miR-122
miR-122(英语:miR-122 microRNA)是一个miRNA,在脊椎动物中保守,但不存在无脊椎动物基因组中,且无旁系同源物[1]。miR-122在肝脏中高表达[2],可调节脂肪酸代谢,也与肝细胞癌和丙型肝炎病毒复制有关[3]。
pri-miR-122 | |
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mir-122的二级结构和保守序列 | |
识别符 | |
代号 | mir-122 |
Rfam | RF00684 |
miRBase | MI0000442 |
miRBase | MIPF0000095 |
其他数据 | |
RNA类型 | Gene; miRNA |
域 | Eukaryota |
表现与调控
编辑miR-122于2002年克隆小鼠组织特异性miRNA的研究中发现,仅在肝脏细胞中表现[2],后续实验在斑马鱼中也发现此miRNA于肝脏细胞中特异性地表现[4]。miR-122的表现在胚胎发育的过程中逐渐增加,成年人肝脏中有高达72%的miRNA为miR-122,为人体所有组织中表现量最大的miRNA[5]。人类的miR-122由18号染色体上的单一基因座编码,该基因座可转录产生miR-122的前驱物pri-miR-122(如右图所示),过程受HNF4A蛋白调控[6];pri-miR-122可再被若干RNA酶切割产生长22nt的成熟miR-122[2][7]。成熟的miR-122之3′端会由GLD-2聚合酶加上一个A,可提升此miRNA的稳定度[8]。
有研究显示miR-122的表现也受昼夜节律蛋白Rev-ErbA alpha调控,因此其表现可能随生理时钟变化,且此miRNA也可调控PPARβ/δ等数个昼夜节律蛋白之mRNA的基因表达[9]。
标的
编辑miR-122可与许多mRNA结合以调控其基因表达,例如它可与CAT-1mRNA的3'UTR结合以抑制其翻译,并使该mRNA被送入处理小体中;而当细胞面临特定逆境时,有另一蛋白HuR会从细胞核移至细胞质中,此蛋白也可与CAT-1之mRNA的3'UTR结合,可将该mRNA自处理小体中释出,并恢复其翻译,解除miR-122的抑制效果[10]。
miR-122的标的mRNA还有CD320、ALDOA与BCKDK等(给小鼠施予miR-122的抑制剂后,以mRNA微阵列的实验分析发现),此miRNA控制许多和脂肪酸代谢相关的基因表达,受抑制剂抑制后会降低小鼠的血脂含量、促进肝脏代谢脂肪酸、并抑制肝脏合成脂肪酸和胆固醇,但具体机制尚未被完整阐明[11][12][13]。此外miR-122的标的mRNA还有HJV与HFE等与铁代谢相关的基因[14],以及SIRT6等与心血管疾病相关的基因[15]。
许多研究亦指出miR-122可调控许多参与干扰素(IFN)反应途径的基因,激活干扰素反应,增强抗病毒基因的表现[16][17][17][18][19][20]。有细胞实验结果显示miR-122过表达的细胞抗RNA病毒的干扰素等先天免疫反应较强[18]。
肝细胞癌患者肝细胞中的miR-122表现量经常较未患病者低,且低miR-122表现与较差的预后呈正相关[21][22]。细胞实验显示miR-122属于肿瘤抑制基因,其表现可抑制癌变,并增强索拉非尼与阿霉素等化疗药物的疗效[23][24]。已知ADAM10、IGF-1R、CCNG1与ADAM17等miR-122的标的基因都与肝细胞的癌变有关[23][24][25]。
调控丙型肝炎病毒
编辑丙型肝炎病毒在肝细胞中的复制仰赖miR-122[26],miR-122可与丙型肝炎病毒RNA5′端两个相邻的位点结合[27],这两个位点在不同基因型的丙型肝炎病毒中均高度保守[28]。miRNA的功能一般为抑制基因表达,miR-122促进丙型肝炎病毒基因表达的机制尚不完全明朗,它可促进丙型肝炎病毒RNA的翻译,例如近期研究发现miR-122结合丙型肝炎病毒RNA后可能改变其二级结构,生成内部核糖体进入位点(IRES)而提升翻译[29],此外可能还有其他机制参与促进病毒的复制[30][31]。miR-122促进丙型肝炎病毒RNA表现的机制应需AGO蛋白的参与[32](但miR-122表现量够高时可能不需[33]),DDX6等其他miRISC复合体的组成蛋白则非必须[34]。
Peginterferon alfa-2a与利巴韦林等现有治疗丙型肝炎病毒的药物疗效有限且副作用强[35],miR-122抑制剂为一种具潜力的药物,即以与miR-122互补的核酸和其结合以抑制其功能,但因低miR-122与肝细胞癌正相关,此类药物需经谨慎测试,且不应长期施用[18]。丹麦制药公司Santaris Pharma开发中的抗丙型肝炎病毒药物Miravirsen即为与miR-122互补的锁核酸[36]。
生物标记
编辑miR-122被用作许多肝病的生物标记,血液中miR-122的含量可作为病毒、酒精或药物性的肝脏损伤[37][38][39]以及肝脏移植后发生排斥的指标[40][41],其含量改变可能比转氨酶含量的改变更早发生,因此可用作肝脏损伤的早期指标[40][42]。此外miR-122还可用作纤维化、高血压、动脉粥状硬化等心血管疾病的早期指标[15]。
参考文献
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