修回日期: 2016-04-21
接受日期: 2016-05-03
在线出版日期: 2016-07-28
消化系恶性肿瘤发生侵袭、转移是导致其治疗效果不佳、预后差的主要原因. 许多研究表明, 上皮间质化(epithelial-mesenchymal transition, EMT)在肿瘤的侵袭和转移过程中具有重要作用, 其主要特征为E-钙黏蛋白(E-cadherins, E-cad)的表达下调和细胞与细胞外基质间黏附力的下降. 大量研究发现, 整合素(integrin)也与肿瘤的侵袭和转移密切相关, 整合素一方面在细胞与细胞间及细胞与细胞外基质间的黏附中发挥作用, 另一方面还通过介导多种信号转导通路, 直接或间接的参与EMT. 目前, 有关消化系恶性肿瘤侵袭转移过程中整合素和EMT的作用机制研究均呈"碎片化", 缺乏"整体化"的系列研究, 本文就肿瘤侵袭转移过程中整合素与EMT的相互关系作一述评.
核心提示: 整合素(integrin)通过多种途径介导肿瘤细胞上皮间质化(epithelial-mesenchymal transition, EMT)的发生, 而EMT又可导致整合素表达上调, 结果导致持续不断的EMT发生, 对消化系肿瘤的侵袭和转移有着重要的作用.
引文著录: 高军, 高品. 消化系肿瘤侵袭转移过程中整合素与EMT的相互关系. 世界华人消化杂志 2016; 24(21): 3255-3261
Revised: April 21, 2016
Accepted: May 3, 2016
Published online: July 28, 2016
Invasion and metastasis are distinctive features of malignant tumors of the digestive system. Studies show that epithelial-mesenchymal transition (EMT), a conversion process with the loss of epithelial cell features and the gain of mesenchymal phenotype, has been recognized as a key element of invasion and metastasis of malignancies. When EMT occurs, down-regulation of E-cadherins and loss of adhesion in extracellular matrix play critical roles, which are regarded as important indicators in the assessment of EMT. Integrin, one of cell adhesion molecule families, is involved in EMT directly or indirectly through mediating either adhesion among cells and between cells and extracellular matrix, or signal pathways. This paper summarizes the relationship between EMT and integrin.
- Citation: Gao J, Gao P. Relationship between integrin and epithelial-mesenchymal transition during invasion and metastasis of digestive system carcinomas. Shijie Huaren Xiaohua Zazhi 2016; 24(21): 3255-3261
- URL: https://www.wjgnet.com/1009-3079/full/v24/i21/3255.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i21.3255
消化系肿瘤的侵袭转移演进过程涉及上皮组织结构和功能的深刻变化, 去分化、黏附约束力丧失及移动和侵袭力增强都是转变为恶性肿瘤的特征. 有趣的是, 这些变化反映了类似的一系列复杂的细胞过程, 即发生在"正常"情况下的生物事件, 如胚胎发生、伤口愈合、组织重构和炎症. 实现这些形态转换的高度保守的基本过程被认为是上皮间质转化[1-3]. 上皮间质转化(epithelial-mesenchymal transition, EMT)是指上皮细胞在特定的生理和病理情况下向间质细胞转化的现象, 其主要特征是上皮细胞表型的缺失及间质特性的获得. 1982年Greenburg等[4]在细胞实验中发现, 上皮细胞会暂时丧失其细胞极性且表现出具有迁移能力的间质细胞的某些特征, 并提出EMT的概念. 上皮细胞发生EMT后其顶底极性丧失, 钙黏蛋白等细胞黏附分子表达下调, 细胞骨架结构发生改变, 并演变为纤维细胞形态, 同时其间质细胞特征性分子表达上调, 例如波形蛋白(vimentin)、骨桥蛋白、Ⅰ型胶原蛋白等间质蛋白高表达, 从而获得高迁移能力及抗衰老和凋亡特性[5-7]. 实质上EMT涉及细胞-细胞黏附系统下调、上皮极性缺失、获得更适合细胞迁移和运动的间叶细胞表型. 癌症生物学家目前认为肿瘤细胞的生理学过程类似于其他细胞的生理过程, EMT也是一种病理机制, 该机制促进上皮肿瘤(癌)成为侵入性和攻击性疾病[8]. 迄今为止, 旨在揭示EMT潜在分子基础的大多数研究集中在细胞间黏附分子的活性下调, 最引人注目的是E-钙黏蛋白的表达或功能缺失是EMT的定义特征[9].
然而, 令人惊讶的是关于黏附受体整合素家族对EMT的调控却很少关注. 整合素(integrin)是一类细胞膜表面跨膜糖蛋白分子, 包括至少25个α亚基和11个β亚基, 由α和β亚基经非共价键连接组成20余种不同的整合素. 整合素主要介导细胞与细胞间及细胞与细胞外基质间的黏附, 同时整合素还作为细胞外基质分子受体接受细胞外分子信号, 并经过信号传导通路将细胞外信号转导入细胞内, 从而影响基因的表达和参与细胞的信号转导, 起到影响细胞增殖和迁移及调控细胞周期等作用[10,11]. α和β亚基均由胞内段(羧基端)、跨膜段、胞外段(氨基端)3部分组成. α亚基的胞外段主要参与细胞与细胞外基质(extracellular matrix, ECM)之间的黏附, β亚基的胞内段在细胞内通过踝蛋白、α-辅肌动蛋白等与肌动蛋白纤维连接成整合素-细胞骨架复合物, 经该复合物介导信号转导通路、调节基质金属蛋白酶(matrix metalloproteinase, MMP)等的表达[12]. 因此, 整合素一方面连接ECM与细胞骨架, 另一方面传导细胞内外信号交流. 整合素的配体多是ECM中的大分子基质蛋白, 整合素与这些配体结合使ECM与细胞内骨架蛋白连接在一起, 以维持细胞的形态并影响细胞的黏附和迁移[13,14]. 肿瘤发生侵袭转移时, 肿瘤细胞的膜受体首先要与基底膜表面的配体如胶原、层黏连蛋白(laminin, LN)、纤维连接蛋白(fibronectin, FN)结合, 诱使肿瘤细胞分泌MMPs等降解酶或诱导基质细胞分泌降解酶以降解基底膜和ECM, 这样肿瘤细胞才能突破ECM的屏障向远处侵袭转移[11]. 一个浸润性癌的细胞必须获得与不同的间质相互作用的能力并随之侵袭基底膜, 更重要的是, 长期以来在肿瘤细胞的组织侵袭和转移能力方面整合素被认为发挥关键作用[15].
研究[16-19]显示, 整合素的异常表达与胰腺癌等多种肿瘤细胞的侵袭转移及其EMT的发生密切相关, 并对疾病的预后产生影响. 研究[5,20]还发现, EMT与胰腺癌、结肠癌、肝癌等消化系肿瘤的侵袭和转移也密切相关. 因此, 针对整合素和EMT的研究不仅有助于阐明消化系肿瘤侵袭转移的发生机制, 同时为消化系肿瘤侵袭转移的防治提供了新的治疗靶点. 鉴于目前有关消化系恶性肿瘤侵袭转移过程中整合素和EMT的作用机制研究均呈"碎片化", 缺乏"整体化"的系列研究, 本文就消化系肿瘤侵袭转移过程中整合素与EMT相互关系的研究作一述评.
已有研究[17,21]显示, 整合素与消化系肿瘤细胞EMT密切相关. 整合素通过多种途径介导肿瘤细胞EMT的发生, 在消化系肿瘤的侵袭转移过程中发挥了作用.
整合素相关激酶(integrin-linked kinase, ILK)是一种胞质内丝氨酸/苏氨酸激酶, ILK具有3个结构域, N端有4个锚蛋白重复序列, 在ILK和其他信号分子及骨架蛋白之间的相互作用方面发挥作用, 中央区有血小板白细胞C激酶底物同源域(PH结构域), 与磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase, PI3K)结合能调节ILK的活性. C端(186-451位氨基酸)有整合素β1和β3亚基结合位点, 与整合素β亚基胞浆区结合可使ILK活化[22]. ILK活化后能使PI3K/AKT信号通路中丝氨酸/苏氨酸蛋白激酶的Ser473磷酸化, 同时PI3K对Thr308具有激活作用, 使得丝氨酸/苏氨酸蛋白激酶完全活化, 调节E-钙黏蛋白、β-catenin、细胞核内转录抑制因子Snail、核因子-κB(nuclear factor-κB, NF-κB)、ZEB等多种信号分子的表达, 诱发EMT的发生[23,24]. Ke等[20]测定了120例肝癌组织整合素α6β1的表达, 用RNA干扰技术检测整合素α6β1与跨膜四蛋白家族成员CD151在癌细胞中的分子效应, 结果显示整合素α6β1和CD151先形成高表达复合物, 再激活P13K/AKT信号通路, 使Snail表达上调, 导致肝癌细胞发生EMT.
糖原合成酶激酶-3(glycogen synthase kinase, GSK-3)是PI3K/AKT信号通路中的信号分子之一, ILK激活PI3K/AKT信号通路使GSK-3 Ser9位点磷酸化导致GSK-3失活, 结果一是可活化激活蛋白-1(activator protein-1, AP-1), 促使细胞分泌MMPs-9和细胞周期蛋白D1(cyclic D1), 参与EMT的发生; 二是可导致β-catenin泛素化失败, 进一步激活Wnt/β-catenin-LEF信号通路[25]. Groulx等[26]对直肠癌细胞中整合素α6A的高表达进行研究发现使用短发夹RNA靶向沉默整合素α6A后的癌细胞生长速率下降, β-catenin呈低水平状态. SB21673(GSK-3药物抑制剂)可翻转β-catenin/TCF4/LEF复合物的低表达. 由此推测整合素α6A能够调节直肠癌细胞的增殖并通过磷酸化GSK-3, 调控Wnt/β-catenin-LEF信号通路.
转化生长因子β(transforming growth factor-β, TGF-β)在胚胎和器官发育及肿瘤生成和转移过程中均发挥重要作用, 是EMT中一个重要的诱导因子. TGF-β信号通路涉及多种转录因子、蛋白及基因等的参与[27]. 整合素与TGF-β信号通路即共用ILK、黏着斑激酶(focal adhesion kinase, FAK)等关键分子, 又共同作用于多种信号分子, 因此整合素与TGF-β信号通路之间存在交互作用. Sarbassov等[28]报道TGF-β与相应受体结合, 通过PI3K/AKT信号通路激活mTOR和S6K1, 对EMT进行调节. 研究发现TGF-β前肽在相关肽、潜在TGF-β连接蛋白及整合素的共同作用下得到激活, 活化的TGF-β反过来通过信号转导通路上调整合素配体如FN、LN, 刺激整合素相关蛋白的表达[29,30].
FAK是一种非受体型酪氨酸蛋白激酶, 位于细胞质内近细胞膜侧, 有羧基端、激酶区和氨基端3个结构域. FAK的羧基端含有一个黏着斑靶向序列FAT, 整合素使FAK发生构象改变, 其羧基端借助FAT与踝蛋白、桩蛋白结合将FAK定位于黏着斑; 羧基端还有一个Tyr925位点, 可与接头蛋白Grb2的SH2结构域结合. FAK的氨基端有Tyr397位点, 是一种自主磷酸化位点, 可与Src家族的SH2结构域结合使FAK的其他氨基酸磷酸化[31]. Hwangbo等[32]研究表明整合素借助FAK介导RAS/MAPK信号通路. FAK与Src形成复合物可使FAK羧基端Tyr925位点磷酸化, 与接头蛋白Grb2的SH2结构域结合, 通过Grb2的SH3结构域与Ras的鸟苷酸交换因子SOS蛋白结合, 实现Ras-Raf-MAPK通路激活. 研究表明, FAK参与肝癌[21]、结直肠癌[33]等消化系肿瘤的侵袭转移过程. Chen等[34]研究发现肝癌细胞FAK通过激活MMPs-2和MMPs-9诱导肝癌细胞发生迁移. Yao等[35]发现整合素/FAK信号通路的抑制剂虫草素能够抑制肝癌细胞的EMT, 此可作为肝癌治疗新的研究方向之一.
Bates等[36]使用结肠癌模型分析具有调节EMT功能的整合素动力学, 出乎意料的发现EMT导致整合素avb6表达上调. 整合素avb6是细胞外基质蛋白FN和腱生蛋白的受体[37,38]. 整合素avb6仅仅由上皮细胞表达且主要在进展期间表达, 而整合素avb6高表达仅限于成人的少数上皮组织. 但是, 当与特定的形态形成事件如炎症和创伤修复同时存在时可以再表达这种受体[39,40]. 有研究[41,42]认为整合素avb6可能现在被认为是一个发生肿瘤的标记, 如同癌胚抗原. 另有研究[43,44]认为整合素avb6具有促进体内肿瘤进展的潜在作用, 这即与EMT本身的机制有关, 也与肿瘤宿主之间的微环境有关. 值得注意的是, 这种EMT诱导的整合素表达上调不仅提高肿瘤细胞的迁移能力, 而且还引起肿瘤细胞额外的选择性优势并最终影响人类疾病. EMT本身不是一个细胞自动过程, 需要启动信号驱动EMT. 特别是, TGF-β已经被认为是EMT事件的一个关键诱导物[45-49]. 有趣的是现在整合素avb6显示出体内的主要功能是作为一个潜在TGF-β活化剂[50]. Bates等[36]的研究显示EMT后细胞的确获得激活潜伏TGF-β的能力, 虽然这种效果完全归因于整合素avb6的水平增加, 也显示这些细胞发生EMT的结果是能自主分泌细胞因子. 因此, 我们预测在一个原位癌的情况下, 自主分泌生产TGF-β将是维持和稳定EMT过程的途径. 反之, 伴随整合素avb6表达会提供一个激活机制允许邻近细胞表达活性细胞因子, 结果导致EMT过程持续不断并创造出一个更适合肿瘤发展的局部微环境.
对人类侵袭性消化系肿瘤来讲最引人注目的研究是定义一种新的、独立的预后指标和治疗靶点. 在增加肿瘤特异性潜力方面, 癌症的分子靶向治疗策略有别于传统的化疗和放疗. 这种靶向分子也可能是更好地被接受, 因为他们通常只影响独一无二的特征性癌细胞和或与肿瘤生存相关的可溶性因子. 最新批准的治疗结直肠癌的药物, 如贝伐单抗(Avastin)和西妥昔单抗(艾比特思), 都是基于干扰细胞表面的受体-配体相互作用和信号传导通路. 整合素通过介导肿瘤细胞EMT在消化系肿瘤的侵袭转移过程中发挥了作用, 其中FAK、ILK是关键的信号分子, 因此以整合素及其相关激酶作为治疗靶点, 有可能成为防治肿瘤侵袭转移的重要选择. 由于整合素的亚型较多, 参与信号转导通路之间的关系复杂且存在交互、协同作用, 因此寻找确切的治疗靶点需要进一步的继续研究.
EMT和整合素在消化系肿瘤的侵袭和转移过程中均具有重要作用. 整合素通过多种途径介导肿瘤细胞EMT的发生, 而EMT又可导致整合素表达上调, 结果导致EMT过程持续不断并创造出一个更适合肿瘤侵袭和转移的局部微环境. 针对整合素及其相关激酶作为治疗靶点, 有可能成为阻断EMT发生及防治消化系肿瘤侵袭转移的重要选择.
关于整合素(integrin)和上皮间质化(epithelial-mesenchymal transition, EMT)在消化系肿瘤侵袭转移中的作用已经进行了大量的研究, 但整合素和EMT相互关系的研究较少. 近来的研究表明整合素和EMT的相互关系, 可能有助于探明消化系肿瘤侵袭转移的发生机制、并有望成为新的治疗靶点.
隋红, 副教授, 副主任医师, 哈尔滨医科大学附属肿瘤医院消化道肿瘤内科
整合素介导肿瘤细胞EMT的有效途径、EMT对整合素表达的影响、整合素和EMT相互关系在消化系肿瘤侵袭转移中的作用及意义、能否成为新的治疗靶点等都是该领域亟待研究的问题.
系统阐述了整合素介导肿瘤细胞EMT的有效途径、EMT对整合素表达的影响、整合素和EMT在消化系肿瘤侵袭转移中的相互关系及其意义.
将整合素及其相关激酶作为治疗靶点, 对阻断EMT发生及防治消化系肿瘤侵袭转移具有潜在的应用前景.
本文具有科学性、创新性和可读性, 能较好地反映我国或国际胃肠病学临床和基础研究的先进水平.
手稿来源: 邀请约稿
学科分类: 胃肠病学和肝病学
手稿来源地: 山东省
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| 1. | Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995;154:8-20. [PubMed] [DOI] |
| 2. | Savagner P. Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays. 2001;23:912-923. [PubMed] [DOI] |
| 3. | Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740-746. [PubMed] [DOI] |
| 4. | Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol. 1982;95:333-339. [PubMed] [DOI] |
| 5. | Farahani E, Patra HK, Jangamreddy JR, Rashedi I, Kawalec M, Rao Pariti RK, Batakis P, Wiechec E. Cell adhesion molecules and their relation to (cancer) cell stemness. Carcinogenesis. 2014;35:747-759. [PubMed] [DOI] |
| 6. | Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178-196. [PubMed] [DOI] |
| 7. | Tania M, Khan MA, Fu J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer. Tumour Biol. 2014;35:7335-7342. [PubMed] [DOI] |
| 8. | Arias AM. Epithelial mesenchymal interactions in cancer and development. Cell. 2001;105:425-431. [PubMed] [DOI] |
| 9. | Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442-454. [PubMed] [DOI] |
| 10. | Gahmberg CG, Grönholm M, Uotila LM. Regulation of integrin activity by phosphorylation. Adv Exp Med Biol. 2014;819:85-96. [PubMed] [DOI] |
| 11. | Schwartz MA. Integrins and extracellular matrix in mechanotransduction. Cold Spring Harb Perspect Biol. 2010;2:a005066. [PubMed] [DOI] |
| 12. | Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9-22. [PubMed] [DOI] |
| 13. | Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69:11-25. [PubMed] [DOI] |
| 14. | Ruoslahti E. Integrins. J Clin Invest. 1991;87:1-5. [PubMed] [DOI] |
| 15. | Bates RC. Colorectal cancer progression: integrin alphavbeta6 and the epithelial-mesenchymal transition (EMT). Cell Cycle. 2005;4:1350-1352. [PubMed] [DOI] |
| 16. | Duan W, Ma J, Ma Q, Xu Q, Lei J, Han L, Li X, Wang Z, Wu Z, Lv S. The Activation of β1-integrin by Type I Collagen Coupling with the Hedgehog Pathway Promotes the Epithelial-Mesenchymal Transition in Pancreatic Cancer. Curr Cancer Drug Targets. 2014;14:446-457. [PubMed] [DOI] |
| 17. | Masugi Y, Yamazaki K, Emoto K, Effendi K, Tsujikawa H, Kitago M, Itano O, Kitagawa Y, Sakamoto M. Upregulation of integrin β4 promotes epithelial-mesenchymal transition and is a novel prognostic marker in pancreatic ductal adenocarcinoma. Lab Invest. 2015;95:308-319. [PubMed] [DOI] |
| 18. | Allen MD, Vaziri R, Green M, Chelala C, Brentnall AR, Dreger S, Vallath S, Nitch-Smith H, Hayward J, Carpenter R. Clinical and functional significance of α9β1 integrin expression in breast cancer: a novel cell-surface marker of the basal phenotype that promotes tumour cell invasion. J Pathol. 2011;223:646-658. [PubMed] [DOI] |
| 19. | Han KS, Li N, Raven PA, Fazli L, Ettinger S, Hong SJ, Gleave ME, So AI. Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma. Mol Cancer Ther. 2015;14:1024-1034. [PubMed] [DOI] |
| 20. | Ke AW, Shi GM, Zhou J, Huang XY, Shi YH, Ding ZB, Wang XY, Devbhandari RP, Fan J. CD151 amplifies signaling by integrin α6β1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells. Gastroenterology. 2011;140:1629-1641.e15. [PubMed] [DOI] |
| 21. | Chen JS, Huang XH, Wang Q, Chen XL, Fu XH, Tan HX, Zhang LJ, Li W, Bi J. FAK is involved in invasion and metastasis of hepatocellular carcinoma. Clin Exp Metastasis. 2010;27:71-82. [PubMed] [DOI] |
| 22. | Ghatak S, Morgner J, Wickström SA. ILK: a pseudokinase with a unique function in the integrin-actin linkage. Biochem Soc Trans. 2013;41:995-1001. [PubMed] [DOI] |
| 23. | Qiao M, Sheng S, Pardee AB. Metastasis and AKT activation. Cell Cycle. 2008;7:2991-2996. [PubMed] [DOI] |
| 24. | Cortez V, Nair BC, Chakravarty D, Vadlamudi RK. Integrin-linked kinase 1: role in hormonal cancer progression. Front Biosci (Schol Ed). 2011;3:788-796. [PubMed] [DOI] |
| 25. | Gil D, Ciołczyk-Wierzbicka D, Dulińska-Litewka J, Zwawa K, McCubrey JA, Laidler P. The mechanism of contribution of integrin linked kinase (ILK) to epithelial-mesenchymal transition (EMT). Adv Enzyme Regul. 2011;51:195-207. [PubMed] [DOI] |
| 26. | Groulx JF, Giroux V, Beauséjour M, Boudjadi S, Basora N, Carrier JC, Beaulieu JF. Integrin α6A splice variant regulates proliferation and the Wnt/β-catenin pathway in human colorectal cancer cells. Carcinogenesis. 2014;35:1217-1227. [PubMed] [DOI] |
| 27. | Chen XF, Zhang HJ, Wang HB, Zhu J, Zhou WY, Zhang H, Zhao MC, Su JM, Gao W, Zhang L. Transforming growth factor-β1 induces epithelial-to-mesenchymal transition in human lung cancer cells via PI3K/Akt and MEK/Erk1/2 signaling pathways. Mol Biol Rep. 2012;39:3549-3556. [PubMed] [DOI] |
| 28. | Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005;17:596-603. [PubMed] [DOI] |
| 29. | Lee KM, Ju JH, Jang K, Yang W, Yi JY, Noh DY, Shin I. CD24 regulates cell proliferation and transforming growth factor β-induced epithelial to mesenchymal transition through modulation of integrin β1 stability. Cell Signal. 2012;24:2132-2142. [PubMed] [DOI] |
| 30. | Margadant C, Sonnenberg A. Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 2010;11:97-105. [PubMed] [DOI] |
| 31. | Roy S, Ruest PJ, Hanks SK. FAK regulates tyrosine phosphorylation of CAS, paxillin, and PYK2 in cells expressing v-Src, but is not a critical determinant of v-Src transformation. J Cell Biochem. 2002;84:377-388. [PubMed] [DOI] |
| 32. | Hwangbo C, Kim J, Lee JJ, Lee JH. Activation of the integrin effector kinase focal adhesion kinase in cancer cells is regulated by crosstalk between protein kinase Calpha and the PDZ adapter protein mda-9/Syntenin. Cancer Res. 2010;70:1645-1655. [PubMed] [DOI] |
| 33. | Pan N, Zhang AR, Mu MS, Hou YC. [Effects of FAK expression level on proliferation and motility of colorectal carcinoma cells]. Xibao Yu Fenzi Mianyixue Zazhi. 2009;25:783-786. [PubMed] |
| 34. | Chen QK, Lee K, Radisky DC, Nelson CM. Extracellular matrix proteins regulate epithelial-mesenchymal transition in mammary epithelial cells. Differentiation. 2013;86:126-132. [PubMed] [DOI] |
| 35. | Yao WL, Ko BS, Liu TA, Liang SM, Liu CC, Lu YJ, Tzean SS, Shen TL, Liou JY. Cordycepin suppresses integrin/FAK signaling and epithelial-mesenchymal transition in hepatocellular carcinoma. Anticancer Agents Med Chem. 2014;14:29-34. [PubMed] [DOI] |
| 36. | Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H, Sheppard D, Oettgen P, Mercurio AM. Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest. 2005;115:339-347. [PubMed] [DOI] |
| 37. | Busk M, Pytela R, Sheppard D. Characterization of the integrin alpha v beta 6 as a fibronectin-binding protein. J Biol Chem. 1992;267:5790-5796. [PubMed] |
| 38. | Yokosaki Y, Monis H, Chen J, Sheppard D. Differential effects of the integrins alpha9beta1, alphavbeta3, and alphavbeta6 on cell proliferative responses to tenascin. Roles of the beta subunit extracellular and cytoplasmic domains. J Biol Chem. 1996;271:24144-24150. [PubMed] [DOI] |
| 39. | Breuss JM, Gillett N, Lu L, Sheppard D, Pytela R. Restricted distribution of integrin beta 6 mRNA in primate epithelial tissues. J Histochem Cytochem. 1993;41:1521-1527. [PubMed] [DOI] |
| 40. | Breuss JM, Gallo J, DeLisser HM, Klimanskaya IV, Folkesson HG, Pittet JF, Nishimura SL, Aldape K, Landers DV, Carpenter W. Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci. 1995;108:2241-2251. [PubMed] |
| 41. | Hamidi S, Salo T, Kainulainen T, Epstein J, Lerner K, Larjava H. Expression of alpha(v)beta6 integrin in oral leukoplakia. Br J Cancer. 2000;82:1433-1440. [PubMed] [DOI] |
| 42. | Regezi JA, Ramos DM, Pytela R, Dekker NP, Jordan RC. Tenascin and beta 6 integrin are overexpressed in floor of mouth in situ carcinomas and invasive squamous cell carcinomas. Oral Oncol. 2002;38:332-336. [PubMed] [DOI] |
| 43. | Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature. 2001;411:375-379. [PubMed] [DOI] |
| 44. | Tuxhorn JA, Ayala GE, Rowley DR. Reactive stroma in prostate cancer progression. J Urol. 2001;166:2472-2483. [PubMed] [DOI] |
| 45. | Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, Ruhland C, Adler G, Gress TM. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001;61:4222-4228. [PubMed] |
| 46. | Portella G, Cumming SA, Liddell J, Cui W, Ireland H, Akhurst RJ, Balmain A. Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ. 1998;9:393-404. [PubMed] |
| 47. | Lehmann K, Janda E, Pierreux CE, Rytömaa M, Schulze A, McMahon M, Hill CS, Beug H, Downward J. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev. 2000;14:2610-2622. [PubMed] [DOI] |
| 48. | Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001;12:27-36. [PubMed] [DOI] |