修回日期: 2011-07-14
接受日期: 2011-07-19
在线出版日期: 2011-07-28
慢性幽门螺杆菌(Helicobacter pylori, H. pylori)感染为胃腺癌和MALT淋巴瘤发病的主要原因之一. 慢性H. pylori感染损伤胃黏膜屏障, 通过影响细胞内信号通路刺激上皮细胞增殖及修复, 诱导上皮细胞发生恶性转化. miRNA作为基因转录后的一种调控方式, 参与细胞增殖、分化以及免疫应答的调节. miRNA在肿瘤形成中所起的作用十分复杂, 部分miRNA的表达起促癌作用, 而亦有miRNA扮演着抑癌基因的角色. 本综述介绍了目前研究报道中与H. pylori感染致病相关的miRNA, 包括miR-21、miR-155和miR-146a等. miRNA与H. pylori关系的研究无疑会加深我们对H. pylori致病机制的认识.
引文著录: 谢川, 徐丽瑶, 刘龚玫子, 杨桢, 吕农华. miRNA与幽门螺杆菌致病的关系. 世界华人消化杂志 2011; 19(21): 2257-2261
Revised: July 14, 2011
Accepted: July 19, 2011
Published online: July 28, 2011
Chronic Helicobacter pylori (H. pylori) infection is one of the main causes of gastric carcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori infection leads to chronic injury to the gastric mucosal barrier, stimulates epithelial cell proliferation and repair by influencing intracellular signaling pathways, and induces malignant transformation of epithelial cells. MicroRNAs (miRNAs) are involved in cell proliferation, differentiation and immune responses by post-transcriptionally regulating gene expression. The role of miRNAs in tumor formation is very complex. Some miRNAs may promote the tumor formation, whereas some others may play roles as a tumor suppress gene. In this article we discuss the association of miRNAs (e.g., miR-21, miR-155 and miR-146a) with the pathogenesis of H. pylori infection. Clarification of the relationship between H. pylori infection and miRNAs will undoubtedly deepen our understanding of the pathogenesis of H. pylori infection.
- Citation: Xie C, Xu LY, Liu GM, Yang Z, Lv NH. Role of miRNAs in the pathogenesis of Helicobacter pylori infection. Shijie Huaren Xiaohua Zazhi 2011; 19(21): 2257-2261
- URL: https://www.wjgnet.com/1009-3079/full/v19/i21/2257.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v19.i21.2257
胃癌为全世界高发的恶性肿瘤. 最新的一份研究报道表明[1], 虽然胃癌在过去的10年中发病总体呈下降的趋势, 但在所有男性和女性恶性肿瘤中, 胃癌发病率分别列第4、第5. 而在发展中国家, 胃癌发病率可能更高. 胃癌的发病机制极其复杂, 涉及到众多基因调控和表达的异常. 其中包括编码蛋白的癌基因和抑癌基因表达异常, 而近年来随着众多的非编码RNA(ncRNA)被发现, 非编码RNA在肿瘤发生过程中扮演的角色引起了人们的高度重视. microRNA(miRNA)是一类含20-25个核苷酸非编码小RNA分子, 通过调控转录后靶mRNA, 对基因表达起负调控作用. 近年来研究表明, miRNA在胃癌的发生发展过程中起重要作用[2]. 1982年Mashall和Warren[3]首次从慢性胃炎和消化性溃疡胃黏膜中分离并培养出幽门螺杆菌(Helicobacter pylori, H. pylori), 作为体内最常见的一种慢性感染, 他与胃癌关系密切. 1994年国际抗癌联盟(UICC)将H. pylori列为Ⅰ类致癌因子. 国内外均有学者单独利用H. pylori成功建立胃癌动物模型[4,5]. 然而, H. pylori的具体致癌机制并未阐明, 其与miRNA的关系也引起学者的关注. 本文就目前与miRNA和H. pylori关系的研究报道综述如下.
miRNA通常由20-25个核苷酸组成, 是一类重要高度保守的非编码的小分子单链RNA, 具有调节基因表达活性的功能. 自首次发现调控秀丽隐杆线虫发育的miRNA lin-4和let-7后[6,7], 已经利用分子克隆和生物信息学方法发现了上千种miRNA[8].
miRNA生物合成起始于初级转录, 一般由RNA聚合酶Ⅱ催化[9], 亦有部分miRNA转录由RNA聚合酶Ⅲ完成[10]. 初级转录后的pri-miRNA具有发夹结构, 经过Drosha和Dicer酶处理加工后, 成熟单链miRNA结合到RNA诱导的沉默复合体(RNA-induced silencing complex, RISC), 进而与靶基因mRNA 3'端非编码区域(3'UTR)结合配对, 降解mRNA或阻碍其翻译, 在转录后水平调控靶基因的表达[11]. 单个miRNA可以直接调节上百个基因的表达, 进而间接对上千个基因表达发挥调控作用[12].
miRNA广泛参与动植物的组织器官发育、细胞增殖分化和凋亡、脂肪代谢、激素的分泌等各种过程, 并与肿瘤的发病密切相关. 已经有研究表明, miRNA在慢性淋巴细胞白血病、儿童Burkit淋巴瘤、胃癌、肺癌和大细胞性淋巴瘤中异常表达[13].
宿主对入侵其病原体发生免疫应答主要包括固有免疫和适应性免疫2种形式. 初始阶段, 胞膜或胞质中的一些识别分子(如TLR或NLR)对病原体进行识别后, 通过信号传递分子将信号逐级传递入胞核内, 进而激活核转录因子, 产生天然免疫应答. 目前研究表明, NF-κB作为一种重要的核转录因子, 在炎症与肿瘤的发生中起关键作用[14,15]. NF-κB的激活能刺激机体产生TNF-α、IL-1、IL-6以及IL-8等一系列促炎因子, 而这些促炎因子同肿瘤的发生亦密切相关[16].
miRNA在固有免疫和适应性免疫中所扮演的角色也逐渐被人们所认识. 其中, miR-146最早被发现参与机体免疫应答. 目前认为, TLR识别病原体后能诱导miR-146生成, 且这一过程依赖NF-κB的激活. 而miR-146通过抑制其作用靶标IRAK1和TRAF6, 对NF-κB的激活起抑制作用, 从而形成负反馈调节环路[17]. 最近还有研究表明, NF-κB/miR-146与乳腺癌、胰腺癌和甲状腺癌[18-20]. 细菌或病毒感染髓样细胞(单核或巨噬细胞)后, TLR信号通路被激活, 分泌的促炎因子能上调miRNA-155的表达, 而miRNA-155又能反馈抑制TLR信号通路中FADD, RIP和IKK的表达[21]. miRNA-155的上调同时伴随miRNA-125b的表达下调, miRNA-125b能抑制TNF-α的合成, 在未发生感染的情况下抑制促炎因子的生成, 而感染时miRNA-125b的表达上调则能迅速激活TLR信号通路[22]. 此外, miR-181b、miR-21、miR-301a、miR-9和miR-199a等和机体免疫应答以及NF-κB也有一定关系[23].
细菌定植宿主产生持续性慢性感染与其逃避机体免疫应答有关, 其机制非常复杂, 而miRNA在其中所起的作用目前研究报道不多. Navarro等[24]首次在植物中发现一种革兰氏染色阴性假单胞菌, 通过Ⅲ型分泌系统将毒力因子注入细胞, 抑制机体内病原体相关分子模式(pathogen-associated molecular patterns, PAMP)相关miRNA的生成. 这一发现提示其他病原体(如H. pylori)可能也能通过干扰miRNA系统从而在体内持续感染.
迄今为止, miR-21与H. pylori及其致胃癌的关系研究得最为广泛深入. 2008年, 我国学者首次提出miR-21可能在H. pylori致胃癌的过程中扮演了重要角色. Zhang等[25]用胃黏膜上皮细胞与H. pylori共培养后发现miR-21的表达显著上调; 进一步分析胃癌组织与胃癌细胞株, 发现其中miR-21均存在不同程度的过表达; 且miR-21能直接抑制抑癌基因RECK的表达, 促进细胞增殖、抑制细胞凋亡. 还有学者通过对胃癌以及癌旁组织进行定量PCR检测后发现, miR-21在92%的胃癌标本中存在过表达, 从而认为miR-21可以作为胃癌诊断的一个肿瘤标志物, 但对患者预后的判断影响不大[26]. H. pylori感染后miR-21上调的机制目前推测可能与感染激活NF-κB有关, NF-κB激活后刺激胃黏膜IL-6分泌增多, 后者进一步激活AP-1和STAT3, 诱导miR-21的表达上调[27,28]. 在上皮细胞中, miR-21抑制PTEN的表达、激活Akt信号通路, 激活NF-κB, 这些机制可能与其发挥癌基因的功能相关[29,30].
miR-155与H. pylori感染的关系亦有文献报道, 研究发现[31]H. pylori感染能诱导胃黏膜上皮细胞和胃黏膜组织中miR-155的表达上调, 其机制可能与感染激活NF-κB和AP-1信号通路有关, 而miR-155通过作用IKKε、Smad2和Fas相关死亡结构域蛋白从而降低NF-κB的活性, 因此可以推断miR-155可能在H. pylori感染引起的炎症反应中起负调控作用.
miR-146a对H. pylori感染的调控也引起了人们的重视. 有研究表明[32], H. pylori感染相关炎性细胞因子IL-8、TNF-α、IL-1β均能通过激活NF-κB通路诱导miR-146a的表达升高; 而miR-146a能够通过抑制其靶基因IRAKl、TRAF6的表达, 降低NF-κB的活性, 从而抑制炎症因子IL-8、MIP-3α、GRO-α的释放; 此外, miR-146a还能直接作用其靶基因炎症启动关键酶COX-2从而抑制炎症的发生, 这表明miR-146a能负性调控H. pylori感染炎症反应.
H. pylori感染能刺激胃黏膜分泌多种促炎和抗炎因子. 而这些促炎和抗炎因子之间的动态平衡能通过调节细胞增殖凋亡影响H. pylori感染后胃黏膜病变转归. 在这个复杂过程中, 转化生长因子β(transforming growth factor-β, TGF-β)参与黏膜免疫应答, 对上皮细胞的增殖、分化和凋亡起关键调控作用[34].
Petrocca等[33]利用基因芯片技术对胃炎、癌前病变和胃癌组织进行分析, 发现胃癌组织miR-106b、miR-93和miR-25表达显著增加, 且miR-106b-25能通过抑制抑癌基因p21发挥癌基因的功能, 其表达与E2F1、Mcm7密切相关. 而关于TGF-β作用机制一直存在争议, TGF-β在正常组织中可以抑制肿瘤的生成, 但在肿瘤中却会促进肿瘤细胞的生长. 因此, Petrocca等[33]认为, miR-106b、miR-93和miR-25能调节胃黏膜上皮细胞对TGF-β的生理应答, 进而调控细胞周期和凋亡.
此外, miR-155、miR-17-92和miR-34a可能在H. pylori诱发MALT淋巴瘤过程中起一定作用[22,34,35].
目前已发现一些miRNA与胃癌相关, 使人们自然联想到这些miRNA在H. pylori感染过程中表达是否异常? TGF-β可能为研究线索之一, H. pylori与胃黏膜上皮细胞和单核细胞供培养后发现TGF-β表达显著上调[36]. 而后者在H. pylori慢性感染过程中调节免疫应答, 影响胃黏膜上皮细胞的转化.
鉴于基因芯片技术高效快速的特点, 其对筛选感染H. pylori后miRNA表达情况无疑起到非常重要的作用. 最近Matsushima等[37]收集临床胃黏膜病理标本后, 分别对H. pylori阳性和阴性标本进行基因芯片分析, 共发现55种miRNA的表达存在差异, 其中30种miRNA表达显著下调. 而在进行H. pylori根除治疗后, 其中14种下调的miRNA表达恢复正常水平.
刘真[38]用正常胃黏膜上皮细胞GES-1感染H. pylori 26695后进行高通量筛选, 其中上调或下调超过2倍显著差异表达的miRNA包括: 表达上调的PREDICTED-miRl91、miR-155、miR-146a、miR-16、miR-92b、miR-30b等, 和表达降低的miR-18lb、miR-324.
上皮间质转化(epithelial-to-mesenchymal transition, EMT)是一种基本的病理生理现象, 以上皮表型缺失和间质表型获得为主要特征. 不仅参与胚胎的形成与发育, 而且与上皮性恶性肿瘤的发生发展及浸润转移密切相关.
有研究报道[39], H. pylori感染胃黏膜上皮细胞后, 其相关毒力因子蛋白(CagA)通过Ⅳ型分泌系统转运进入宿主细胞, 引起细胞形态延长和伸展, 细胞间紧密连接和黏合连接被破坏. 极性单层上皮细胞形态向具有侵袭性的间质形态发生转化. 最初发现发生转化的机制与CagA影响转录抑制因子Twist、Snail和Zeb1, 进而引起E-cadherin的缺失相关[40,41]. 其中Twist能抑制P21的表达, 而后者又能逆转Twist对E-cadherin的抑制作用[42,43]. 最近有学者指出, CagA进入极性上皮细胞后, miR-17和miR-20a在抑制P21的表达方面起主导作用, 促进细胞发生EMT[44]. 此外还有文献报道, miR-200家族, 包括miR-200a、b、c, miR-141和miR-429在抑制EMT以及肿瘤细胞侵袭方面均发挥一定作用[45-48].
有研究报道, CagA能诱导β-catenin结合E-cadherin, 进而激活Wnt/β-catenin信号通路[49]. 而β-catenin的异常表达在许多胃肠道肿瘤的形成、侵袭以及转移中起关键作用. 之前有文献报道, 肝脏腺瘤和腺癌中发现β-catenin过度激活和miR-375表达下调[50]. 其具体机制仍有待进一步阐明.
miRNA的发现以及其对基因转录后表达的修饰, 使人们对基因表达调控方式有了更深刻的认识. 而miRNA与H. pylori关系的探讨, 亦使我们对H. pylori致病机制有了全新的认识. 目前, 已经应用基因芯片技术筛选出一些与H. pylori感染相关的miRNA. 然而, 在H. pylori慢性感染过程中, 这些miRNA其作用靶标及具体机制如何? miRNA是否为H. pylori致病致癌的始作俑者? 仍有待进一步研究.
幽门螺杆菌是人体内最常见的一种慢性感染, 1994年国际抗癌联盟将其列为Ⅰ类致癌物质. 近年来, 人们miRNA与肿瘤发病的关系进行了广泛的研究, 而miRNA在幽门螺杆菌致病机制中所扮演的角色亦逐渐引起人们的重视.
李军祥, 教授, 北京中医药大学附属东方医院消化内科; 樊晓明, 主任医师, 复旦大学附属金山医院消化科
目前幽门螺杆菌致胃癌的确切机制仍不清楚, 而miRNA可能在其中发挥了重要作用. 明确各种miRNA在幽门螺杆菌致胃癌过程中所起的作用, 进而探索胃癌诊断与基因治疗的方法, 是当前以及今后的研究热点.
目前研究发现, 在幽门螺杆菌慢性感染胃黏膜过程中存在一些miRNA的表达异常. 而这些miRNA的异常表达在胃癌发病过程中起着十分重要的作用.
如能深入研究幽门螺杆菌慢性感染过程中miRNA的变化及其机制和生物学作用, 对探讨miRNA在幽门螺杆菌致癌的机制有着重要的意义, 也为胃癌及其癌前病变防治策略提供新的理论和实验依据.
本文设计合理, 选题新颖, 有一定的可读性.
编辑:曹丽鸥 电编:何基才
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