Akt/mTOR signaling pathway. Our results showed that TSN inhibits pancreatic cancer progression via downregulating Akt/mTOR signaling. Since the concentrations of TSN used in current study is very low, our results demonstrated that TSN can inhibit pancreatic cancer progression thereby implying that TSN can be used as a potential pharmacological agent especially in treatment of pancreatic cancer. Copyright 脗漏 2017 Elsevier Inc. All rights reserved.
[本文引用:1]
|
| [35] |
Abstract Hepatocellular carcinoma (HCC) is difficult to diagnose early, resulting in only 30% resection rate. HCC is a relatively chemo-resistant tumor, molecular targeted therapy can only benefit approximately 30% patients with liver cancer. Bufalin (Bu) is one of the topoisomerase II inhibitors, many studies have recently focused on the anticancer activities of bufalin. In the present study, we report that bufalin can inhibit the proliferation, invasion and metastasis of liver cancer cells via the Hh signaling pathway. The human high metastasis potential LM3 hepatoma cells (HCC-LM3) were cultured in聽vitro, bufalin and/or Hedgehog signaling pathway inhibitors (GANT61, cyclopamine) was added into cell culture fluid for 72聽h to observe the antitumor effect of bufalin. The results showed that bufalin was able to inhibit epithelial mesenchymal transition (EMT), and extracellular matrix (ECM) degradation and angiogenesis of liver cancer cells by influencing the expression of Ptch1'Gli1'Gli3 proteins in Hh signaling pathway. Bufalin could downregulate the downstream target molecules of MMP-2, MMP-9, 尾-catenin and VEGF in liver cancer cells by influencing the Gli1 and Gli3 expression of Hh signaling pathway, and upregulate the E-cadherin expression of liver cancer cells by influencing the Gli3 expression of Hh signaling pathway. Therefore, the present study shows that bufalin combined with Hedgehog signaling pathway inhibitors can significantly reduce the malignant biological behavior of the liver cancer cells.
[本文引用:1]
|
| [36] |
It has been reported that there are multiple mechanisms by which bufalin could exert its antimetastatic effect. HIF-1α has been reported to be involved in tumor migration and invasion by regulating EMT. However, it is not known whether bufalin could exert the antimetastatic effect by modulating HIF-1α expression in hepatocellular carcinoma. In the present study, we aimed to evaluate the antimetastatic potential of bufalinin vivoandin vitro. Our results demonstrated that the liver/lung metastases were significantly reduced in bufalin-treated mice, as tested in the orthotopic transplanted and tail vein injection tumor models. Furthermore, the epithelial-to-mesenchymal transition (EMT) was inhibited in bufalin-treated tumors, as reflected the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, Snail. Similar results were observed in SMMC7721 cells treated with bufalin. Moreover, the transforming growth factor-β1 (TGF-β1)-induced EMT was also abrogated by bufalin. Mechanistically, our study demonstrated that hypoxia-inducible factor-1α (HIF-1α) played an important role in the antimetastatic effect of bufalin in hepatocellular carcinoma. Importantly, HIF-1α expression may be regulated through the inhibition of the PI3K/AKT/mTOR pathway. Taken together, our results suggest that bufalin suppresses hepatic tumor invasion and metastasis and that this process may be related to the PI3K/AKT/mTOR/ HIF-1α axis.
[本文引用:1]
|
| [37] |
Cordycepin, also known as 3-deoxyadenosine, is an analogue of adenosine extracted from the traditional Chinese medicine 090008Dong Chong Xia Cao090009. Cordycepin is an active small molecular weight compound and is implicated in modulating multiple physiological functions including immune activation, anti-aging and anti-tumor effects. Several studies have indicated that cordycepin suppresses tumor progression. However, the signaling pathways involved in cordycepin regulating cancer cell motility, invasiveness and epithelial-mesenchymal transition (EMT) remain unclear. In this study, we found that cordycepin inhibits hepatocellular carcinoma (HCC) cell proliferation and migration/invasion. Treatment of cordycepin results in the increasing expression of epithelial marker, Ecadherin while no significant effect was found on N-cadherin 02±-catenin and 0205-catenin. Furthermore, although the expression of focal adhesion kinase (FAK) was slightly reduced, the level of phosphorylated FAK was significantly reduced by the treatment of cordycepin. In addition, cordycepin significantly suppresses the expression of integrin 02±3, integrin 02±6 and integrin 02051 which are crucial interacting partners of FAK in regulating the focal adhesion complex. These results suggest cordycepin may contribute to EMT, antimigration/ invasion and growth inhibitory effects of HCC by suppressing E-cadherin and integrin/FAK signaling. Thus, cordycepin is a potential therapeutic or supplementary agent for preventing HCC tumor progression.
[本文引用:1]
|
| [38] |
Abstract Ginseng has become one of the most commonly used alternative herbal medicines and its active component, ginsenoside Rg1, possesses known pharmacological effects, including anticancer properties. However, the effects of ginsenoside Rg1 on metastasis have not been investigated. The present study demonstrated that ginsenoside Rg1 was able to suppress transforming growth factor62β1 (TGF62β1)62induced invasion and migration in HepG2 liver cancer cells. This suppression was associated with the inhibition of TGF62β162induced epithelial to mesenchymal transition (EMT). Furthermore, TGF62β1 induced HepG2 cells to undergo EMT and significantly promoted cell invasion and migration. When cells were pretreated with ginsenoside Rg1 for 2402h and subsequently exposed to TGF62β1 for 2402h, the results demonstrated that ginsenoside Rg1 inhibited the initiation of TGF62β162induced EMT. In addition, HepG2 cells exhibited a mesenchymal phenotype when exposed to TGF62β1, but when exposed to ginsenoside Rg1 this effect was reversed and the cells exhibited a classical epithelial morphology. Ginsenoside Rg1 also increased the expression of the epithelial phenotype marker E62cadherin and repressed the expression of the mesenchymal phenotype marker vimentin. In conclusion, the results of the present study suggest that ginsenoside Rg1 may suppress liver cancer invasion and migration in02vitro through inhibiting TGF62β162induced EMT.
[本文引用:1]
|
| [39] |
Tumor invasion and metastasis are closely associated with epithelial-mesenchymal transition (EMT). EMT refers to epithelial cells under physiological and pathological conditions that are specific to mesenchymal transition. Curcumin inhibits EMT progression via Wnt signaling. The Wnt signaling pathway is a conservative EMT-related signaling pathway that is involved in the development of various tumors. In the present study, MTS assays were employed to analyze the proliferation of curcumin-treated cells. Naked cuticle homolog 2 (NKD2), chemokine receptor 4 (CXCR4) and antibodies associated with EMT were examined in SW620 colorectal cancer cell lines using western blot analysis and real-time qPCR. NKD2 small-interfering RNA (siRNA) and CXCR4 expression plasmid was synthesized and transfected into the colorectal cancer cell lines, and NKD2 and CXCR4 expression levels were detected. The results showed that curcumin significantly inhibited the proliferation of colorectal cancer cells and upregulated the expression of NKD2 in SW620 colorectal cancer cells and in the xenograft, resulting in the downregulation of key markers in the Wnt signaling. In addition, the progression of ETM was inhibited due to the overexpression of E-cadherin as well as the downregulation of vimentin. Curcumin also inhibited tumor metastasis by downregulating the expression of CXCR4 significantly. The results suggested involvement of the NKD2-Wnt-CXCR4 signaling pathway in colorectal cancer cells. In addition, curcumin is inhibit this signaling and the development of colorectal cancer.
[本文引用:1]
|
| [40] |
In this study, we investigated the potential anticancer effects of calycosin against human glioblastoma cells, including the impacts on cell proliferation, apoptosis, and cell cycle distribution. We further studied its inhibitory activity on migration and invasion in U87 and U251 cells. Furthermore, transforming growth factor beta-mediated reductions of mesenchymal-associated genes/activators, matrix metalloproteinases-2, and -9 were detected in this process. Administration of calycosin in a glioblastoma xenograft model showed that calycosin could not only reduce tumor volume but also suppress transforming growth factor beta as well as its downstream molecules. These results revealed calycosin as a potential antitumor agent in human glioblastoma.
[本文引用:1]
|
| [41] |
Abstract Glioblastoma multiforme (GBM) is one of the most lethal types of tumors and highly metastatic and invasive. The epithelial-to-mesenchymal transition (EMT) is the crucial step for cancer cells to initiate the metastasis and could be induced by many growth factors. In this study, we found that GBM8401 cells were converted to fibroblastic phenotype and the space between the cells became expanded in response to insulin-like growth factor-1 (IGF-1) treatment. Epithelial markers were downregulated and mesenchymal markers were upregulated simultaneously after IGF-1 treatment. Our results illustrate that IGF-1 was able to induce EMT in GBM8401 cells. Osthole would reverse IGF-1-induced morphological changes, upregulated the expression of epithelial markers, and downregulated the expression of mesenchymal markers. Moreover, wound-healing assay also showed that osthole could inhibit IGF-1-induced migration of GBM8401 cells. By using dual-luciferase reporter assay and real-time PCR, we demonstrated that osthole inhibited IGF-1-induced EMT at the transcriptional level. Our study found that osthole decreased the phosphorylation of Akt and GSK3尾 and recovered the GSK3尾 bioactivity in inhibiting EMT transcription factor Snail and Twist expression. These results showed that osthole inhibited IGF-1-induced EMT by blocking PI3K/Akt pathway. We hope that osthole can be used in anticancer therapy and be a new therapeutic medicine for GBM in the future.
[本文引用:1]
|
| [42] |
Renal cell carcinoma (RCC) is associated with a high frequency of metastasis and only few therapies substantially prolong survival. Honokiol, isolated from Magnolia spp. bark, has been shown to exhibit pleiotropic anticancer effects in many cancer types. However, whether honokiol could suppress RCC metastasis has not been fully elucidated. In the present study, we found that honokiol suppressed renal cancer cells' metastasis via dual-blocking epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties. In addition, honokiol inhibited tumor growth in vivo. It was found that honokiol could upregulate miR-141, which targeted ZEB2 and modulated ZEB2 expression. Honokiol reversed EMT and suppressed CSC properties partly through the miR-141/ZEB2 axis. Our study suggested that honokiol may be a suitable therapeutic strategy for RCC treatment.
[本文引用:1]
|
| [43] |
Gastric cancer stem cells (GCSCs) have an important role in metastasis and recurrence of gastric cancer, and novel treatment strategies that target GCSCs are urgently required. Although evodiamine (Evo), a derivative of the traditional herbal medicine Evodia rutaecarpa, has been reported to have various biological effects, its effect on GCSCs remains unknown. In order to determine the effect of Evo on apoptosis of GCSCs, an MTS assay, flow cytometry and western blot analysis were performed. The effect of Evo on self62renewal in GCSCs was measured by alterations in the sphere formation ability, the expression of induced62pluripotent stem cell factors, expression of epithelial-to-mesenchymal transition (EMT) factors and oxaliplatin resistance of gastric cancer cells (GCCs). Evo inhibited proliferation, promoted the Bax/B62cell lymphoma2 ratio and altered active caspase623 expression of GCSCs. In addition, Evo decreased the sphere formation ability, the expression of Sox2, KLF4, Bmi621 and Oct4, and oxaliplatin resistance in GCCs. Evo decreased the expression of Slug, Twist, Zeb1 and vimentin, suggesting an inhibitory effect on EMT. Furthermore, the expression of β62catenin, c62Myc and cyclinD1 was decreased in Evo62treated spheroids from GCCs. In conclusion, Evo inhibited the Wnt/β62catenin signaling pathway to inhibit proliferation and stem cell properties of GCSCs and repressed the EMT. The present findings highlight the prospect of Evo as a CSCs-targeted therapy in gastric cancer.
[本文引用:1]
|
| [44] |
Metastasis is the main cause of death in osteosarcoma. Targeting the process of metastasis is a main strategy for osteosarcoma therapy. As a traditional Chinese medicine, Zanthoxylum nitidum (Roxb) has been applied to treat various diseases, including cancer. However, no evidence has been shown on the anti-metastasis effect of nitidine chloride (NC) that was extracted from Zanthoxylum nitidum (Roxb) on osteosarcoma cells, or its underling mechanisms. In the present study, we aimed to demonstrate the role of NC on the migration and invasion of osteosarcoma cells. Viability and proliferation of osteosarcoma cells were examined by MTT assay. Then, by appling scratch wound healing assay and Transwell assays, we evaluated migratory and invasive ability of the cells, respectively. Moreover, the expression of epithelial-to-mesenchymal transition (EMT) markers were determined after treatment with NC. Furthermore, the expression of Akt, GSK-3β and Snail were detected by western blot analysis. In addition, the GSK-3β activity was examined by GSK-3β kinase assay. Finally, an inhibitor of GSK-3β, lithium chloride (LiCl) was applied to testify the effect of NC on the expression of EMT markers and Snail. We found that the proliferative, migratory and invasive ability of the U2OS osteosarcoma cells were all suppressed when treated with NC. NC increased the expression of E-cadherin and decreased the expression of N-cadherin, vimentin and fibronectin in a dose-dependent manner. NC also exerted its ability to suppress the phosphorylation of Akt and GSK-3β so as to activate GSK-3β. Then, by using an GSK-3β inhibitor, LiCl, we revealed the effect of GSK-3β in the expression of EMT markers. The expression of Snail was inhibited when treated with NC and LiCl also reversed the NC-inhibited Snail expression. Taken together, these results revealed that NC suppressed EMT and decreased the invasive ability of osteosarcoma cells via the Akt/GSK-3β/snail signaling pathway.
[本文引用:1]
|
| [45] |
APS (Acta Pharmacologica Sinica), the top pharmacology research journal based in China, publishes original articles and reviews on all aspects of pharmacology and the related life sciences
[本文引用:1]
|
| [46] |
Tanshinone IIA (Tan-IIA) is an extract from the widely used traditional Chinese medicine (TCM) Danshen (Salvia miltiorrhiza), and has been found to attenuate the proliferation of bladder cancer (BCa) cells (The IC50were: 5637, 2.6 渭g/mL; BFTC, 2 渭g/mL; T24, 2.7 渭g/mL, respectively.). However, the mechanism of the effect of Tan-IIA on migration inhibition of BCa cells remains unclear. This study investigates the anti-metastatic effect of Tan-IIA in human BCa cells and clarifies its molecular mechanism. Three human BCa cell lines, 5637, BFTC and T24, were used for subsequent experiments. Cell migration and invasion were evaluated by transwell assays. Real-time RT-PCR and western blotting were performed to detect epithelial-mesenchymal transition (EMT)-related gene expression. The enzymatic activity of matrix metalloproteinases (MMP) was evaluated by zymography assay. Tan-IIA inhibited the migration and invasion of human BCa cells. Tan-IIA suppressed both the protein expression and enzymatic activity of MMP-9/-2 in human BCa cells. Tan-IIA up-regulated the epithelial marker E-cadherin and down-regulated mesenchymal markers such as N-cadherin and Vimentin, along with transcription regulators such as Snail and Slug in BCa cells in a time- and dose-dependent manner. Mechanism dissection revealed that Tan-IIA-inhibited BCa cell invasion could function via suppressed chemokine (C-C motif) ligand 2 (CCL2) expression, which could be reversed by the addition of CCL2 recombinant protein. Furthermore, Tan-IIA could inhibit the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) (Tyr705), which cannot be restored by the CCL2 recombinant protein addition. These data implicated that Tan-IIA might suppress EMT on BCa cells through STAT3-CCL2 signaling inhibition. Tan-IIA inhibits EMT of BCa cells via modulation of STAT3-CCL2 signaling. Our findings suggest that Tan-IIA can serve as a potential anti-metastatic agent in BCa therapy.
[本文引用:1]
|
| [47] |
Here we showed that Osthole, 7-methoxy-8-(3-methyl-2-butenyl) coumarin, a bioactive coumarin derivative extracted from medicinal plants, inhibited migration, invasion, epithelial to mesenchymal transition (EMT) in androgen-independent prostate cancer (AIPC) cellsin vitroand metastasis of AIPCin vivo. In patients, high Snail levels were correlated with a higher histological Gleason sum and poor survival rates. Osthole inhibited the TGF-β/Akt/MAPK pathways, reduced Snail-DNA-binding activity and induced E-cadherin. We found that osthole decreased miR-23a-3p. Ectopic miR-23a-3p suppressed E-cadherin 3′ untranslated region reporter activity and E-cadherin expression, and relieved the motility suppression caused by osthole treatment.
[本文引用:1]
|
| [48] |
Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis fruit is widely used in Chinese medicine for the treatment of hepatic, renal, heart, cerebrovascular and infectious diseases. AIM OF THE STUDY: To investigate the effects of Schisandra chinensis fruit extract (SE) on albuminuria and podocyte injury as well as the underlying mechanism in the mouse model of streptozotocin (STZ)-induced diabetic nephropathy and in cultured mouse podocyte cells. MATERIALS AND METHODS: SE was orally administrated in STZ-induced diabetic nephropathy mice for 7 weeks, at a daily dose of 5g/kg body weight. The urinary albumin/creatinine ratio and urine albumin excretion rate were measured at the 6th and 9th week of the experiment. The extent of glomerulosclerosis and extracellular matrix deposition were determined by periodic acid-silver methenamine and Masson's trichrome staining. The amount of podocytes and the integrity of the slit diaphragm were detected by immunohistological staining of podocyte markers, Wilms' tumor 1 and nephrin. Alpha-smooth muscle actin, E-cadherin and plasminogen activator inhibitor-1 were measured by western blot and immunohistological staining to evaluate the level of epithelial-to-mesenchymal transition (EMT). Real-time reverse transcription PCR was used to detect the mRNA level of E-cadherin, alpha-SMA and snail in cultured podocyte cells. RESULTS: Treatment with SE significantly decreased the urine albumin excretion rate and urinary albumin/creatinine ratio. In addition, SE attenuated glomerulosclerosis and protected against podocyte loss and integrity of the slit diaphragm. Furthermore, SE effectively prevented the EMT of podocytes caused by diabetic nephropathy. CONCLUSIONS: Our studies suggest that SE might be beneficial for diabetic nephropathy. The effects of SE on attenuating albuminuria and glomerulosclerosis are possibly mediated by preserving podocyte integrity through suppressing EMT. Copyright 漏 2012 Elsevier Ireland Ltd. All rights reserved.
[本文引用:1]
|
| [49] |
Abstract Aristolochic acid (AA) is known as a potent mutagen that induces significant cytotoxic and mutagenic effects on renal tubular epithelial cells. Clinically, the persistent injury of AA results in the infiltration of inflammatory cells, epithelial-to-mesenchymal transition (EMT), and renal tubulointerstitial fibrosis. There are no truly effective pharmaceuticals. In this study, we investigated the potential role of the extract of Sedum sarmentosum Bunge (SSB), a traditional Chinese herbal medicine, on rat tubuloepithelial (NRK-52E) cells after AA injury in vitro. Evidence revealed that AA induced mitochondrial-pathway-mediated cellular apoptosis, accompanied by cell proliferation in a feedback mechanism. Treatment with SSB also induced cells to enter early apoptosis, but inhibited cell proliferation. In cultured NRK-52E cells, AA induced the imbalance of MMP-2/TIMP-2 and promoted EMT and ECM accumulation. SSB treatment significantly alleviated AA-induced NRK-52E cells fibrosis-like appearance, inhibited the induction of EMT, and deposition of ECM. SSB also decreased the activity of the NF-脦潞B signaling pathway, resulting in down-regulated expression of NF-脦潞B-controlled chemokines and pro-inflammatory cytokines, including MCP-1, MIF, and M-CSF, which may regulate the macrophage-mediated inflammatory reaction during renal fibrosis in vivo. Therefore, these findings suggest that SSB exerts protective effects against AA-induced tubular epithelial cells injury through suppressing the synthesis of inflammatory factors, EMT, and ECM production.
[本文引用:1]
|
| [50] |
These findings suggest that SSBE may have therapeutic potential for fibrotic kidney diseases.
[本文引用:2]
|
| [51] |
|
| [52] |
Chemotherapy is the main approach for treating advanced and recurrent carcinoma, but the clinical performance of chemotherapy is limited by relatively low response rates, drug resistance, and adverse effects that severely affect the quality of life of patients. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance has been investigated in recent studies. Our recent studies have found that the aqueous extract of Solanum nigrum (AESN) is a crucial ingredient in some traditional Chinese medicine formulas for treating various types of cancer patients and exhibits antitumor effects. We evaluated the suppression of EMT in MCF-7 breast cancer cells treated with AESN. The mitochondrial morphology was investigated using Mitotracker Deep-Red FM stain. Our results indicated that AESN markedly inhibited cell viability of MCF-7 breast cancer cells through apoptosis induction and cell cycle arrest mediated by activation of caspase-3 and production of reactive oxygen species. Furthermore, mitochondrial fission was observed in MCF-7 breast cancer cells treated with AESN. In addition to elevation of E-cadherin, downregulations of ZEB1, N-cadherin, and vimentin were found in AESN-treated MCF-7 breast cancer cells. These results suggested that AESN could inhibit EMT of MCF-7 breast cancer cells mediated by attenuation of mitochondrial function. AESN could be potentially beneficial in treating breast cancer cells, and may be of interest for future studies in developing integrative cancer therapy against proliferation, metastasis, and migration of breast cancer cells.
[本文引用:1]
|
| [53] |
Abstract BACKGROUND: Angelica sinensis (Oliv) Diels (Apiaceae) is a traditional medicine that has been used for more than 2000 years in China. It exhibits various therapeutic effects including neuroprotective, anti-oxidant, anti-inflammatory, and immunomodulatory activities. Angelica polysaccharides (APs), bioactive constituents of Angelica have been shown to be responsible for these effects; however, the utility of APs for the treatment of glioma and their mechanism of action remain to be elucidated. PURPOSE: In this study, we investigated the inhibitory effects of APs on a glioma cell line and their molecular mechanism of action. STUDY DESIGN: U251 cells were utilized to confirm the effects of APs on glioma. METHODS: The human glioblastoma cell line U251 was utilized for both in vitro and in vivo models, in which we tested the effects of APs. Flow cytometry, gene expression analysis, western blotting, and MTT assays were used to elucidate the effects of APs on cell proliferation, cell cycle, and apoptosis. RESULTS: The results demonstrated that APs significantly inhibited the growth and proliferation of U251 cells and induced their apoptosis. Furthermore, APs effectively reduced the expression of several cell cycle regulators: cyclins D1, B, and E. The apoptosis suppressor protein Bcl-2 was also downregulated, and the expression of pro-apoptotic proteins Bax and cleaved-caspase-3 increased. Additionally, APs inhibited the transforming growth factor (TGF)-尾 signaling pathway and stimulated the expression of E-cadherin, thus prohibiting cell growth. CONCLUSION: In conclusion, the results indicate that APs attenuate the tumorigenicity of glioma cells and promote their apoptosis by suppressing the TGF-尾 signaling pathway. The present study therefore provides evidence of the inhibitory effects of APs against glioma progression, and proposes their potential application as alternative therapeutic agents for glioma. Copyright 漏 2017 Elsevier GmbH. All rights reserved.
[本文引用:1]
|
| [54] |
|
| [55] |
Abstract AIM OF THE STUDY: Celastrus orbiculatus has been used as a folk medicine in China for the treatment of many diseases. In the laboratory, the ethyl acetate extract of Celastrus orbiculatus (COE) displays a wide range of anticancer functions. However, the inhibition of the metastasis mechanism of COE in gastric cancer cells has not been investigated so far. The present study was undertaken to determine if the antimetastatic effects of COE were involved in inhibition of the epithelial-mesenchymal transition (EMT) of human gastric adenocarcinoma SGC-7901 cells. METHODS: The adhesion, invasion, and migration of SGC-7901 cells were determined by COE treatment in vitro, using Matrigel-coated plate, transwell membrane chamber, and wound healing models, respectively. In vivo, the growth-inhibiting and antimetastatic effects of COE on the nude mice model of gastric cancer were tested and the mechanisms were explored. The expression of EMT markers and nuclear factor κB (NF-κB)/Snail signaling pathway were evaluated by using western blotting and immunohistochemistry. RESULTS: Treatment with COE dose-dependently inhibited the proliferation, adhesion, invasion, and migration of SGC-7901 cells in vitro, which was realized by enhancing the expression of E-cadherin and reducing N-cadherin and vimentin expression. Moreover, COE suppressed the activation of NF-κB/Snail signaling pathway induced by tumor necrosis factor-α. In addition, COE effectively suppressed tumor growth and metastasis in the nude mice model due to reduced expression of N-cadherin, vimentin, NF-κB p65, and Snail and increased expression of E-cadherin in the tumor tissues. CONCLUSION: Our findings provided new evidence that COE is an effective inhibitor of metastatic potential of SGC-7901 cells through suppression of EMT and NF-κB/Snail signal pathway. Based on these findings, COE may be considered a novel anticancer agent for the treatment of metastasis in gastric cancer. 08 The Author(s) 2015.
[本文引用:1]
|
| [56] |
To investigate the effects and possible mechanisms of action of Curcuma wenyujin Y. H. Chen et C. Ling n-Butyl alcohol extract (CWNAE) on repression of human gastric cancer (GC) AGS cell invasion indu
[本文引用:1]
|
| [57] |
Diabetic nephropathy (DN) is a major cause of chronic kidney failure and characterized by interstitial and glomeruli fibrosis. Epithelial-to-mesenchymal transition (EMT) plays an important role in the pathogenesis of DN. Tong xinluo (TXL), a Chinese herbal compound, has been used in China with established therapeutic efficacy in patients with DN. To investigate the molecular mechanism of TXL improving DN, KK-Ay mice were selected as models for the evaluation of pathogenesis and treatment in DN. In vitro, TGF-??1 was used to induce EMT. Western blot (WB), immunofluorescence staining, and real-time polymerase chain reaction (RT-PCR) were applied to detect the changes of EMT markers in vivo and in vitro, respectively. Results showed the expressions of TGF-??1 and its downstream proteins smad3/p-smad3 were greatly reduced in TXL group; meantime, TXL restored the expression of smad7. As a result, the expressions of collagen IV (Col IV) and fibronectin (FN) were significantly decreased in TXL group. In vivo, 24???h-UAER (24-hour urine albumin excretion ratio) and BUN (blood urea nitrogen) were decreased and Ccr (creatinine clearance ratio) was increased in TXL group compared with DN group. In summary, the present study demonstrates that TXL successfully inhibits TGF-??1-induced epithelial-to-mesenchymal transition in DN, which may account for the therapeutic efficacy in TXL-mediated renoprotection.
DOI:10.1155/2014/123497
PMID:24864150
[本文引用:1]
|
| [58] |
Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies.Epithelial to mesenchymal transition (EMT) plays an important role in DN.The physiological role of microRNA-21 (miR-21) was closely linked to EMT.However, it remained elusive whether Tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-Induced EMT in DN.This study was to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-尾1/smads signals.Real-time RT-PCR, cell transfection and in situ hybridization (ISH) and laser confocal microscopy were used, respectively.Here, we revealed that TXL dose-dependently lowered miR-21 expression in tissue, serum and cell.Over-expression of miR-21 can enhance a-SMA expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression.Interestingly, TXL also increased E-cadherin expression and decreased a-SMA expression by regulating miR-21 expression.More importantly, TXL decreased col-鈪, FN, GBM, GA and albumin creatinine ratio (ACR), whereas, increased creatinine clearance ratio (Ccr).The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-Induced EMT, which was one of the mechanisms to protect DN, and that miR-21 was novel therapeutic target for TXL in diabetic nephropathy.
[本文引用:1]
|
| [59] |
This study discussed the effect of Tangzhiqing granules on podocyte epithelial-mesenchymal transition in kidney of diabetic rats. The diabetic rats were divided randomly into five groups: DM group treated with vehicle, Tangzhiqing granules low-dose treatment group, Tangzhiqing granules middle-dose treatment group, and Tangzhiqing granules high-dose treatment group. Eight Wistar rats used as control group were given saline solution. The intervention was all intragastric administration for 8 weeks. At the end of the 8 weeks, biochemical parameters and kidney weight/body weight ratio were measured. The kidney tissues were observed under light microscope and transmission electron microscopy. To search for the underlying mechanism, we examined the epithelial-to-mesenchymal transition (EMT) related molecular markers and TGF-??/smad signaling pathway key proteins expression. The results showed that Tangzhiqing granules relieved the structural damage and functional changes of diabetic kidneys. Kidney podocyte EMT related molecular markers nephrin and CD2AP expression were increased, when desmin and ??-SMA levels were decreased by Tangzhiqing granules in diabetic rats. Further TGF-??/smad signaling pathway key proteins TGF-??1 and p-smad2/3 levels were decreased in diabetic rats after treatment with Tangzhiqing granules. These findings suggest that Tangzhiqing granules may protect the podocytes of diabetic nephropathy rats via alleviating podocyte EMT and likely activating TGF??/smad signaling pathway.
[本文引用:1]
|
| [60] |
Objective:To investigate the effect of the Uremic Clearance Granule(UCG,尿毒清颗粒),a Chinese patent medicine,on tubular epithelial-to-mesenchymal transition(EMT)in a unilateral ureteral obstruction(UUO)model in vivo and transforming growth factor(TGF)-β1 induced EMT of HK-2 cells in vitro.Methods:In vivo study,50 Sprague Dawley rats were divided into three groups:a sham operation group(n=10),a UUO group(n=20),and a UUO with UCG treatment group(n=20).The UCG was given at a dose of 4.5 g/kg body weight per day by gavage after surgery.In vitro study,HK-2 cells were cultured in 10%fetal bovine serum(FBS),10%healthy rat serum,10%FBS and TGF-β1(10 ng/mL),10%healthy rat serum and TGF-β1,or10%rat serum containing the uremic clearance granule and TGF-β1.The expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin andα-smooth muscle actin(α-SMA)in kidney tissues and HK-2 cells were investigated by Western blot analysis and immunofluorescence staining.Results:The rats of the UUO group showed obvious tubulointerstitial fibrosis,compared with the sham operation group rats.Tubulointerstitial fibrosis score was reduced by 17.5%±1.1%at day 7 and by 20.0%±1.2%at day 14 in the UCG-treated group,compared with the UUO group.The UCG could maintained expression of E-cadherin and suppressed expression of vimentin andα-SMA in kidney tissues of UUO rats at days 7 and 14,as determined by Western blot analysis and immunofluorescence staining.Rat serum containing the UCG partially inhibited TGF-β1-induced fibroblast phenotype of HK-2 cells and maintained the epithelial morphology of HK-2 cells in vitro.This occurred partially through a reduction of vimentin expression and an increase of E-cadherin expression.Conclusion:These results suggest that the UCG prevents tubular EMT and may be a promising agent for treating tubulointerstitial fibrosis.
[本文引用:1]
|
| [61] |
These results demonstrated that Huangkui capsule and the flavonoids components prevent tubulointerstitial fibrosis in CRF rat involvement in the action mechanism of inhibiting NADPH oxidase/ROS/ERK pathway.
[本文引用:1]
|
| [62] |
To investigate the mechanism of action of Fuzheng Huayu recipe (FZHY) and vitamin E (Vit E) against renal interstitial fibrosis related to transforming growth factor-beta1 (TGF-β1) mediated tubular epithelial-to-mesenchymal transition. Renal interstitial fibrosis was induced by administration of HgCl 2 at a dose of 8 mg/kg body weight once a day for 9 weeks. Rats were randomly divided into four groups: normal, model, FZHY, and Vit E group. Rats in the latter two groups were treated with the FZHY recipe and Vit E respectively. HK-2 cells were treated with TGF-β1 for 24 h, followed by incubation with either SB-431542 (a potent and specific inhibitor of TβR-I kinase) or FZHY drug-containing serum for another 24 h. Hyp content in rat kidney tissue was assayed with Jamall's method and collagen deposition in kidney was visualized using Masson stain. Protein expression of TGF-β1, TβR-I, Smad2, p-Smad2, Smad3, and p-Smad3 was analyzed by Western blotting. Protein expression and the location of Smad3 in kidney was assayed by immunohistochemistry, E-cadherin, cytokeratin 18 (CK-18), α-SMA and TGF-β1 by immunofluorescent stain. FZHY and Vit E inhibited renal collagen deposition and reduced Hyp content significantly. They upregulated E-cadherin protein expression and down-regulated the protein expression of α-SMA, TGF-β1, p-Smad2, p-Smad3, and TβR-I. Lastly, they inhibited the nuclear translocation of Smad3 in fibrotic kidney tissue. FZHY drug-containing serum significantly upregulated the expression of CK-18 and down-regulated the expression of α-SMA, TβR-I, p-Smad2/3 in TGF-β1 stimulated HK-2 cells. The mechanism of action of FZHY and Vit E against renal interstitial fibrosis is related to the reversal of tubular EMT induced by TGF-β1.
[本文引用:1]
|
| [63] |
Epithelial-mesenchymal transition (EMT) refers to the transition of epithelial cells into mesenchymal cells. Emerging evidence suggests that EMT is a key point in renal interstitial fibrosis (RIF). Traditional Chinese Medicine Shenqiwan (SQW) is widely used in clinical treatment of chronic kidney disease, but the underlying mechanism remains unclear. The purpose of this study is to investigate the effect of SQW on renal fibrosis and its association with TGF-??1/Smads signaling pathway. A rat model of adenine (150???mg/kg) was established and intragastrically treated with various concentrations of SQW at dose of 1.5???g/kg, 3???g/kg, and 6???g/kg. Control group and model group were given the same volume of saline. Meanwhile, the positive control group was treated with Enalapril (4???mg/kg). Animals were sacrificed on 21st day after administration. The results showed that SQW could significantly relieve renal pathological damage caused by adenine, increase gene and protein expression of E-cadherin, and decrease the expression of Vimentin in kidney samples. In addition, SQW efficiently inhibited the mRNA and protein expression of p-Smad2/3 by upregulating Smad7. These results suggest that SQW could slow down the progression of renal fibrosis, possibly by inhibiting TGF-??1/Smads signaling pathway.
[本文引用:1]
|
| [64] |
Pulmonary fibrosis (PF) is a fatal inflammatory disease with limited effective strategies. Epithelial-mesenchymal transition (EMT) is a pivotal origin of myofibroblasts that secrete extracellular matrix (ECM) in the development of PF. High mobility group box 1 (HMGB1), one of the mediators of inflammation, has been proved abnormal activation in the pathogenesis of PF. The present study was aimed to investigate the potential effects of total glycoside of Yupingfeng (YPF-G), the natural compound extracted from Yupingfeng san, on HMGB1 activation and EMT in bleomycin-induced PF, which was a serious disease of respiratory system. The Sprague-Dawley (SD) rat model of PF was duplicated by intratracheal instillation of bleomycin (5 mg kg(-1)). After that, YPF-G (5, 10 mg kg(-1)) and prednisone (5 mg kg(-1)) were separately administered intragastrically, and then the rats were killed at days 14 and 28, respectively. Hematoxylin and eosin and Masson's trichrome staining were performed to assess the histopathologic level of lung tissues, western blotting and the common kits were utilized to investigate the hallmarks molecule expression of ECM and EMT, and the level of HMGB1 in lung tissues and serum. We found that both dose of YPF-G markedly reduced bleomycin-induced alveolitis and PF in rats. Besides, the levels of HMGB1, laminin, hyaluronic acid, and hydroxyproline were effectively reduced. Meanwhile, the increased protein expression of HMGB1 and the mesenchymal markers including vimentin and alpha-smooth muscle actin, and the decreased protein expression of epithelial marker E-cadherin were dramatically inhibited after YPF-G treatment. Our results demonstrated that YPF-G could ameliorate bleomycin-induced PF by reducing HMGB1 activation and reversing EMT.
[本文引用:1]
|
| [65] |
Abstract Activation of hepatic stellate cells (HSCs) depending on epithelial-to-mesenchymal transition (EMT) reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET) of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY) recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-0205 1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-0205 1 at both transcription and translation levels. Restoration of TGF-0205 1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) as characterized by the abolishment of EMT markers (02±-SMA and desmin) and reoccurrence of MET marker (E-cadherin). In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activated HSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4-) induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs.
[本文引用:1]
|
| [66] |
|
| [67] |
Metastasis is the leading cause of cancer-related mortality in almost all types of cancers, including colorectal cancer (CRC). Epithelial-mesenchymal transition (EMT) is a critical process during the metastatic cascade. This process may be a potential target for the diagnosis and treatment of CRC. Pien Tze Huang (PZH), a well-known traditional Chinese formula, has been demonstrated to be clinically effective in treating various types of human malignancies, including CRC. Our published data suggest that PZH can induce apoptosis, as well as inhibit cell proliferation and tumor angiogenesis, thus suppressing CRC growth in02vitro and in02vivo. We evaluated the therapeutic efficacy of PZH against CRC metastasis using a CRC liver metastasis mouse model to further explore the mechanisms underlying the antitumor action of PZH. MTT, migration, and Matrigel invasion assays were used to assess the effect of PZH on cell viability, migration and invasion. We then established an orthotopic liver metastasis model02of colon cancer using microsurgical techniques. Mice were intragastrically administered 23402mg/kg/day dose of either PZH or saline for 1402days. The body and tumor weights of the mice were measured after they were sacrificed. Moreover, we examined the effect of PZH inhibition on liver metastasis. Finally, EMT-related proteins and the TGF-β signaling pathway were assessed using immunohistochemical staining (IHS). The present data revealed that PZH significantly inhibited the migration and invasion of CT-26 cells in a dose-dependent manner, which affirmed the inhibitory effect of PZH on CRC cell metastasis. No significant change was observed between the in02vivo primary tumor growth and body weight. However, the control group had five cases of liver metastasis02(5/6), whereas one case was found in the PZH group02(1/6). Thus, PZH exhibited therapeutic efficacy against CRC metastasis without apparent toxicity. The inhibitory effect of PZH on EMT resulted in an increase in E-cadherin expression, as well as a decrease in N-cadherin expression. In addition, PZH significantly inhibited TGF-β, as well as the phosphorylation of Smad2/3 and Smad4 in the tumor tissues, indicating its suppressive action on TGF-β signaling. These molecular effects ultimately resulted in the inhibition of cancer cell EMT and tumor metastasis.
[本文引用:1]
|
| [68] |
Abstract Tumor metastasis, a complex process involving the spread of malignant tumor cells from a primary tumor site to a distant organ, is a major cause of failure of cancer chemotherapy. Epithelial-mesenchymal transition (EMT) is a critical step for the initiation of cancer metastasis. The processes of EMT and metastasis are highly regulated by a double-negative feedback loop consisting of TGF-尾1/ZEB pathway and miR-200 family, which therefore has become a promising target for cancer chemotherapy. Pien Tze Huang (PZH), a well-known traditional Chinese formula first prescribed in the Ming Dynasty, has been demonstrated to be clinically effective in the treatment of various types of human malignancy including colorectal cancer (CRC). Our published data proposed that PZH was able to induce apoptosis, inhibit cell proliferation and tumor angiogenesis, leading to the suppression of CRC growth in vitro and in vivo. To further elucidate the mode of action of PZH, in the present study we evaluated its effects on the metastatic capacities of human colorectal carcinoma HCT-8 cells and investigated the underlying molecular mechanisms. We found that PZH significantly inhibited the migration and invasion of HCT-8 cells in a dose-dependent manner. In addition, PZH treatment inhibited the expression of key mediators of TGF-尾1 signaling, such as TGF-尾1, Smad2/3 and Smad4. Moreover, PZH treatment suppressed the expression of ZEB1 and ZEB2, two critical target genes of TGF-尾1 pathway, leading to a decrease in the expression of mesenchymal marker N-cadherin and an increased expression of epithelial marker E-cadherin. Furthermore, PZH treatment upregulated the expression of miR-200a, miR-200b and miR-200c. Collectively, our findings in this study suggest that PZH can inhibit metastasis of colorectal cancer cells via modulating TGF-尾1/ZEB/miR-200 signaling network, which might be one of the mechanisms whereby PZH exerts its anticancer function.
[本文引用:1]
|
| [69] |
Hypoxia-induced activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway is frequently observed in solid tumors and is strongly associated with numerous pathophysiological processes, including the induction of epithelial-mesenchymal transition (EMT), which result in cancer progression and metastasis. Thus, inhibiting EMT through the suppression of the HIF-1 pathway may be a promising strategy for anticancer chemotherapy. Pien Tze Huang (PZH), a well-established traditional Chinese medicine has been prescribed for >450 years and has been used for centuries to clinically treat various types of human cancer. We previously reported that PZH suppresses multiple intracellular signaling pathways and thereby promotes the apoptosis of cancer cells and the inhibition of cell proliferation and tumor angiogenesis. In the present study, to further explore the mechanisms underlying the antitumor action of PZH, HCT-8 human colon carcinoma cells were cultured under hypoxic conditions and the effect of PZH on hypoxia-induced EMT was assessed. Hypoxia was found to induce EMT-associated morphological changes in HCT-8 cells, including loss of cell adhesion and the development of spindle-shaped fibroblastoid-like morphology. In addition, hypoxia was observed to reduce the expression of the epithelial marker E-cadherin, but increase that of the mesenchymal marker N-cadherin. In addition, hypoxia significantly enhanced HCT-8 cell migration and invasion and induced the activation of the HIF-1 pathway. However, treatment of the HCT-8 cells with PZH significantly inhibited the hypoxia-mediated EMT and HIF-1 signaling. These findings suggest that PZH inhibits hypoxia-induced cancer EMT through the suppression of the HIF-1 pathway, which may be one of the molecular mechanisms by which PZH exerts its antitumor activity.
[本文引用:1]
|
| [70] |
The traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used as a folk remedy for cancer. To elucidate the mode of action of PZH against cancer, in the present study we used a 5-FU resistant human colorectal carcinoma cell line (HCT-8/5-FU) to evaluate the effects of PZH on multidrug resistance (MDR) and epithelial-mesenchymal transition (EMT) as well as the activation of TGF-?? pathway. We found that PZH dose-dependently inhibited the viability of HCT-8/5-FU cells which were insensitive to treatment of 5-FU and ADM, demonstrating the ability of PZH to overcome chemoresistance. Furthermore, PZH increased the intercellular accumulation of Rhodamine-123 and downregulated the expression of ABCG2 in HCT-8/5-FU cells. In addition, drug resistance induced the process of EMT in HCT-8 cells as evidenced by EMT-related morphological changes and alteration in the expression of EMT-regulatory factors, which however was neutralized by PZH treatment. Moreover, PZH inhibited MDR/EMT-enhanced migration and invasion capabilities of HCT-8 cells in a dose-dependent manner and suppressed MDR-induced activation of TGF-?? signaling in HCT-8/5-FU cells. Taken together, our study suggests that PZH can effectively overcome MDR and inhibit EMT in human colorectal carcinoma cells via suppression of the TGF-?? pathway.
[本文引用:1]
|
| [71] |
This study aims to investigate mechanism of YiQi ChuTan Recipe (YCR) for inhibiting epithelial mesenchymal transition (EMT) of A549 cells under hypoxia. Flow cytometry was used to optimize YCR dosage by measuring A549 apoptosis, which were subjected to different treatments, including normal condition, hypoxia, hypoxia+YCR. Cell morphology and expression of EMT were measured with differential interference contrast microscopy, real-time PCR and western blot. Optimized condition of 4 mg/ml YCR and 2% O2 for 72 h was used to establish hypoxia. Under hypoxic condition, morphology of A549 cells changed from oblate fusi-form to elongated spindle. E-cadherin expression decreased while vimentin and fibronectin increased. EMT-related genes expression were significantly increased in hypoxia group compared to control group (P<0.05). After treatment with YCR, mesenchymal cells obviously decreased and EMT-related genes expression was significantly decreased (P<0.05). Changes of E-cadherin, vimentin and fibronection were significantly attenuated by YCR when compared to hypoxia group. Expression of proteins GRP78, SRC, MAPK, smad2/3 were significantly increased in hypoxia group compared to control group, but was significantly inhibited by YCR treatment. In conclusion, A549 cells underwent EMT under hypoxia while YCR reversed the EMT through GRP78, smad2/3 and SRC/MAPK signal pathway.
[本文引用:1]
|
| [72] |
Based on these above data, the conclusion could be put forward that BFD probably attenuated TGF-β1 mediated EMT in A549 cells via decreasing canonical Smad signaling pathway both in vitro and in vivo , which may help restrain the malignant phenotype induced by TGF-β1 in A549 cells to some extent.
[本文引用:1]
|
| [73] |
Lung cancer is a leading cause of cancer-associated mortality worldwide, including in developing countries such as China. Traditional Chinese medicine may provide a novel insight for the treatment of patients with lung cancer. The present study aimed to uncover the mechanism by which the Chinese herbal medicine, Fuzheng Kang-Ai (FZKA), functions on lung cancer cell metastasis. The results demonstrated that treatment with FZKA markedly inhibited cell viability, migration and invasion of lung cancer cells, as determined by cell viability and Transwell assays. Notably, the activity and expression of matrix metalloproteinase 9 (MMP9) was significantly inhibited by FZKA treatment on lung cancer cells, as determined by an MMP9 activity assay and western blot analysis. Furthermore, FZKA markedly inhibited epithelial-mesenchymal transition (EMT) of lung cancer cells by inhibiting the expression of the mesenchymal markers N-cadherin and vimentin. In addition, activation of the oncoprotein signal transducer and activator of transcription 3 (STAT3) was suppressed following treatment with FZKA. Conversely, overexpression of STAT3 was able to rescue MMP9 activity following FZKA treatment. The present study indicated that FZKA may inhibit lung cancer metastasis via the STAT3/MMP9 pathway and EMT, suggesting that FZKA may serve as a novel promising therapeutic strategy for the treatment of patients with late stage lung cancer.
[本文引用:1]
|
| [74] |
JPJD was an ideal alternative traditional Chinese medicine compound in the prevention and treatment of CRC, but its underlying mechanisms has not been fully elucidated. In this study, we demonstrated in vitro that TGF-??-induced EMT promoted the invasion and metastasis of CRC cells, reduced the expression of E-cadherin, and elevated the expression of Vimentin. However, JPJD could inhibit the invasive and migratory ability of TGF-??-stimulated CRC cells in a concentration-dependent manner through increasing the expression of E-cadherin and repressing the expression of Vimentin, as well as the inhibition of TGF-??/Smad signaling pathway. Meanwhile, JPJD reduced the transcriptional activities of EMT-associated factors Snail and E-cadherin during the initiation of TGF-??-induced EMT. In vivo, the results demonstrated that JPJD can significantly inhibit the liver and lung metastasis of orthotopic CRC tumor in nude mice, as well as significantly prolonging the survival time of tumor-bearing in a dose-dependent manner. Additionally, JPJD can upregulate the expression of E-cadherin and Smad2/3 in the cytoplasm and downregulate the expression of Vimentin, p-Smad2/3, and Snail in the orthotopic CRC tumor tissues. In conclusions, our new findings provided evidence that JPJD could inhibit TGF-??-induced EMT in CRC through TGF-??/Smad mediated Snail/E-cadherin expression.
[本文引用:1]
|
| [75] |
Background: Shenling Baizhu San (SBS) is a well-known and classical Chinese medicine formula. It has been used for treatment of gastrointestinal disorders for about nine hundred years. Recent reports showed that it was effective in curing colitis and ameliorating the major manifestations of postoperational colorectal cancer (CRC). This study was to evaluate the effects of SBS on azoxymethane (AOM) and dextran sodium sulfate (DSS) induced colitis associated CRC (caCRC) and to analyze the underlying mechanism of SBS in preventing CRC. Methods: The colon tissue of mice in different group was determined by immunohistochemistry and western blot. TGF-02051 in serum was measured by ELISA. Myeloid-derived suppressor cells (MDSCs) were identified by flow cytometry and immunohistochemistry. Results: The formed neoplasms phenotypically resembled human caCRC with upregulated 0205-catenin, p53 and proliferating cell nuclear antigen (PCNA). SBS treatment reduced the death rate of mice and decreased the incidence and multiplicity of colonic neoplasms. SBS decreased the number of MDSCs and the level of transforming growth factor 02051 (TGF-02051). SBS alleviated epithelial mesenchymal transition (EMT) through downregulating N-cadherin (N-cad), Vimentin, Fibronectin, Snail, and upregulating E-cadherin (E-cad). It reduced the activation of Wnt5a and EMT induced by TGF-02051. Conclusions: SBS reduced the death rate through decreasing the incidence and multiplicity of colonic tumors. SBS lowered MDSCs infiltration and inhibited TGF-02051 induced EMT to exert its anti-caCRC effects.
[本文引用:1]
|
| [76] |
Shaoyao decoction (SYD) is a traditional Chinese medicine prescription formulated by Liu Wan-Su, a master of traditional Chinese medicine in Jin-Yuan Dynasty. SYD is effective in treating ulcerative colitis. Paeonol, a component of SYD, inhibits colorectal cancer (CRC) cell proliferation and induces CRC cell apoptosis. In this study, azoxymethane (AOM)/dextran sodium sulfate (DSS)–induced colitis-associated CRC (caCRC) model and CRC cell lines were used to examine the effects of SYD on CRC in vivo and in vitro. A translational medicine strategy based on phytomics quality control was adopted. Liquid chromatography was employed for the chemical characterization and chemical fingerprinting of SYD. Protein expression and macrophage existence were determined by immunohistochemistry and western blot. Serum cytokines were quantified by Luminex assay. AOM/DSS-induced caCRC phenotypically resembled human caCRC. SYD significantly increased the survival rate of the mice, ameliorated the general well-being of the mice, and reduced the incidence and multiplicity of colonic neoplasms. SYD inhibited epithelial–mesenchymal transition (EMT), as indicated by upregulated epithelia cadherin and downregulated neuronal cadherin, fibronectin, vimentin, and transcription factor Snail. SYD reduced the expression levels of serum interleukin 1β, interleukin-6, tumor necrosis factor α, tumor-associated macrophages, and p65. These results showed that SYD can attenuate proinflammatory cytokines and inhibit EMT. SYD ameliorates caCRC by suppressing inflammation and inhibiting EMT. SYD might be an alternative therapy for caCRC.
[本文引用:1]
|
| [77] |
Background. Yiqi Huayu Jiedu Decoction (YHJD) can obviously improve the quality of life of those patients with gastric cancer and prolong their survival. Methods. In vitro experiments, we observe YHJD???s effect on the cells??? proliferation by MTT assay. Cell adhesion assay, wound-healing assay, and Transwell invasion assay serve to detect its influence on cells??? adhesion, migration, and invasion, respectively. Inhibitor (10?????M/L of SB431542) and activator (10???ng/mL of TGF-??) of TGF-??/Smad pathway were used to estimate whether YHJD???s impact on the biological behavior of gastric cancer cells was related to TGF-??/Smad pathway. In in vivo studies, YHJD was administered to the nude mice transplanted with gastric cancer to observe its effect on the tumor. Western blotting and immunohistochemical assay were used to test relevant cytokines of TGF-??/Smad pathway and epithelial-mesenchymal transition (EMT) in MGC-803 cells and the tumor bearing nude mice. Results. YHJD inhibited proliferation, adhesion, migration, and invasion of MGC-803 gastric cancer cells in vitro. In in vivo studies, YHJD reduced the volume of the transplanted tumors. It also enhanced the expression of E-cadherin and decreased the levels of N-cadherin, TGF-??, Snail, and Slug in both MGC-803 cells and the transplanted tumor by western blot assay. The immunohistochemical assay revealed that YHJD raised E-cadherin in the tumors of the mice; on the contrary, the expression of N-cadherin, Twist, vimentin, TGF-??R I, p-Smad2, p-Smad3, Snail, and Slug reduced. Conclusion. YHJD can effectively inhibit the invasion and metastasis of gastric cancer cells. The mechanism may be related to TGF-??/Smad pathway.
[本文引用:1]
|
| [78] |
Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors in the world. In China, traditional medicine is commonly used in the treatment of cancer. Among these medicines, Jianpi Huayu Decoction (JHD) is a typical clinical prescription against multiple tumors. However, the exact function and targets of JHD are currently unknown. The aim of this study is to assess the efficacy of JHD against HCC. JHD was shown to be an effective therapeutic strategy against HCC.
[本文引用:1]
|
| [79] |
Abstract The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype, referred to as epithelial-mesenchymal transition, is a critical process for embryonic development that also occurs in adult life, particularly during tumour progression. Tumour cells undergoing epithelial-mesenchymal transition acquire the capacity to disarm the body's antitumour defences, resist apoptosis and anticancer drugs, disseminate throughout the organism, and act as a reservoir that replenishes and expands the tumour cell population. Epithelial-mesenchymal transition is therefore becoming a target of prime interest for anticancer therapy. Here, we discuss the screening and classification of compounds that affect epithelial-mesenchymal transition, highlight some compounds of particular interest, and address issues related to their clinical application.
[本文引用:1]
|
