修回日期: 2011-03-28
接受日期: 2011-04-11
在线出版日期: 2011-04-18
结肠癌的发生是多阶段、多步骤的病变过程, 是从良性息肉-浸润性腺癌-癌远处转移的演变过程. 这些病理变化与编码蛋白质的原癌基因和肿瘤抑制基因的异常激活或失活有关. 但最近关于微小RNA(microRNAs, miRNAs)的研究改变了我们对非编码蛋白质基因在肿瘤发生中的作用的理解. 在结肠癌组织中多种miRNAs的表达水平不同, 这些miRNAs通过细胞内信号网络的相互作用改变细胞的增殖、凋亡和转移过程. 在临床应用中, 从血液或粪便中分离出来的miRNAs可作为早期诊断结肠癌的生物标志物, miRNAs结合位点的多态性与结肠癌的发病风险相关, miRNAs表达水平的改变或miRNAs相关基因的多态性与患者的生存率和治疗效果相关. 随着RNA传递技术的发展和对结肠癌中miRNAs调节异常的进一步研究将会产生以miRNAs为基础的新一代诊治方法. 本文主要综述了结肠癌相关miRNAs的转化医学研究进展.
引文著录: 尹少朋, 徐峰, 庞智. 结肠癌相关miRNA的转化机制. 世界华人消化杂志 2011; 19(11): 1101-1108
Revised: March 28, 2011
Accepted: April 11, 2011
Published online: April 18, 2011
Colon carcinogenesis is a stepwise progression from polyps to adenocarcinomas and distant metastasis. These pathologic changes are contributed by aberrant activation or inactivation of protein-coding proto-oncogenes and tumor suppressor genes. However, recent discoveries in microRNA research have reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. In this regard, a remarkable number of microRNAs exhibit differential expression in colon cancer tissues. These microRNAs alter cell proliferation, apoptosis and metastasis through their interactions with intracellular signaling networks. From a clinical perspective, polymorphisms within microRNA-binding sites are associated with the risk for colon cancer while microRNAs isolated from feces or blood may serve as biomarkers for early diagnosis. Altered expression of microRNAs or polymorphisms in microRNA-related genes have also been shown to correlate with patient survival or treatment outcome. Further insights into microRNA dysregulation in colon cancer and the advancement of RNA delivery technology will make it very likely to develop novel microRNA-based therapeutics.
- Citation: Yin SP, Xu F, Pang Z. Colon cancer-related microRNAs: implications for translational research. Shijie Huaren Xiaohua Zazhi 2011; 19(11): 1101-1108
- URL: https://www.wjgnet.com/1009-3079/full/v19/i11/1101.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v19.i11.1101
结肠癌是临床上最常见的三大恶性肿瘤之一, 也是世界上癌症相关死亡的主要原因. 据2008年估计, 全球每年其新患结肠癌患者数约120万人, 约有60.87万患者死于此病[1-3]. 大多数结肠癌为散发性, 一些内在因素(如年龄、男性、糖尿病、肥胖和炎症性肠病)和外在因素(如吸烟、膳食纤维摄入不足、酗酒、进食红色肉类和高脂肪食物)均与患结肠癌的风险增加有关[2,4-8], 超过1/5的患者都有家族遗传性倾向, 常有两个以上的一级亲属都患有结肠癌, 但只有6%的患者能够被诊断出癌家族综合征(如Lynch综合征和家族性结肠腺瘤样息肉)[9]. 结肠癌是个多阶段、多步骤的病变过程, 是由良性腺瘤向恶性腺癌和癌远处转移的演变过程, 使筛查和早期诊断对于及时发现结肠癌, 减少患病率成为理想的选择[10], 这迫切需要开发新的筛查工具和诊断性生物标志物, 包括手术、化疗、放疗和新型靶向治疗(西妥昔单抗和贝伐单抗)在内的几种治疗方法业已在临床上用于结肠癌的治疗. 然而, 转移性结肠癌患者的预后仍然很差[11], 因此, 必须进一步研究结肠癌的分子发病机制, 并且开发新型靶向治疗.
虽然结肠癌的发生是多因素的, 但是原癌基因和肿瘤抑制基因的遗传学和表观遗传学改变仍然是其基本的致病机制, 这些基因的异常表达和癌蛋白功能的改变可影响肿瘤发生的多个方面, 包括细胞的增殖、凋亡、转移、血管生成、多药耐药和维持遗传以及基因稳定等过程[12]. 与癌蛋白对比, RNA长期以来被认为在肿瘤的发生中起着相对被动的作用, 主要参与从DNA的转录到蛋白质的翻译过程. 然而, 近年来对非编码基因组序列的研究揭示存在几类非编码RNA(non-coding RNA, ncRNA), 包括反义RNA[13]、核仁小分子RNA(small nuclear molecule RNA, snoRNA)[14,15]和微小RNA(micro RNA, miRNA), 在肿瘤的发病机制中发挥着新的重要作用. 由于在肿瘤中经常出现miRNA的调节异常, 这已引起人们的极大的关注和研究热潮. 本文试图对结肠癌相关miRNA的转化医学进行简要综述.
miRNA是一类长度约为22个核苷酸的重要转录后调节因子. miRNA通过与靶mRNA的3'非翻译区(untranslated region, UTR)结合抑制其表达从而发挥其生物学功能. 单个miRNA可以调节多个靶标, 因此miRNA可作为一类主要的调节因子控制基因的表达. 生物信息学分析表明, 尽管miRNA只占人类基因组的1%-3%, 但高达30%人体基因可受到miRNA的调节[16]. 大多数的miRNA编码基因作为独立的转录单位进行运作, 其中包含自己的启动子和调控元件. 然而, 1/4的miRNA基因是内含子, 伴随其宿主基因一道进行转录. 在核内miRNA基因经RNA聚合酶Ⅱ转录, 产生初级miRNA, 由一个5'端帽、至少一个约70个核苷酸的发夹结构和一个3'poly(A)尾组成. 多顺反子的初级miRNA最多包含7个发夹结构, 可产生不同的成熟miRNA. 转录后, RNaseⅡ drosha及其辅助因子DGCR8将初级miRNA加工成前体miRNA, 剔除5'端帽, 3'poly(A)尾和侧翼发夹结构的序列. 前体miRNA在转运蛋白5的作用下由核内转到胞质中. 在细胞质, 前体miRNA由另一种RNaseⅢ Dicer进一步加工处理, 产生短双链RNA片段(即成熟的 miRNA链和其互补的miRNA链, 长度约20-25个核苷酸)[17]. 由于非对称热稳定性, 成熟的miRNA链优先与其他蛋白质一起组成RNA诱导沉默复合体(RNA-induction silencing complex, RISC), 靶向作用内源性mRNA使其沉默[18]. miRNA与靶mRNA在种子区域(2-8个核苷酸位置)之间的完全和部分互补性结合, 从而引起靶 mRNA的降解或者翻译抑制[19]. Argonautes蛋白是一类构成RISC的蛋白质, 具有内切酶的活性, 可诱导mRNA的剪切. RISC诱导翻译抑制的机制较为复杂, 可能包括翻译起始区的帽依赖性抑制, 真核生物翻译起始因子6(Eukaryotic translation initiation factor 6, eIF-6)招募到RISC, 新生蛋白的降解, 核糖体离散, 预防poly(A)结合蛋白和eIF-4G之间的相互作用, 其结果导致脱腺苷化[19,20].
在结肠癌中, miRNA介导的基因沉默可能失调. 在伴有高微卫星不稳定性的结肠癌患者中, 已经明确癌组织中的Ago2和TNRC6A发生突变和下调[21]. Ago2是Argonaute家族的一个成员, 与Tnrc6A相互作用并与靶mRNA结合, 诱导基因沉默. 与此相反, RISC的另一组成部分, Snd1在癌前病变变性隐窝病灶和结肠癌中表达上调. 在正常肠上皮细胞内稳定转染Snd1则导致接触抑制和细胞极性的消失, 而且结肠腺瘤性息肉(adenomatous polyposis coli, APC)抑癌基因出现下调[22]. 然而, 涉及到RISC功能的Snd1上调表达发挥其致瘤作用的这一机制尚不明确, 需要进一步阐明.
细胞增殖失控是恶性肿瘤的共同特点. 在结肠癌中已证实, 有许多miRNA可通过细胞内信号网络之间的相互作用改变细胞的增殖. 研究已表明几种miRNA是通过影响k-ras基因而抑制结肠癌细胞的增殖. 例如, 体外培养的人结肠癌细胞用在结肠癌中经常下调的一种miRNA let-7a转染后, 可显著地抑制细胞生长和下调Ras蛋白的表达[23,25]. miR-143是作用于k-ras靶基因的另一种miRNA. 在结肠癌组织中, KRAS蛋白和miR-143之间的表达呈负相关. 此外, 经miR-143拮抗剂处理的Lovo细胞显示细胞增殖加速, 而miR-143的过表达具有相反的效果[26]. miR-143过表达也降低结肠癌细胞在软琼脂培养基上的集落形成能力[27]. 事实上, miR-143是一种公认的在结肠癌中下调表达的miRNA[2]. 除了KRAS的, 现已确定ERK5和DNMT3A可作为miR-143的直接靶标[2]. miR-18a的靶标是KRAS, 抑制miR-18a则增加细胞的增殖, 在软琼脂培养基上促进HT29不依赖支持物生长[28]. 相反, miR-200b是一种可由化疗药物氟尿嘧啶上调的miRNA, 通过抑制KRAS阻遏基因PTPN12的表达能间接激活k-ras基因, 认为miR-200b介导的k-ras基因激活可以作为一个自我调节机制, 以抵消5-氟尿嘧啶的细胞毒作用[29].
业已证实几种miRNA靶向作用于二氢叶酸还原酶而抑制细胞周期. 研究表明miR-24在结肠癌中表达减少, miR-24通过直接作用于二氢叶酸还原酶抑制结肠癌细胞的增值和诱导G2/S细胞周期阻滞. 尽管miR-24上调p53和p21基因, 但其抗有丝分裂作用与P53的功能无关[30]. 相反, miR-192和miR-215两者的靶标也是二氢叶酸还原酶, 均可诱导G1和G2细胞周期阻滞, 但其作用需要P53的存在[31-33]. miR-192和miR-215均由p53基因诱导[31], 表明这两种miRNA可参与正反馈回路, 以介导P53肿瘤抑制作用. miR-215另一个显著的特点是在CD133+HI/CD44+HI细胞中该miRNA的表达明显增加, 具有干细胞样特性. 为此, miR-215表达的增加可以减少这类细胞的增殖率和化疗抵抗[34]. 多项研究均已表明, miR-34a和miR-675通过直接或间接对E2F转录因子家族的调控而改变结肠癌细胞增殖. 在原发性结肠癌组织中miR-34a的表达水平降低[35], 在一些结肠癌细胞系中可检测到miR-34a启动子的CpG甲基化[36], miR-34a可通过激活P53进行诱导表达[37], miR-34a靶向作用于E2F1/3诱导细胞衰老. 此外, miR-34a通过P53依赖的p21基因的诱导, 可降低细胞周期进程[35]. 研究已揭示miR-675是一种在结直肠癌中上调表达的miRNA, 能作用于E2F转录因子的一个拮抗剂视网膜母细胞瘤蛋白pRB, 促进结肠癌细胞的增殖和集落形成[38].
组织的內稳依赖于细胞增殖和细胞死亡之间的复杂平衡, 而后者通常是以细胞凋亡的形式出现. 这种平衡的破坏导致两个极端的组织功能障碍, 即组织萎缩和肿瘤形成. Hanahan和Weinberg提出, 细胞凋亡的逃避是肿瘤细胞的6个主要标志之一[39]. 研究发现结肠黏膜凋亡的减少率与结肠腺瘤的风险增加有关, 这表明凋亡在结肠致癌机制中具有重要的作用[40]. Bcl-2家族中促凋亡和抗凋亡成员的反向活动控制线粒体膜通透性. 在结肠癌中失调的miRNA是通过改变Bcl-2家族成员的表达而调节细胞凋亡的. 例如, 在结肠癌组织中miR-195表达下调, 作用于抗凋亡蛋白Bcl-2, 诱导结肠癌细胞系HT29和Lovo凋亡[41]. miR-143是另一种在结肠癌中经常表达下调的miRNA, 伴随着miR-143对Bcl-2的下调, 在接触5-氟尿嘧啶后结肠癌细胞活力减少, 细胞死亡增加[42]. 在实体肿瘤中通过异常CpG甲基化使得miR-34a经常沉默[36]. 在结肠癌细胞中miR-34a通过靶向作用于具有脱乙酰化和使P53失活的SIRT1酶, 促进P53依赖的PUMA促凋亡蛋白表达和凋亡[43]. miR-34a可导致P53乙酰化水平的提高. miR-34a的促凋亡作用只能在含野生型P53的结肠癌细胞中观察到, 表明miR-34a促进凋亡是通过SIRT1-P53-PUMA级联反应进行的[43]. miR-34a也可减少Bcl-2的表达和增加结肠癌细胞对5氟尿嘧啶的敏感性[44]. 在结肠癌细胞中, 失调的miRNA可作用于凋亡信号通路中的其他调节因子. 例如, 在结肠癌组织和细胞系中miR-133的表达明显下调, 在结肠癌细胞中, miR-133过表达时通过直接作用于肝细胞生长因子受体c-Met而诱导凋亡[45]. miR-145通过靶向作用于caspase-3的底物DNA片段因子-45, 参与了星形孢菌素诱导的细胞凋亡. 其他的miRNA, 如miR-26、miR-107、miR-210和miR-342, 也涉及到凋亡应答的调控[2,46,47].
研究已表明几种miRNA可调控结肠癌细胞的浸润和转移. 例如, miR-196a通过直接作用于一类称之为同源盒的转录因子而促进结肠癌细胞的离散、迁移和浸润[48]. 在这个过程中, miR-196a结合到HoxA7、HoxB8、HoxC8和HoxD8的3 UTR并下调其表达. 这些同源蛋白的下调与增加Akt的磷酸化水平相关联. miR-196a还促进小鼠尾静脉注射结肠癌细胞后的肺部转移[48]. 除了miR-196a, 也有报道称miR-21和miR-141能促进结肠癌细胞的活动或浸润[49,50]. miR-21可靶向作用于PDCD4, 后者是一种肿瘤抑制基因, 常常在实体瘤中下调表达, 并与疾病进展和转移有关. 而miR-141下调E-cadherin转录抑制基因SIP1的表达, 抑制肿瘤细胞从间质向上皮转移[49,50]. 涉及调控结肠癌浸润和转移的其他miRNA包括miR-26、miR-145和miR-200c[2,51,52].
除了细胞增殖, 凋亡和转移, miRNA还能调控其他的肿瘤相关表型. 例如, miR-107通过抑制缺氧诱导因子介导的血管内皮生长因子表达而抑制血管新生[53]. 几种miRNA还涉及到药物敏感性的调节. miR-143可促进由5-氟尿嘧啶诱导的结肠癌细胞的细胞死亡, 而miR-192和miR-215有相反的效果[33,42]. miR-215还可以减少结肠癌细胞对甲氨蝶呤和胸苷酸合成酶抑制剂Tomudex的敏感性[34]. 此外, miRNA直接参与了遗传完整性的维护, 其中miR-155通过靶向作用于涉及DNA修复的3种酶hMSH2、hMSH6和hMLH1促进基因突变[54]. 最近的一项研究也表明, 由肿瘤抑制因子ZEB1诱导的miR-200家族, 靶向作用于Sox2和Klf2, 抑制结肠癌细胞的干细胞样特性[55]. 炎症是肿瘤的诱发因素, 研究已显示miR-21和miR-181b-1两者都由活化的STAT3诱导, 分别通过靶向作用于PTEN和CYLD导致炎症向癌症的转变[56].
基于个体基因组构成的疾病风险预测是个体化治疗的主要目的. 已有不少研究对促进了结肠癌相关基因多态性进行了鉴定. 迄今, 一些基因(包括SMAD7、EIF3H、RHPN2、BMP4、CDH1)的多态性已知与结肠癌的患病风险或复发相关[57], miRNA通过与靶mRNA的3UTR结合来发挥他的细胞功能. 因此, miRNA结合位点的序列变化可改变miRNA与靶标之间的相互作用, 并影响肿瘤相关miRNA的癌基因或肿瘤抑制功能. 对两个基因, 即CD86和INSR, 进行miRNA结合位点多态性的预测, 已表明他们都与增加患结肠癌的风险有关[58], 利用高分辨率的SNP微阵列和下一代测序技术辅佐的全基因组关联研究得到更多的信息, 从而能够在miRNA基因和miRNA结合位点中发现更多的多态性, 有了这些信息, 医生就能更准确的评估个体患结肠癌的遗传易感性.
miRNA有望成为诊断结肠癌的新的生物标志物. 正常细胞和癌细胞都能释放miRNA到外周血. 循环中的miRNA被高度稳定的复合体(最常见的是胞外体和微小囊泡)包裹, 以阻止miRNA被RNA酶降解[59,60]. miR-17-3p和miR-92a在结肠癌患者血浆中明显升高, 而在切除肿瘤组织后, 这两种miRNA都显著下降, miR-92a还能与结肠癌和其他疾病, 如胃癌和炎症性肠病进行鉴别, 进一步分析表明, miR-92a能够产生88.5%的ROC面积, 在相对RNU6B核内小RNA表达的临界值为240时, 其敏感性和特异性分别为89%和70%[61]. miR-92a的诊断价值进一步被确定[62], Huang等指出, miR-92a和miR-29a能从正常人群中区分结肠癌和高危的腺瘤, 从而证实miR-92a对早期诊断结肠癌有用. 除了外周血, 因为结肠细胞不断脱落到肠腔中, 大便中也有结肠癌特异性的miRNA, 可作为另一有价值的诊断途径. 相对于无结肠癌的人来说, miR-21和miR-106a在腺瘤和结肠癌患者的粪便中含量较高[63].
有大量学者业已探讨了miRNA调节异常和结肠癌之间的关系, 在这些调节异常的miRNA中, 研究最多的是miR-21, miR-21高表达与结肠癌淋巴结转移、癌远处转移和晚期TNM分期有关[64,65], 还与无瘤间隔期缩短, 疗效不佳有关[64,66]. miR-21的表达也与包括TNM分期的临床特异性癌症死亡相关[64,67]. 除了miR-21, 其他的miRNA与肿瘤大小的增加、癌转移和/或患者的生存期相关. 如miR-152和miR-148a的低表达与肿瘤体积较大和晚期pT分期相关[68], 最大直径>50 mm的肿瘤, miR-143和miR-145低表达, 这两个miRNA被认为是肿瘤抑制因子[65]. 令人费解的是, miR-143过表达的患者无瘤间隔期却缩短[66]. miRNA-31与肿瘤深度浸润和晚期TNM分期成正相关[69]. 在无癌的结肠组织中表达的miRNA也与淋巴结转移相关, miR-129*和miR-137在有淋巴结转移和无淋巴结转移的结肠癌患者中表达程度也不一样[70]. miR-106a的下调与无瘤生存期和总生存期缩短有关, 而miR-200c高表达的患者比低表达的患者生存时间缩短[71,72]. miR-320和miR-498的表达水平与Ⅱ期结肠癌患者的无复发生存期有关, 联合测定17种miRNA的表达谱可预测结肠癌的发生, 其精确度为81%[73].
在miRNA基因或miRNA结合位点中, miRNA表达的改变或其多态性与结肠癌患者的治疗效果相关. let-7g和miR-181b的表达水平与5-氟尿嘧啶类的抗代谢药物的化疗效果密切相关[74], 在有远处转移的野生型KRAS结肠癌患者中, k-ras基因的3'UTR let-7 miRNA结合位点的多态性与塞妥昔布单抗的治疗反应成正相关[75,76]. 而且, pri-miR26a-1和pri-miR-100的SNPs rs7372209和rs1834306, 分别与用5-氟尿嘧啶和伊立替康进行治疗的结肠癌转移患者的肿瘤应答或肿瘤进展时间相关, 对miRNA生物合成过程的研究发现, 在同一组患者中, 细胞出核蛋白5基因的SNP rs11077与疾病的控制率也相关[77].
miRNA作为一类转录后调节因子, 在包括结肠癌在内的多种肿瘤中表达不同. 这些调节异常的miRNAs能促进细胞的分裂、抑制细胞凋亡, 通过细胞内信号网络的相互作用促进结肠癌细胞进行转移. 进一步阐明miRNA调节异常的原因和结果将会更好地帮助我们理解结肠癌的致病机制和开发新的抗癌治疗的分子靶点. 从临床角度看, 许多调节异常的miRNAs都可作为诊断和预测结肠癌进展的潜在生物学标志物, 将这些miRNAs与已有的一组生物标志物联合在一起进行检测将会提高结肠癌诊断的敏感性和特异性. 然而, 还需要更多的研究来确定这些潜在的miRNA标志物, 特别是在不同种族中, 迫切需要建立以miRNA为基础的对临床有用的诊断和预后判断的方法, 同时对癌前病变患者相关的血浆和大便中新的miRNA进行鉴定, 能帮助早期诊断和筛查结肠癌. 在治疗方面, 低表达miRNA者可给予miRNA类似物进行补充, 而过表达miRNA者则可成为一些新合成的寡核苷酸(如与胆固醇偶联的miRNA反义核苷酸抑制剂)的靶点[78]. 尽管如此, 由于这些miRNA在基因表达方面的多效性作用, 这些调节因子的全身递送不是一种很好的途径. 虽然miRNA的器官特异性递送仍然是我们目前面临的一种挑战, 但是已有报道, 通过使用经生物工程处理的益生菌, 在小鼠肠腔中递送siRNA却能预防结肠癌的发生, 也可以采用类似的策略对miRNA进行递送[79]. 随着RNA递送技术的发展, 相信在不久的将来以miRNA为基础的靶向治疗将会成为治疗人类癌症的新方法.
长期以来RNA被认为在肿瘤的发生中起着相对被动的作用, 主要参与从DNA的转录到蛋白质的翻译过程. 然而, 近年来对非编码基因组序列的研究揭示小分子RNA(miRNA), 在肿瘤的发病机制中发挥着新的重要作用.
黄培林, 教授, 东南大学
由于在肿瘤中经常出现miRNA的调节异常, 这引起人们的极大的关注和研究热潮.
Hanahan和Weinberg提出, 细胞凋亡的逃避是肿瘤细胞的6个主要标志之一.
随着RNA传递技术的发展和对结肠癌中miRNA调节异常的进一步研究将会产生以miRNA为基础的新一代治疗方法.
本文新颖性较好, 具有较好的科学性和可读性.
编辑:李薇 电编:何基才
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