修回日期: 2016-11-08
接受日期: 2016-11-21
在线出版日期: 2017-01-18
已有研究表明转化生长因子-β(transforming growth factor-β, TGF-β)是最重要的促肝纤维化(hepatic fibrosis, HF)因子之一, TGF-β/Smad信号转导通路是HF主要的信号转导通路. 而微小RNA(microRNA, miRNA)在HF发生过程中存在异常表达, 并对HF的发生和发展有着不可忽视的作用. 近年来有研究提示: 通过外源性调控相关miRNA表达可能影响TGF-β/SMAD通路, 从而影响HF的发生发展. 文章就TGF-β/SMAD通路及与其相关的miRNA分子与HF的关系作一综述.
核心提要: 已有研究表明转化生长因子-β(transforming growth factor-β, TGF-β)是最重要的促肝纤维化(hepatic fibrosis, HF)因子之一, TGF-β/Smad信号转导通路是HF主要的信号转导通路. 而微小RNA(microRNA, miRNA)在HF发生过程中存在异常表达, 并对HF的发生和发展有着不可忽视的作用. 近年来有研究提示: 通过外源性调控相关miRNA表达可能影响TGF-β/SMAD通路, 从而影响HF的发生发展. 文章就TGF-β/SMAD通路及与其相关的miRNA分子与HF的关系作一综述.
引文著录: 冉龙娇, 梁健, 邓鑫. MicroRNA调控TGF-β/SMAD通路调节肝纤维化机制. 世界华人消化杂志 2017; 25(2): 166-171
Revised: November 8, 2016
Accepted: November 21, 2016
Published online: January 18, 2017
Studies have shown that transforming growth factor-β (TGF-β) is one of the most important factors to promote hepatic fibrosis (HF), and the TGF-β/Smad pathway is a major signaling pathway involved in HF. Abnormal expression of microRNAs (miRNAs) has a key role in the development of HF. In recent years, studies suggest that regulating miRNAs may affect the TGF-β/Smad pathway. This paper discusses the TGF-β/Smad pathway and the related miRNAs that are associated with HF.
- Citation: Ran LJ, Liang J, Deng X. MicroRNAs regulate hepatic fibrosis via TGF-β/Smad pathway. Shijie Huaren Xiaohua Zazhi 2017; 25(2): 166-171
- URL: https://www.wjgnet.com/1009-3079/full/v25/i2/166.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v25.i2.166
肝纤维化(hepatic fibrosis, HF)是由多种因素引起的肝实质细胞破坏和组织的自我修复, 以细胞外基质(extracellular matrix, ECM)过量产生和沉积为主要表现, 若不积极干预, 则可能发展为肝硬化或肝癌, 严重影响患者的生活质量及疾病的预后. 转化生长因子-β(transforming growth factor-β, TGF-β)是最重要的促HF因子之一[1], TGF-β/Smad信号转导通路可调节肝星状细胞(hepatic stellate cells, HSC)的活化, 促进ECM生成, 是HF主要的信号转导通路.
微小RNA(microRNA, miRNA)是一类具有调控功能的内源性的非编码小分子RNA, 可以调节人体约30%的基因[2], 参与了诸多疾病的发生发展过程, 其在肿瘤方面[3-6]的研究较多, 而在器官纤维化方面的研究相对较少. 据研究证实miRNA在HF发生过程中存在异常表达[7,8], 并受到Wnt/β-catenin通路[9]、NF-κB通路[10]、HH通路[11]、PI3K/Akt通路[12]、TGF-β/Smad通路[13]等多条信号通路及细胞因子的影响. 研究[14]发现, miRNA的检测可能对评估慢性HBV感染有关的炎性肝损伤和HF是有用的. 有学者[15]通过对活检肝组织和血清样本中的miRNA进行分析, 发现血清miRNA的水平在重症纤维化(F3, F4)下降, 而在F2及炎症活动早期阶段则升高, 可能反映急性肝损伤、慢性肝病和HF. 据报道miRNA可通过抑制HSC的活化[16-18]、增殖[19]、凋亡[20-22]及迁移[23-25]等来治疗HF. 可见miRNA是HF重要的候选诊断标志和潜在的治疗靶点, 在HF进程中的作用正逐渐引起人们重视. 现就TGF-β/SMAD通路及与其相关的miRNA分子与HF的关系予以综述.
TGF-β是一个庞大的家族, 迄今已发现6种不同的亚型(TGF-β1-TGF-β6), 而在哺乳动物中只表达TGF-β1-TGF-β3亚型. 其中TGF-β1在肝脏中含量最高且具有生物活性, 正常成人肝脏的肝窦内皮细胞、Kupffer细胞中TGF-β1表达水平较高, 而TGF-β2和TGF-β3的表达水平则相对较低但可以检出; HSC正常状态下表达极少的TGF-β, 肝损伤后, 3种TGF-β表达均显著增加, 是肝损伤时TGF-β的主要来源[26,27]. HSC表面的TGF-β有Ⅰ型和Ⅱ型两种受体, 两者结构相似, 均为氨基酸残基组成的受体丝氨酸/苏氨酸蛋白激酶[28]. Ⅱ型受体的胞外端首先与配体结合, 其胞内段的丝氨酸/苏氨酸激酶被活化, 进而使Ⅰ型受体的胞内近膜端高度保守的富含甘氨酸/丝氨酸的结构域磷酸化, Ⅰ型受体活化后成为丝氨酸/苏氨酸激酶, 将信号向细胞内传导.
Smad蛋白有1-8种, 分为受体调节型Smad(receptor regulatory smads, R-Smads), 其中包括Smad1、Smad2、Smad3、Smad5和Smad8; 通用型Smad(common mediator smads, Co-Smads), 只有Smad4; 抑制型Smad(inhibitory smads, I-Smads), 有Smad6和Smad7. R-Smad能被Ⅰ型受体直接磷酸化激活, Smad4是TGF-β信号转导必需的中间分子, Smad6、Smad7则是TGF-β/Smad途径的抑制分子.
TGF-β信号的转导主要有两类途径, Smad依赖途径和非Smad依赖途径. Smad蛋白家族是一类细胞内的TGF-β受体激酶的底物, 在胞外信号经由膜受体转导进入细胞核内的过程中发挥核心作用.
刺激因子作用于HSC后, TGF-β配体结合到细胞表面的TGF-β的Ⅱ型受体, 形成异源三聚体, Ⅱ型受体磷酸化Ⅰ型受体并激活Ⅰ型受体, Ⅰ型受体再次磷酸化而激活Smads蛋白, Smads蛋白被跨膜受体磷酸化, 该Smad再与协同Smad4结合, 形成复合物后转入细胞核内, 激活的复合物和两类DNA结合辅助因子结合, 决定靶基因的转录活性[1]. Smad复合体进入细胞核后与靶基因启动子的特异序列结合形成稳定的复合物, 间接地对靶基因进行调节. 同时, Smad复合体直接与细胞核内DNA结合进而直接激活目的基因的转录. HSC活化后分泌大量ECM沉积在肝细胞间, 同时活化后的HSC可自分泌TGF-β1而形成级联环状放大反应促使纤维化发生.
Chen等[29]研究发现抑制TGF-β/SMAD通路可导致HSC的增殖及细胞凋亡, 进而抑制HF. 据报道[30], 可通过调控TGF-β/SMAD通路, 影响HSC的活化, 减轻CCl4诱导的HF. TGF-β/SMAD通路[31,32]的信号转导下调可抑制HF. 通过对血吸虫感染的小鼠HF模型的研究[33], 发现外源性骨形成蛋白7可能是通过TGF-β/SMAD信号通路来减轻HF的. 可见TGF-β/SMAD通路与HF密切相关.
HF的发生和发展是个多因素、多环节的过程, 由多种相关基因失衡导致. 实验已证实TGF-β/SMAD通路与HF密切相关. 据研究证实miRNA可能阻断TGF-β/SMAD通路来达到抗HF的目的. 因此了解与TGF-β/SMAD通路相关的miRNA的调控机制, 进而研究如何切断TGF-β/SMAD通路对预防和治疗HF至关重要.
现有研究显示miR-19b[34]、miR-33a[35]可通过抑制TGF-β信号通路, 进而抑制细胞中α-SMA和胶原蛋白的表达, 参与HF的发生和发展. TGF-β1[36]可能介导了miR-130a和miR-130b表达下调, 影响HSC的活化, 从而影响HF. miR-200a[19]可作用于TGF-β信号通路从而影响HSC活化来影响HF的发生及进展. miR-214[37]通过EGFR和TGF-β信号通路参与了HF的发展, 是潜在抗纤维化的治疗途径之一. 低水平的miR-let-7[38]可能通过激活HSC中的TGF-β信号通路影响HF的发生. miR-101[39]抑制纤维化TGF-β信号及由此产生的促纤维化细胞因子的上调, 抑制TGF-β诱导的肝细胞凋亡和细胞增殖, 可能是HF的潜在的治疗靶标.
miR-30[13]通过抑制HSC活化过程中TGF-β/Smad7信号通路的传导, 抑制HSC的增殖和迁移, 达到抑制CCl4诱导的HF的目. miR-146a[40]通过转录后抑制Smad4的表达参与调控TGF-β1诱导的HSC的增殖. miR-21[41,42]可能通过作用于靶基因SMAD7, 调控TGF-β/Smad通路, 从而达到抗纤维化的作用. miR-31/FIH1通路[43]与HF是联系在一起的, 可能是通过参与HSCTGF-β/Smad3信号转导. Zheng等[44]研究发现miR-150可抑制HSC的活化, 在HF中的表达显著降低, 可直接结合SP1和COL4A4减少Ⅳ型胶原, 但不经过TGF-β/Smad信号通路. 在TGF-β1处理的LX-2细胞中, miR-454[45]被下调了, 并且miR-454可通过直接靶向作用Smad4, 抑制HSC的活化, 从而为血吸虫诱导的HF提供了一种新的治疗方法. miR-33a[46]可在HSC中的表达高于HF相关的细胞, 且其在血清中的水平与HF的进程呈正相关; 过表达的miR-33a可能是通过调节Smad7表达的潜在机制来调节LX-2细胞中TGF-β的活化, 从而可能是一种新的HSC活化与HF进展的标志, 为HF的治疗提供新的靶点. Wang等[47]研究发现miR-29b与TGF-β介导的纤维化有关, 其表达在人和小鼠的肝组织中及活化的HSC中是下调的, 其下调由Smad3直接介导, 同时miR-29b可以抑制Smad3的表达; Liang等[48]也证实了miR-29b与TGF-β1/Smad3信号通路之间相互作用, 从而促进HF. miR-17-5p[49]经过TGF-β/Smad信号通路至少部分作用于Smad7促进HSC的增殖和活化, 进而影响Ⅰ型胶原和α-SMA, 为HF的治疗提供了新靶点. 下调mmu-miR-322[50]从而上调Smad7表达, 抑制TGF-β1/Smads信号通路可能是扶正化瘀方抗HF的部分作用机制. 尽管与HSCTGF-β/SMAD通路相关miRNA的作用机制尚未完全清楚, 不过这可能是HF防治的潜在作用靶点.
诸多研究表明miRNA可通过调控细胞增殖、凋亡、脂代谢/脂肪酸代谢等一系列相关信号通路在病毒性肝炎、酒精性或非酒精性脂肪性肝病、HF和原发性肝细胞癌等慢性肝脏疾病的发生发展过程中发挥重要的生物学作用. miRNA因此也成为HF研究领域的重要部分, 而其中HSCTGF-β/SMAD通路相关miRNA得到越来越多的重视. 尽管近年来已初步明确了一些miRNA的作用机制, 但由于miRNA数目多, 且一个靶基因可受不同的miRNA同时调控以及同一miRNA可对不同的靶基因进行调控, 这种错综复杂的关系导致对它的研究仍处于初级阶段. 虽然miRNA在HF的调控机制未被完全揭示, 不过目前可以肯定的是: miRNA在HF的预防、诊治和预后方面一定发挥着不容忽视的作用, 有待进一步研究证实.
已有研究表明转化生长因子-β(transforming growth factor-β, TGF-β)是最重要的促肝纤维化因子之一, TGF-β/Smad信号转导通路是肝纤维化主要的信号转导通路. 而微小RNA(microRNA, miRNA)在肝纤维化发生过程中存在异常表达, 并对肝纤维化的发生和发展有着不可忽视的作用. 近年来有研究提示: 通过外源性调控相关miRNA表达可能影响TGF-β/SMAD通路, 从而影响肝纤维化的发生发展.
本文就TGF-β/SMAD通路及与其相关的miRNA分子与肝纤维化的关系作一综述. 综述的内容对于阐明miRNA参与肝纤维化的调控机制具有重要意义.
本文就TGF-β/SMAD通路及与其相关的miRNA分子与肝纤维化的关系作一综述, 主要总结了近年来相关miRNA通过TGF-β/SMAD通路调节肝纤维化.
本文有利于对肝纤维化相关机制的了解, 为以后肝纤维化的诊断、治疗等方面的研究提供了线索.
龚作炯, 教授, 武汉大学人民医院感染科; 阳学风, 教授, 南华大学附属南华医院消化内科; 张明辉, 主任医师, 河北省唐山市人民医院
本文综述了TGF-β/SMAD通路及与其相关的miRNA分子与肝纤维化的关系的最新研究进展, 内容较详尽, 提出了一些新的观点, 可为拟从事此领域研究的相关研究者提供一定的参考.
手稿来源: 自由投稿
学科分类: 胃肠病学和肝病学
手稿来源地: 广西壮族自治区
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