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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 May 28;48(5):743–749. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.220129

微RNA-15a和微RNA-16在纤维化疾病中作用的研究进展

Research progress in effects of microRNA-15a and microRNA-16 on fibrotic diseases

WEN Dada 1,2, WANG Jie 1,✉
Editor: 郭 征
PMCID: PMC10930399  PMID: 37539577

Abstract

MicroRNA (miR) is a class of highly conserved non-coding single-stranded RNA widely existing in mammals, which can negatively regulate the expression of targeting genes after transcription. As a key regulator, miR negatively regulates the expression of the targeting genes and disrupts important molecular signaling pathways, leading to the imbalance of multiple pathways such as tissue repair and inflammation involved in the fibrotic process. Among them, miR-15a/16 can participate in regulating and controlling the fibrotic process of various organs, including liver, lung, heart, kidney and other fibrotic diseases by acting on cell proliferation and transformation, extracellular matrix proteins production and degradation, inflammation and other important cell functions. It has potential diagnostic and therapeutic value. Clarifying the biological function of miR-15a/16 and its mechanism for action and therapeutic application prospects in various fibrotic lesions are of great significance for the molecular targeted treatment of fibrotic diseases.

Keywords: microRNA-15a, microRNA-16, fibrotic diseases, extracellular matrix, inflammation

微RNA(microRNA，miR)是一类短小的、内源性非编码单链核糖核酸，全长为18~22个核苷酸。MiR可通过完全或者不完全结合靶基因的3'-非编码区(untranslated region，UTR)、编码区或5'-UTR，直接降解靶基因mRNA或抑制其蛋白质翻译，起到负性调节基因表达的作用[1]。据预测，miR可以靶向50%以上的人类蛋白质编码基因，影响数百个基因转录本，从而参与调控细胞生长周期、增殖转化、侵袭迁移和凋亡等关键环节[2]。

除少数miR拥有自己的调节元件，可作为单独的转录单元发挥功能外，大部分位于基因组内的miR都依赖于宿主基因得以转录和表达[3]，其生成的经典途径：核内编码miR的基因在RNA聚合酶Ⅱ的作用下，转录成为初级miR(pri-miR)；pri-miR经核糖核酸酶Ⅲ/Drosha酶及其辅因子DGCR8重新剪切成更小的茎环结构，成为前体miR(pre-miR)；pre-miR通过出口蛋白5(exportin 5)释放到细胞质内，随后Dicer酶、人类免疫缺陷病毒(human immunodeficiency virus，HIV)-1反式激活应答元件RNA结合蛋白(trans-activation response RNA binding protein，TRBP)和Argonaute 2(AGO2)将其加工剪切成双链RNA，其中一条链被降解，而另一条成熟miR链被加载到由miR诱导的沉默复合物(miR-induced silence complex，RISC)中，可与靶基因3'-UTR内的微小核糖核酸识别元件不完全结合，导致转录后基因沉默，或者完全互补结合导致mRNA降解[4-5]。

纤维化是指由于组织内修复和炎症等各种途径的失常，造成脏器实质细胞发生坏死，以及组织内细胞外基质(extracellular matrix，ECM)成分异常增多和降解减少的病理过程，如果继续进展则可致脏器结构破坏和功能下降，甚至衰竭[6]。多种miR参与调节纤维化疾病的发生和发展，其中具有细胞特异性调控潜能的miR-15a/16在纤维化疾病中异常表达。阐明miR-15a/16的生物学特性及其在纤维化疾病中的表达和调控机制，可为纤维化疾病的分子靶向治疗提供新思路。

1. MiR-15家族

1.1. MiR-15家族成员的特征

MiR的特异性取决于其5'-第2~8个核苷酸序列即“种子区域”，该区域可以与靶基因mRNA的特殊碱基互补配对。因此，具备高度相似的种子区域且存在共同靶基因的miR可归类为同一个超家族[7]。“规范的”miR-15超家族是一类种子区域为AGCAGC(AGCx2)序列的miR，包括miR-15a/b、miR-16-1、miR-16-2、miR-195、miR-424和miR-497。此外，与典型的miR-15家族的种子区域不同，miR-503仅在第8个核苷酸上。MiR-503及5'-起始序列为AGCx2的miR-103、miR-107和miR-646都被归类为“扩展的”miR-15家族成员[8-9]。

在miR-15家族成员中，成熟的miR-16-1与miR-16-2具有相同的5p序列，因此不加区分地称为miR-16-5p。MiR-15a-5p与miR-15b-5p仅有4个核苷酸存在差异，但其种子区域序列完全一致，所以可能共享大量的靶基因。而miR-15a-3p与miR-15b-3p的种子序列差异很大，可能导致这2个miR集群的功能存在差异[10]。其中miR-15a与miR-16构成具有高度保守性的miR-15a/16-1基因簇，该基因簇位于人类13号染色体(13q14)和小鼠14号染色体(14qC3)长链非编码RNA(long non-coding RNA，lncRNA)淋巴细胞白血病缺失基因2(deleted in lymphocytic leukemia 2，DLEU2)的内含子中，受其启动子调控[11]。

1.2. MiR-15家族的表达调控

多种因素参与调控miR-15a/16的表达，包括遗传因素、表观遗传修饰、转录因子以及lncRNA等。等位基因突变、杂合性缺失以及miR生物合成过程异常等遗传因素可导致miR-15a/16表达失调[12]。许多研究表明DLEU2基因启动子区域的组蛋白乙酰化修饰可引起miR-15a/16-1的失调，Chen等[13]发现在敲除组蛋白去乙酰化酶3(histone deacetylase 3，HDAC3)以及其抑制剂的处理下可上调miR-15a/16-1启动子区域的乙酰化，进而上调其表达。同样，转录因子c-Myc、BSAP(B细胞特异性激活蛋白)都被证明可直接结合DLEU2基因，并招募HDAC3负向调控DLEU2基因启动子来抑制miR-15a/16的表达[14-15]。此外，Liu等[16]发现lncRNA核仁小分子宿主基因12(small nucleolar host gene12，SNHG12)是引起结直肠癌细胞内miR-16表达失调的上游因素；lncRNA肺纤维化相关RNA(pulmonary fibrosis-associated RNA，PFAR)也被证明可负性调控miR-15a的表达发挥促肺纤维化的作用[17]。总之，这些因素增加了调控miR-15a/16表达的复杂性，并可能通过相互作用参与miR-15a/16的调控过程。

2. MiR-15a/16在纤维化形成中的作用及其机制

由关键靶点、下游信号蛋白质和转录因子所构成的多层调控网络是发挥调控作用的关键，正是基于这种独特的作用机制使得miR-15a/16能够通过靶向信号通路中的mRNA，从而调控细胞转化、ECM合成与降解、炎症的发生等关键的纤维化特征。

2.1. 调控细胞转化

静息状态的成纤维细胞表型转化为胶原合成能力更强的肌成纤维细胞是纤维化疾病中关键的病理特征。成纤维细胞的表型转化离不开细胞因子的作用，其中转化生长因子(transforming growth factor β，TGF-β)可通过激活Smad蛋白及其下游信号，诱导成纤维细胞异常增生和表型转化为肌成纤维细胞，发挥强大的促纤维化功能[18]。Zhu等[19]研究发现：在丙型肝炎病毒引起的肝纤维化中miR-16的表达上调，高表达的miR-16能抑制肝细胞生长因子和Smad7的表达，从而促进肝纤维化。其中Smad7是TGF-β/Smad信号通路的抑制性蛋白，可以有效地抑制信号激活因子(Smad2和Smad3)的磷酸化以及下游信号的活化[20]。而另有研究表明，miR-16能显著抑制成纤维细胞中Smad2[21]、Smad3[22]、Smad5[23]的表达，从多方面抑制TGF-β所诱导的成纤维细胞向肌成纤维细胞的表型重塑过程，发挥抗纤维化的作用。

此外，上皮-间充质转化(ephethlial-mesenchymal transition，EMT)是肌成纤维细胞来源的重要途径之一。研究[24]表明：Notch、Wnt和TGF-β等信号通路均可激活EMT相关转录因子如Twist，诱导分化良好的上皮细胞发生EMT转变为肌成纤维细胞。Zhang等[25]研究发现：MiR-15a/16可直接结合靶基因Twist1，降低Twist1、神经钙黏素(N-cadherin)、α-SMA、纤连蛋白等EMT活化相关蛋白的表达水平，阻碍EMT进程，抑制上皮细胞转化。

2.2. 调控ECM合成与降解

纤维化是ECM组分合成与降解失衡的结果。Pan等[21]研究发现：在TGF-β、磷脂酰肌醇3激酶(phosphoinositide 3-kinase，PI3K)-Akt、丝裂原激活蛋白激酶(mitogen activation protein kinase，MAPK)-细胞外信号调节激酶(extracellular signal-regulated kinase，ERK)等信号通路的协同作用下，肌成纤维细胞内降解ECM成分的基质金属蛋白酶(matrix metalloproteinases，MMPs)活性受到抑制，金属蛋白酶组织抑制剂(tissue inhibitor of metalloproteinase，TIMP)表达增加，进而导致胶原和蛋白多糖等ECM的过度沉积，降解减少。而miR-16可通过靶向Smad2负向调控TGF-β信号转导，上调纤维溶解依赖性MMPs(MMP-2等)的表达，并且抑制I型和III型胶原蛋白等ECM的分泌[26-27]。

MiR-15a/16还可调控其他与ECM形成相关的信号通路。Yao等[28]研究发现：MiR-16-5p通过靶向Notch2抑制Notch信号通路的激活，进而增加人皮肤成纤维细胞中MMP-1和MMP-8的表达，减少胶原等ECM的沉积，从而发挥抗纤维化作用。Chen等[29]研究发现：过表达miR-15a可抑制Hippo通路中关键效应分子Yes相关蛋白1(Yes-associated protein 1，YAP1)，影响下游信号YAP1/TEA结构域转录因子(TEAD)4/Twist的激活，从而抑制肺成纤维细胞合成胶原等ECM。同样，miR-16模拟给药能够抑制人肺成纤维细胞中雷帕霉素靶向蛋白的雷帕霉素不敏感组分(Rictor)的表达，影响哺乳动物雷帕霉素复合物2(mammalian target of rapamycin complex 2，mTORC2)信号通路，进而下调ECM相关蛋白如富含半胱氨酸的酸性分泌糖蛋白(secreted protein，acidic and rich in cysteine，SPARC)的表达，最终改善体内外的肺纤维化[30]。这些发现均提示miR-15a/16可通过抑制ECM过度沉积改善组织器官的纤维化病变。

2.3. 调控炎症的发生

由各种刺激引起的持续性、慢性炎症反应是导致纤维化的主要原因。损伤部位的炎症细胞如巨噬细胞以及不同的淋巴细胞亚群被激活后，分泌大量促炎因子和促纤维化介质如白介素(interleukin，IL)-1、IL-6、IL-8、肿瘤坏死因子(tumor necrosis factor，TNF)-α、血小板衍生生长因子(platelet-derived growth factor，PDGF)、成纤维细胞生长因子(fibroblast growth factor，FGF)和角质细胞生长因子(keratinocyte growth factor-1，KGF-1)，导致损伤处的成纤维细胞异常增殖和转化，间质内胶原合成增加，从而引起组织纤维化[31]。而miR-15a/16参与调控炎症相关的纤维化调节因子的生成，与纤维化疾病的发生和发展密切相关。

转录因子NF-κB作为信号转导通路的中心在炎症中发挥重要作用。Gao等[32]研究发现：过表达的miR-16-5p可通过直接靶向IκB激酶β(IκB kinase β，IKKβ)，抑制NF-κB信号通路的激活，下调细胞中粒细胞-巨噬细胞集落刺激因子、嗜酸性粒细胞趋化因子、IL-1β、IL-6和IL-8等促炎细胞因子水平，进而逆转IL-13诱导的炎症反应。同样，Liang等[33]研究发现：MiR-16通过靶向程序性细胞死亡因子4(programmed cell death 4，PDCD4)，激活MAPK通路(包括p38和ERK1/2)和NF-κB通路，同时抑制JNK通路，降低血浆和组织中IL-6、TNF-α、单核细胞趋化蛋白-1(monocyte chemoattractant protein-1，MCP-1)和IL-1β等促炎细胞因子的水平，促进抗炎细胞因子IL-10的分泌，从而抑制炎症和纤维瘢痕组织的形成。

此外，miR-16可以调控巨噬细胞与活化T细胞之间的相互作用，通过下调控制巨噬细胞与T细胞相互作用和T细胞激活的关键免疫抑制因子，即程序性细胞死亡配体1(programmed cell death-ligand 1，PD-L1)的表达，将巨噬细胞的M2极化转化为M1，并激活CD4+T细胞，减少炎症细胞因子的分泌[34]。

3. MiR-15a/16与纤维化疾病

MiR-15a/16在纤维化疾病中异常上调或者下调，通过靶向不同基因促进或者抑制肝、肺、心肌、肾纤维化及其他纤维化疾病的进程。

3.1. 肝纤维化

肝纤维化是肝脏结构恶化的交汇点，最终导致肝硬化、肝细胞癌的发生。其主要的病理特征是肝星状细胞被激活，表型转化为肌成纤维细胞，合成大量胶原和脂肪等ECM成分。Guo等[35]通过微阵列分析证实miR-15a/16在活化的肝星状细胞中表达明显下调。Liu等[36]也发现肝病患者miR-16的表达水平显著低于健康对照组，且与肝纤维化指标密切相关。MiR-16可直接结合Smad2/3/5、赖氨酰氧化酶样蛋白1(lysyl oxidase like 1，LOXL1)等靶基因，协同作用于肝星状细胞活化所必需的信号通路(TGF-β通路)，消除肌成纤维细胞的表型特征，包括抑制胶原和脂肪生成，介导肝纤维化的修复[21, 37]；此外，miR-15a/16可通过靶向线粒体凋亡通路的关键成员Bcl-2及其下游蛋白酶联信号(caspase 1/3/8/9)，抑制肝星状细胞的凋亡抵抗效应[35-36]。Kim等[38]研究发现：miR-16的下调引起肝纤维化中鸟嘌呤核苷酸结合α-亚基(guanine nucleotide-binding α-subunit 12，Gα12)蛋白过表达，通过与自噬相关基因(autophagy-related gene，ATG)5/12偶联促进细胞自噬，从而激活肝星状细胞。由此可见，miR-15a/16可通过整合TGF-β、线粒体凋亡和细胞自噬等信号通路，调节肝星状细胞的激活，从而影响肝纤维化的进展。

3.2. 肺纤维化

特发性肺纤维化(idiopathic pulmonary fibrosis，IPF)是一种进行性、间质纤维化性肺病，其特征是细胞增殖、间质炎症以及纤维化。MiR-16已被证明是IPF的关键调控因子，可作为IPF早期诊断和治疗的指标。在IPF患者的血清中检测到较低水平的抗纤维化miR(如miR-16、Let-7d)和较高水平的促纤维化miR(如miR-21)[39]。MiR-15a/16在博来霉素诱导的肺纤维化小鼠模型中表达下调，在肺部损伤初期靶向调控细胞凋亡以及炎症相关通路(如Wnt信号通路、TLR信号通路)，在损伤晚期可以靶向TGF-β信号通路等纤维化相关通路[40]。其他研究也证实了miR-15a/16可通过靶向Wnt配体(Wnt10b、Wnt3a)[41]、Toll样受体4(Toll-like receptor 4，TLR4)[42]、Rictor/mTORC2通路[30]、lncRNA PFAR/YAP1/Twist轴[17]等，调控肺纤维化组织中成纤维细胞的活化与凋亡、炎症和纤维化反应。因此，这些基因被认为是治疗IPF的潜在靶点。

3.3. 心肌纤维化

心肌纤维化在心房结构重构的发生和发展中起关键作用，是高血压性心脏病、心肌梗死、心力衰竭等心血管疾病的共同病理特征。MiR-15家族是一种通过抑制TGF-β信号通路引起的心肌肥厚和纤维化的新型调节因子，miR-15家族能同时靶向TGF-β信号的激活因子(TGF-β受体1、Smad3、p38、内啡肽)和抑制因子(Smad7)，然而，其净效应似乎是抑制TGF-β的表达和信号转导活性[43]。在以进行性心肌纤维化为特征的糖尿病患者心脏、糖尿病小鼠模型以及高糖诱导的心肌细胞中，miR-15a/b的表达明显下调，TGF-β和结缔组织生长因子(connective tissue growth factor，CTGF)的表达上调，且通过恢复miR-15a/b的表达能逆转上述情况，减少心脏成纤维细胞的分化，改善心肌纤维化[44]。在高血压心脏病中，miR-16能够联合miR-19b下调肾上腺素受体A1a(ADRA1A)的表达，显著促进心脏纤维化和心肌细胞凋亡[45]。由此可见，miR-15a/16调控的复杂性，在不同病因引起的心纤维化中发挥不同的作用。

3.4. 肾纤维化

肾纤维化主要累及肾小球或肾小管间质，是多种慢性肾脏疾病的常见并发症。MiR-16在正常肾脏各区域的细胞中高度表达[46]。糖尿病大鼠模型的尿外泌体中miR-16和miR-451的表达上调，而在该模型的肾组织中表达下调[47]；这可能是由于细胞内的miR-16在肾组织损伤破裂后释放到体液中，从而引起尿外泌体中miR-16表达上调，提示其在肾组织中发挥保护作用。低剂量紫杉醇可通过上调miR-15a的表达显著改善大鼠肾功能，减轻肾次全切除后的肾损伤和肾小管间质纤维化，而miR-15a在一定程度上促进了紫杉醇对肾的保护作用，且这种作用与TGF-β/Smad信号通路密切相关[48]。MiR-16上调也被证明可抑制炎症诱导的肾纤维化和肾小球损伤，并通过靶向DEC2基因，抑制TLR4信号通路激活，从而抑制肾组织增生和系膜细胞增殖，减轻肾纤维化[49]。这为寻找新的肾纤维化生物标志物提供了新思路，是一个有吸引力的治疗靶点。

3.5. 其他纤维化疾病

系统性硬化症属于一种自身免疫性纤维化疾病，以局部或弥漫性皮肤增厚和内脏器官纤维化为特征。MiR-16可通过促进内皮细胞凋亡，使胞内miR-16释放到系统性硬化症患者的血清中，从而在血清中被检测出来[50]。MiR-16可能通过靶向控制细胞周期和凋亡的核蛋白存活蛋白(survivin)和p53，影响系统性硬化症的重要致病事件，即抑制内皮细胞增殖并促进细胞凋亡[51]。同样，miR-16-5p可通过调控Smad3、Notch2的表达来抑制人类皮肤成纤维细胞的增殖和转化，减少胶原蛋白等ECM的合成，从而发挥抗纤维化作用[22, 28]。在胰腺纤维化中，miR-15a/16可通过靶向抗凋亡蛋白Bcl-2和抑制TGF-β/Smad信号通路，进而诱导胰腺星形细胞凋亡，抑制炎症和胰腺纤维化的进展[23]，在一定程度上支持了miRs治疗是未来治疗胰腺纤维化患者的潜在疗法。

4. 结 语

在肝、肺、心肌、肾和其他纤维化疾病中miR-15a/16表达失调，其调控纤维化疾病的分子机制为通过靶向纤维化信号通路、炎症信号通路、细胞增殖和凋亡信号通路以及胶原合成等相关基因，抑制细胞增殖和转化，阻碍ECM的合成和促进其降解，调节炎症细胞因子的生成。在纤维化疾病中，特异性改变的miR-15a/16可以作为诊断纤维化的生物标志物，也可被开发为抗纤维化的治疗靶点。但仍需探索miR-15a/16在纤维化疾病中的确切机制和生物学功能以及构建miR-15a/16基因敲除小鼠模型以进一步研究其分子诊断和治疗的效果。

目前，将miR转化为治疗药物的临床研究仍处于起步阶段，其作为治疗药物还存在许多障碍[52]，亟需解决以下问题：1)怎么保持miR在体内的稳定性？2)如何开发将miR递送到靶细胞的高效递送系统，从而达到组织特异性输送？3)如何保持最小数量的潜在脱靶，尽量减少脱靶效应？4)如何做到细胞特异性和最小毒性？5)如何确保细胞对miR的摄取达到适度的生理水平？为解决这些关键问题，已开发出了各种病毒和非胶原蛋白、脂质体等非病毒传递系统以提高其输送的稳定性[53-54]，且通过结合糖缀合物、多肽和抗体等靶向结合物来达到特定纤维化类型的靶向传递[52]，但其安全性和可靠性尚需进一步研究。

基金资助

国家自然科学基金(81271154)；湖南省自然科学基金(2020JJ4881，2022JJ30695)。

This work was supported by the National Natural Science Foundation (81271154) and the Natural Science Foundation of Hunan Province (2020JJ4881, 2022JJ30695), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

文妲妲 论文撰写与修改；王洁 论文指导及修改。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202305743.pdf

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