修回日期: 2012-07-09
接受日期: 2012-07-20
在线出版日期: 2012-07-28
上皮间质转化是一种已知的分子事件, 他不仅在正常组织器官发育过程中起着重要的作用, 而且在疾病状态也发挥着重要的作用. 越来越多的证据显示在人类大肠癌形成和肿瘤侵袭过程中发生了上皮间质转化, 而且其也参与了慢性炎症相关性纤维化和黏膜的修复过程. 在大肠癌发生发展过程中越来越多的证据支持转化生长因子β(transforming growth factor-β, TGF-β)和他下游的Smad信号传导、磷酸酰肌醇3'激酶/Akt/mTOR轴、Ras丝裂原活化蛋白激酶/Snail/Slug/FOXC2途径、Hedgehog信号通路和microRNAs等介导的上皮细胞间质转化(epithelial-to-mesenchymal transition, EMT)所发挥的重要作用. 现将对这些途径在大肠癌上皮细胞间质转化启动和发展过程中的作用进行综述. 对EMT在大肠癌发生发展过程中所起到的诱导和调控作用进行深入了解, 将会促进对相关信号通路和潜在治疗靶点分子的认识.
引文著录: 朱庆超, 秦环龙. 上皮细胞间质转化在大肠癌发生发展中的研究进展. 世界华人消化杂志 2012; 20(21): 1949-1956
Revised: July 9, 2012
Accepted: July 20, 2012
Published online: July 28, 2012
Epithelial-mesenchymal transition is a well established biological event that plays an important role not only in the normal development of tissues and organs but also in the pathogenesis of many diseases. Increasing evidence has established its presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis, and mucosal healing. A large body of evidence supports the role of transforming growth factor-β and its downstream Smad signaling, the phosphatidylinositol 3'-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microRNAs in epithelial-mesenchymal transition in the development of colorectal cancers. Here we discuss the role of these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeutic targets.
- Citation: Zhu QC, Qin HL. Progress in understanding the role of epithelial-mesenchymal transition in the pathogenesis of colorectal tumors. Shijie Huaren Xiaohua Zazhi 2012; 20(21): 1949-1956
- URL: https://www.wjgnet.com/1009-3079/full/v20/i21/1949.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i21.1949
目前, 大肠癌已是欧洲排名第2位的肿瘤致死性疾病, 占肿瘤致死性疾病的10%左右. 引起大肠癌发生的原因众多, 如基因突变引起的家族性腺瘤性息肉病(familial adenomatous polyposis, FAP)、DNA错配修复基因(MMR)突变引起的遗传性非息肉性结肠癌(herediarynonpolyposiscolorectalcancer, HNPCC)、Crohn's病、溃疡性结肠炎、上皮细胞内癌基因激活和抑癌基因失活等均与大肠癌的发生发展密切相关[1]. 上皮细胞间质转化(epithelial-mesenchymal transition, EMT)是指在生理或病理情况下发生细胞上皮-间质转变, 同时伴随细胞形态与相关基因表达的改变. EMT在胚胎形成以及组织器官发育过程中也起着重要作用(如中胚层和神经冠结构形成以及心脏形态发生过程[2]), 但也可引起器官纤维化和参与肿瘤形成过程, 在此过程中上皮细胞顶-底极性改变、桥粒等紧密连接结构消失、细胞骨架重组, 波形蛋白表达上调、角蛋白表达下调,从而使细胞离体、获得迁移能力, 并能抵抗细胞凋亡[3]. 近来研究发现EMT在大肠癌发生发展过程中起着重要作用, 并与肿瘤细胞的浸润和转移有着非常密切的关系.
慢性炎症被认为是包括大肠癌在内的许多种人类肿瘤疾病的原因之一, 流行病学和临床研究均证实两种主要的炎症性肠病(inflammatory bowel disease, IBD): 溃疡性结肠炎和Crohn's病[4]发展成大肠癌的风险明显升高. 慢性炎症可以通过诱导细胞DNA修饰导致肠上皮细胞发育不良, 此外还可通过DNA甲基化和组蛋白修饰等作用影响肠上皮发育过程[5]. Bataille等[6]在Crohn's病瘘管形成过程中发现肠道上皮标志物E-cadherin和β-catenin表达降低(β-catenin在EMT的起始阶段合成增加, 而在EMT最终阶段合成明显减少[7]); 间质标志物β-integrin表达增多(TGF-β激活EMT的过程依赖于β-integrin, 然后通过Smad3依赖性的转录过程或者非Smad3依赖性、p38MAPK激活和GTP酶调节的信号传导途径[8]), 而该蛋白随着EMT的进展逐渐由胞膜向胞质、胞核转移, β-catenin移位被认为是Crohn's病发展过程中EMT的关键分子步骤.
在肿瘤相关炎症(cancer related inflammation, CRI)相关分子中发现一些重要的始动因子, 包括NF-κB、STAT3[9]、IL-1β、IL-6、IL-10和TNF-α等. NF-κB是一种关键的内源性炎症/免疫调节因子[10]. Douglas等在大肠癌细胞中发现了异常的NF-κB调节, 且证实在结肠肿瘤起始和发展中NF-κB和CRI之间存在密切联系, 通过靶向灭活IkappaB使肿瘤浸润白细胞中NF-κB失活抑制了炎症相关大肠癌的发生, 从而为结肠肿瘤中NF-κB和炎症细胞的作用提供了基因水平证据. IL-6是NF-κB激活的一个主要效应分子, 并且与STAT3存在密切关系, 他具有促进生长和抗凋亡能力[11]. 研究发现IL-6能保护正常肠上皮细胞和癌前细胞免受凋亡, 并促进肿瘤起始细胞增殖, 在此过程中NF-κB-IL-6-STAT3通路起着重要作用. Lee等[12]发现大肠癌中NF-κB的活化状态需要STAT3维持, 提示STAT3是肿瘤细胞增殖和存活的关键因子, 并调控了c-Myc、Mcl-1、Cyclin D和Bcl-2表达[13]. 抑制因子从不同水平上调控NF-κB信号通路, Tir8是表达于肠黏膜上IL-1R家族的一员, 他能够通过阻止IRAK-1和TRAF-6, 抑制信号从IL-1R/TLR复合物传导[14]. 在小鼠大肠癌肿瘤模型中发现NF-κB下游分子CCL2、CCL3、IL-1和IL-6能够促进炎症相关的肿瘤形成, 并发现NF-κB激活过程中Tir8的缺失直接导致了大肠癌形成[15]. 肿瘤相关巨噬细胞(tumor associated macrophages, TAM)分泌的TNF通过抑制GSK-3β促进了Wnt/β-catenin信号传导, 促进了结肠上皮细胞向间质转化, 此过程在大肠癌发展中起着重要作用[16]. 此外, 炎症细胞中NF-κB激活也造成了COX-2和ROS水平升高, ROS能诱导DNA损伤、DNA甲基化、转录后修饰和肿瘤抑制基因突变等[7]; 控制炎症反应和诱导肿瘤细胞凋亡的TGF-β和低氧诱导因子-1(hypoxia-inducible factor-1, HIF-1)同样是炎症微环境中促使上皮细胞发生间质转化的潜在诱导因子[17].
Grivennikov等[17]证实IL-6与其受体sIL-6α结合后停留在细胞表面并能借助胞内TGF-β通路促进结肠上皮向恶性转化; IL-10激活STAT3(信号传导蛋白-转录激活物)后通过与IL-6相似的途径介导细胞恶性转变[18]. TGF-β作为炎症因子可造成包括肠道在内的多器官自身免疫性疾病, 且可激活多种信号通路如Erk、c-Jun、JNK、PI3K和RhoA等[19], 也能诱导某些转录因子和转录调节因子在EMT中的表达, 包括δEF1、SIP1和Snail等, 从而有利于结肠上皮EMT的发生[20]. TNF-α在IBD发病机制中是一种重要的炎症因子, 在炎症相关大肠癌(colitis associated colorectal cancer, CAC)中也起着重要作用[21], TNF-α在CAC中主要依赖激活胞内转录因子NF-κB进行信号传导, 通过NF-κB的多向性转录激活作用(NF-κB可以结合至靶基因MMP-9、IL-8、uPA、VEGF、CXCR4、骨桥蛋白等的启动子或增强子之上进行调控[22])诱导结肠上皮细胞向肿瘤细胞分化、增殖, 并抑制细胞凋亡、促进肿瘤侵袭和转移[23]. 此外, 其他炎症因子如IL-12、IL-13和INF-γ等在慢性大肠炎发展过程中也参与了肿瘤形成过程, 而TGF-β、IL-10则能在此过程中发挥协同作用[24].
目前已证实上述参与炎症发生和发展的各种细胞因子如, TGF-β、TNF-α和NF-κB等均是EMT信号通路的关键因子, 可见EMT参与了炎症促进大肠癌发生和发展的相关过程, 但是EMT在此过程中的详尽机制尚待进一步研究.
FAP在结肠腺瘤性息肉疾病中占有主要地位, 相关研究证实位于染色体5q21的APC突变失活是FAP的主要原因[25], APC突变被认为启动了大肠癌发生的多步骤过程, 最终FAP往往发展成为大肠癌[26]. 与FAP相同的是绝大多数散发大肠癌病例起源于结肠腺瘤且同时伴有APC突变. Vécsey-Semjén等[27]证实小鼠敲除APC外显子exon14后可导致结肠腺瘤发生, 免疫组织化学检测该模型结肠上皮细胞中可见Wnt信号通路的关键因子β-catenin在胞质和胞核中积累, 且编码C-Myc和Cyclin D1的mRNA也显著增加. APC是一种肿瘤抑制基因, 可以作为Wnt/β-catenin的负性调控因子, 在正常结肠上皮细胞APC/β-catenin复合物被丝氨酸-苏氨酸激酶(GSK3β)磷酸化, 导致β-catenin降解, 而在APC突变失活及Wnt信号转导通路开启时GSK3β的磷酸化作用被抑制[28], 使其不能诱发β-catenin降解, 从而造成胞质内的β-catenin持续累积, 后者作用于靶基因C-Myc和Cyclin D1等, 最终导致Wnt通路介导的EMT发生, 正常结肠黏膜上皮向间质转化, 最终结肠上皮细胞发生恶性转化[29,30].
Lochter等[31]利用COGA-8结肠上皮细胞培养发现Cyclin D1与CDK4、CDK6结合, 诱导生成Cyclin A和Cyclin E, 再与CDK2结合从而使结肠上皮细胞从G1期进入S期. C-Myc启动子区域有β-catenin结合位点, 因此C-Myc表达可以被Wnt通路上调, C-Myc过表达使其结合至Cyclin D2启动子特定的DNA序列并促进Cyclin D2的转录过程[32]. Wnt通路还能直接上调Cyclin D1, 因为Cyclin D1启动子区域包含LEF-1结合位点, 而该位点被认为是Wnt通路的直接作用靶点[33]. β-catenin在胞核内与淋巴细胞增强子结合因子1(LEF-1)和T细胞因子-4(Tcf-4)结合并作为转录共激活子启动下游基因(Slug、Cdx-1、Id2和ENC1等)表达. APC上β-catenin结合位点的减少程度与Wnt通路中β-catenin/LEF-1/Tcf-4复合物增加的程度呈负相关[34], 而β-catenin/LEF-1/Tcf-4的增加导致了结肠上皮细胞间紧密连接蛋白ZO-1减少、胞间桥粒等连接蛋白降解、细胞骨架重组、细胞离体和获得迁移能力[35], 还可以直接作用于AP-1转录因子复合物中c-jun和fra-1的启动子部位使该转录复合物增多、上调uPAR转录[36]. 此外, 该复合物还能上调ZEB1表达(高表达于FAP腺瘤、结肠腺癌上皮细胞, 且与胞核β-catenin水平呈正相关[37]), 而ZEB1能抑制E-cadherin生成[38], 且该转录激活复合物参与了腺瘤转变为腺癌甚至肿瘤转移的全过程[39]. 以上过程最终使结肠上皮细胞经历EMT过程(如细胞间连接蛋白降解、细胞迁移能力增强和获得间质表型等)并向恶性转化.
另外, CK2α是一种高度保守的丝氨酸-苏氨酸蛋白激酶, 可以磷酸化多种底物并在多种生理病理过程中起重要作用[40]. 正常结肠上皮细胞逐渐演变成腺瘤或腺癌的过程被认为与EMT及E-cadherin、Vimentin和β-catenin等基因表达改变紧密相关. Zou等[40]发现CK2α表达于正常结直肠上皮细胞和结直肠腺瘤/腺癌细胞, 通过调节参与细胞周期的癌基因c-myc和抑癌基因p53和p21等影响了大肠癌的演变过程. CK2α敲除或转染CK2α SiRNA后上皮标志物E-cadherin表达显著升高、间质标志物vimentin表达降低, 还能造成细胞中转录因子Snail1、Smad 2/3和癌基因c-myc的表达下降, 以上结果说明CK2α能够对上皮间质转变起到某种程度的抑制作用, 但是CK2α影响结肠腺瘤向大肠癌转变的具体机制尚未完全明确.
microRNAs是一类长度在18-25 nt的单链寡核糖核苷酸的非编码RNA, 具有高度的保守性、组织特异性和发育时序性[41], 在转录后水平通过负向调节mRNA发挥其功能, 与mRNA的靶向识别以与3'末端UTR互补性结合为基础[42]. microRNAs翻译水平的抑制作用常伴随由poly(A)尾加速脱腺苷化和后续核酸外切消化导致的靶mRNA水平减少[43], 而且microRNAs控制其靶点特异性的关键区域在5'末端2-7个碱基对的种子序列[44], 可以在细胞增殖、分化、凋亡、新陈代谢及胚胎发育等过程中起调控作用[45], 部分microRNAs通过调控癌基因和肿瘤抑制基因的表达; 部分通过直接作为癌基因或肿瘤抑制基因参与了大肠癌的病理过程[46]. 虽然microRNAs参与大肠癌发生发展的相关研究较多, 但有关microRNAs在大肠癌中介导EMT的研究仍较少.
研究证实在许多原发肿瘤及相应转移瘤中存在不同程度的microRNA表达, 在蛋白络氨酸磷酸酶(PTP)Pez诱导MDCK的细胞系中发现了TGF-β参与EMT的过程, 因为在该细胞系中发现了细胞间连接缺失和间质表型过表达. 此外通过RT-PCR还发现miR-200家族(miR-200a、miR-200b、miR-200c、miR-141和249)及miR-205表达的下调, 而稳定的miR-200s过表达可以阻止TGF-β诱导的EMT, 提示miR-200s是EMT的关键调控因子, 且miR-200s是通过抑制ZEB1和SIP1的翻译来调控EMT的[47]. 关于miR-200家族、ZEB1和SIP1, 我们推测上皮细胞和间质细胞表型之间的转化是由ZEB1和SIP1的水平决定的. ZEB1和SIP1结合至目的基因如上皮细胞关键基因E-cadherin启动子成对的ZEB样E-Boxs(CACCTG)上从而抑制这些基因的转录[48]. 以上证据提示miR-200s的丢失可能导致肿瘤的侵袭性增强, 甚至造成远处转移. TGFβ、TNFα由浸润的炎症细胞或肿瘤细胞产生, 已被证实能够诱导结肠癌细胞发生EMT, 在结肠癌SW480细胞系中通过miRNA表达分析发现稳定敲除ZEB1能够导致胞间连接蛋白E-cadherin表达上调、细胞迁移和侵袭的能力下降, 而miR-141、miR-200b和miR-200c的表达水平明显升高, 且miR-141、miR-200c的表达上调最为明显. 此结果也被RT-PCR检测所证实, 提示这两种miRNA参与了结肠癌EMT过程[49]. 而Colwell[50]利用TGFβ/TNFα诱导LIM1863大肠癌细胞发生EMT的过程中发现miR-21和miR-31表达水平明显升高; 蛋白定量分析发现miR-21和miR-31促进了TGFβ诱导的EMT的过程, 与miR-200抑制EMT上游调控因子ZEB1/2不同, miR-21和miR-31主要作用于EMT下游因子T淋巴瘤侵袭转移蛋白1(TIAM1), 后者是一种Rac GTPase交换因子[51]. 此外, miR-9和miR-335通过直接抑制E-cadherin和SOX4合成促进了大肠癌细胞转移. 以上结果说明某些microRNA可以在TGF-β信号通路的下游发挥作用从而促进结直肠癌的发生和转移.
启动子超甲基化和肿瘤抑制基因沉默是肿瘤形成的重要分子标志. Davalos等[52]通过大肠癌原发肿瘤微切除证实5'-CpG岛超甲基化相关的miR-200b/200a/429和miR-200c/141多顺反子转录沉默是调节EMT和MET转变的重要步骤, 也是大肠癌肿瘤进展的关键, 并发现miR-200超甲基化和ZEB1/ZEB2上调与CDH1、CRB3和LGL2表达下调相关; TGFβ诱导的EMT中miR-200超甲基化失活伴随着E-cadherin丢失和Vimentin增加[53]; Twist基因启动子获得CpG岛超甲基化后即可诱导结肠上皮细胞发生间质转化. 此外, 其他组蛋白修饰基因, 如LSD1、CREB结合蛋白、SIRT1等也参与了EMT过程. de Krijger等[46]发现36%的大肠癌原发肿瘤中miR-34a表达下降, 部分归因于TP53的突变, 部分是由于启动子甲基化; EMT激活因子TGFβ上调也促进了miR-21和miR-31表达, 后两者在大肠癌中促进了TGFβ诱导的EMT过程. 此外, miR-373、miR-126和miR-196a转染的大肠癌细胞则显示出明显肺转移潜能.
Sreekumar等[54]证实E-cadherin表达受miR-9直接调控而转录抑制, miR-199和miR-218则是间质特征性蛋白N-cadherin的潜在直接调控microRNA. miR-138、miR-488和miR-151能够在EMT过程中调节FAK的表达水平从而影响大肠癌肿瘤细胞的迁移能力.
在EMT介导大肠癌发生发展过程中伴随着众多信号通路的激活, 将胞外信号传导入胞内引起E-cadherin、Vimentin等异常、表型改变、基底膜降解、上皮细胞向间质转变和细胞迁移等一系列变化, 最终导致正常结肠上皮细胞转变为大肠癌细胞.
Wnt信号需要通过标准和非标准的信号通路传导, FGF信号通过PI3K-AKT、MAPK和PLCγ通路传导. GSK3β是Wnt标准信号传导通路和FGF依赖性PI3K-AKT信号传导通路的关键分子.
标准的Wnt信号通路决定细胞的分化方向, 非标准的信号通路控制细胞的极性和运动潜能,前者通过卷曲家族受体(Frizzled)和LRP5/LRP6受体进行信号转导, 后者通过Frizzled和ROR1/2共同受体进行信号传导. LRP5和LRP6是LDL家族的蛋白分子, 胞外有Wnt结合位点, 胞内有Axin模体结构. 除Wnt信号外, β-catenin为实现在蛋白化及蛋白酶体介导的降解而与GSK3β结合并被后者磷酸化[55], 标准的Wnt信号诱导Frizzled-Dishevelled复合物与LRP5/LRP6-AXIN-FRAT结合, 使β-catenin从GSK3β释放, 最终在胞核中稳定的累积. β-catenin与TCF/LEF、BCL9/9L结合成TCF/LEF-β-catenin-Legless-PYGO复合物, 作为Wnt信号通路的效应物[56]. 非标准Wnt信号通路中ROR1和ROR2是受体型络氨酸激酶, 胞外为Wnt结合位点, 胞内为CKIε结合结构域, RhoA、c-JUN、N末端激酶(JNK)、Nemo样激酶(NLK)是非标准Wnt信号通路的效应物. FGF与受体结合后诱导受体二聚化、络氨酸激酶活化及受体自身磷酸化, FRS2、FRS3和PLCγ与磷酸络氨酸残基相互作用被募集至FGF受体, 然后FRS2/3招募GRB2、SHP2, FRS2/SHP2/GRB2复合物募集GAB1激活PI3K, 导致GSK3β活性下降、Snail-EMT级联反应激活、E-cadherin/α-catenin表达下调、结肠上皮细胞恶性转化, 最终参与了大肠癌的发生发展过程[57]. 基因分析发现Dishevelled是Wnt通路的正向调控蛋白, 它发挥作用时处于受体下游、β-catenin的上游, 能导致c-Myc和cyclin D基因在结肠癌细胞中出现扩增[58].
Ras蛋白在调节大肠癌发生发展的信号通路中起着重要作用. 生长因子活化的受体激活后, 活化的Ras通过Raf激酶激活MAPK激酶(MEK1、MEK2), 导致胞外ERK1、ERK2激活[59]. ERKs位移至细胞核并激活核转录因子, 如Elk-1、ATF-2、ETS1/2, 使癌基因转录迅速开启. 首先, BRAF是Raf家族的一员, 他的突变与增强了的激酶活性有关, 且在9%-11%的结直肠癌中发现此现象; 其次, 在30%-40%的腺瘤和76%的结直肠癌肿瘤中证实MEK磷酸化及激活; 再次, 结直肠癌中呈现ERK的高度激活, 且证实ERK1、ERK2活性在肠道肿瘤中明显升高; 最后, 试验证实阻断MEK/ERK抑制了结肠癌细胞的生长, 表明ERK参与了结肠癌细胞的增殖. MEK1通过Egr-1、Fra-1增强Snail1/2表达而下调E-cadherin[60]. 另有研究证实结肠上皮细胞表达活化的MEK1获得了向肿瘤细胞转变及转移的潜质. 除MAPK途径外, Ras还可通过PI3K和Rho GTPase或与TGF-β协同诱导大肠癌EMT. PI3K激活后影响EMT过程的机制如前所述; 此外, PI3K/Akt能够使Rho GTPase激活, 也能与TGFβ通路相互作用从而影响大肠癌EMT过程[61].
磷酸酰肌醇3激酶(PI3K)通路对正常细胞代谢、生长及肿瘤进展起着重要作用. PI3K的抑制因子PTEN缺失(10号染色体上磷酸酶和张力蛋白同源敲除)与结肠肿瘤相关, 证实PI3K信号通路在大肠癌发生过程中起着重要作用. 近年来研究提示66%-70%的大肠癌中PTEN表达下调, 且与微卫星不稳定紧密相关. 此外还证实TNFα造成了PTEN下调. IEC-6和HIE细胞敲除PTEN后β-catenin表达水平明显升高, 大肠癌SW480细胞中V-catenin表达也有轻度升高, 提示β-catenin的表达受PTEN调控. 利用LY294002或Wortmannin抑制PI3K降低了c-Myc和cyclin D1表达, 而在RIE-1细胞中敲除PTEN则显著上调了上述蛋白的表达; 同样在IEC-6和HIE细胞中使PTEN沉默增加了c-Myc和cyclin D1的表达, 说明PTEN丢失可以通过促进细胞增殖、抑制凋亡而影响大肠癌的发生[62]. Bowen等[63]发现在野生型PTEN结肠肿瘤细胞中Akt2过表达导致了肿瘤微转移的形成, 提示Akt可能是作为TGF-β1下游调控因子发挥作用的. PI3K/Akt通路下游的效应分子mTOR激酶调控着CRC肿瘤的发生, 且证实mTORC1和mTORC2通过RhoA和Rac1通路调控着结肠癌细胞的迁移能力.
Notch通路在胚胎发育和内环境稳定中发挥着重要作用, 其异常激活参与了多种肿瘤的发展过程. 该通路激活是由Notch配体(Jag1、Jag2、DLL1、DLL3和DLL4)结合至相应受体上引起的. 配体在细胞外被蛋白酶裂解、在胞内被γ-分泌酶裂解[64], 使得Notch胞内结构域(NICD)转至细胞核, 在胞核中与CSL和其他共刺激因子如Maml 1、2、3构成转录激活复合物, 最终激活Notch通路的靶基因Hes和Hey1, 使上皮细胞恶性转化. 研究显示大肠癌EMT的诱导因子ZEB1可通过抑制miR-200表达而稳定Notch通路的Jag1、Maml2和Maml3, 并证实ZEB1通过提高Jag1的表达而增强Notch通路激活[65].
Hedgehog通路与通过抑制E-cadherin表达而参与EMT过程的Wnt、EGR/FGR和TGFβ/Activin/Nodal/BMP通路存在交互作用[66]. 虽有研究[67]证实Hedgehog通路能诱导Snail l表达上调, 但是尚未证实Hedgehog对Snail l有直接转录激活作用. 另外Hedgehog能诱导JAG2表达上调、促进TGFβ分泌[68], TGF-β1激活使胞核内NF-κB调控的ZEB1和ZEB2表达上调, 同样使Smad-Sp1调控的间质标志物Vimentin等表达上调从而促进大肠癌细胞迁移及侵袭.
在胚胎发育中EMT是必需的生理过程, 而肿瘤组织诱导产生的EMT则是肿瘤浸润和转移的重要机制之一. 目前, 越来越多的证据表明EMT在肿瘤发生、发展机制中起着重要的作用, 随着对EMT作用机制的研究不断深入以及对其信号通路和关键分子的逐步了解, 相关的研究结果为临床治疗肿瘤提供了重要的靶点与途径. 由于EMT主要是由E-cadherin的转录抑制因子诱发的, 因此借助靶向抑制Snail等的治疗方法为防止肿瘤进展提供了可能. 此外, EMT信号传导通路中的关键分子GSK-3β、PAK和TGFβ等将来也有可能成为阻断EMT的重要靶点. 虽然目前对EMT发生机制的研究尚未完全清楚, 但是随着相关研究的不断深入, 人们对EMT的了解将会变得更加清晰.
大肠癌是一种多因素、长期形成的、复杂的病变过程, 其发病机制复杂, 近来研究发现上皮细胞间质转化(EMT)在大肠癌发生发展过程中起着重要作用, 并与肿瘤细胞的浸润和转移有着非常密切的关系.
王娅兰, 教授, 重庆医科大学基础医学院病理教研室
EMT主要是由E-cadherin的转录抑制因子诱发的, 因此借助靶向抑制Snail等转录因子的治疗方法为防止肿瘤进展提供了可能. 而EMT信号传导通路中的关键分子GSK-3β、PAK、TGFβ等也有可能成为阻断EMT的重要靶点.
有研究发现在多种细胞系中加入过氧化氢(H2O2)能够激活NF-κB, 此外细胞中激活NF-κB的物质也造成了ROS水平明显升高, 而ROS能够诱导DNA损伤、转变细胞信号传导通路; 由于DNA损伤是肿瘤形成的原因之一, 因此由炎症生成的ROS被认为参与了肿瘤形成的过程.
本文系统综述了EMT在大肠癌发生发展中的研究进展, 重点总结了慢性肠道炎症、大肠腺瘤性息肉病、microRNAs在大肠癌发生发展中的作用以及EMT的有关信号通路(包括Wnt/β-catenin、FGF、Ras、PI3K、Notch和Hedgehog信号通路), 其他文献并未对上述方面进行过系统的总结, 并明确其重要意义.
随着对EMT作用机制的研究不断深入以及对其信号通路和关键分子的逐步了解, 相关的研究结果为临床治疗肿瘤提供了重要的靶点与途径.
上皮细胞间质转化: 指在生理或病理情况下发生上皮细胞与间质细胞之间的转变, 同时伴随细胞形态与相关基因表达的改变, 在此过程中上皮细胞顶-底极性改变、桥粒等紧密连接结构消失、细胞骨架重组, 波形蛋白表达上调、角蛋白表达下调, 从而使细胞离体、获得迁移能力,并能抵抗细胞凋亡.
本文对EMT在大肠癌发生发展中的作用及其相关信号传导途径的相关研究进行了综述, 对于进一步认识EMT与大肠癌的关系有较好的参考价值.
编辑:曹丽鸥 电编:鲁亚静
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