MicroRNA在肝纖維化中的研究進(jìn)展*

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MicroRNA在肝纖維化中的研究進(jìn)展*

*基金項(xiàng)目:國(guó)家自然科學(xué)基金青年基金(81501821)。

張春燕 綜述，田亞平 審校

(中國(guó)人民解放軍總醫(yī)院生化科/轉(zhuǎn)化醫(yī)學(xué)中心，北京 100039)

關(guān)鍵詞:肝纖維化；肝星狀細(xì)胞；microRNA；轉(zhuǎn)化生長(zhǎng)因子-β

肝纖維化是肝內(nèi)彌漫性細(xì)胞外基質(zhì)(ECM) 過度沉積的病理過程，是多數(shù)慢性肝病發(fā)展至最后的共同通路，又是肝病進(jìn)一步惡化的前期病變[1]。目前尚缺乏肝纖維化有效的治療，是因?yàn)閷?duì)肝纖維化發(fā)生、發(fā)展的機(jī)制并不完全理解。MicroRNA(miRNA)是一種長(zhǎng)度約為22個(gè)核苷酸的非編碼單鏈RNA，在轉(zhuǎn)錄后水平上調(diào)節(jié)目的基因的表達(dá)[2]。越來越多的研究表明，miRNAs通過對(duì)靶基因的調(diào)控，參與肝纖維化過程[3-5]。本文就參與肝纖維化發(fā)生、發(fā)展過程的miRNAs及其作用機(jī)制作一綜述。

1肝纖維化發(fā)病機(jī)制

肝纖維化是多種原因引起的慢性肝損害所致的病理改變，包括慢性乙肝病毒感染、酒精、肥胖、自身免疫性肝炎、寄生蟲病、代謝紊亂、毒物藥物導(dǎo)致肝損傷等[6]。在肝纖維化進(jìn)展中，炎癥和肝損傷導(dǎo)致了膠原蛋白沉積，影響正常肝功能發(fā)揮作用[7]。研究表明，肝星狀細(xì)胞(HSC)的激活是肝纖維化的中心環(huán)節(jié)，HSC占肝臟細(xì)胞的5%~ 8%[8]，卻是導(dǎo)致肝纖維化形成的主要原因。Mederacke等[9]在新型LratCre轉(zhuǎn)基因小鼠中標(biāo)記了99%HSC，揭示了HSC在模型中的成纖維化、膽汁淤積及脂肪肝形成的原因中占82%~96%。正常情況下HSC處于靜止?fàn)顟B(tài)，具有儲(chǔ)脂、儲(chǔ)維生素A的功能，一旦受到成纖維因素刺激，便活化出現(xiàn)肌成纖維母細(xì)胞樣表型[10]。同時(shí)，HSC的活化與ECM的合成和沉積顯著增加密切相關(guān)，包括α-平滑肌機(jī)動(dòng)蛋白(α-SMA)、膠原蛋白、組織金屬蛋白酶的抑制劑(TIMP1)和肌間線蛋白的高表達(dá)，細(xì)胞因子例如成纖維細(xì)胞生長(zhǎng)因子(FGF)、白介素6(IL-6)、細(xì)胞黏附分子(ICAM-1) 和單核細(xì)胞趨化蛋白1(MCP-1)的釋放[11- 12]。

目前認(rèn)為，肝纖維化的分子發(fā)病機(jī)制主要有三個(gè)[6,13]：第一，肝細(xì)胞間或肝細(xì)胞與基質(zhì)間交互作用的改變?cè)诟卫w維化過程中發(fā)揮重要作用；第二，氧化應(yīng)激，慢性乙肝病毒感染及嗜酒增加活性氧(ROS)導(dǎo)致肝細(xì)胞損傷。氧化應(yīng)激可以增加線粒體的通透性引起肝細(xì)胞的壞死或凋亡。而ROS可直接影響HSC和成纖維細(xì)胞的功能。ROS通過活化信號(hào)轉(zhuǎn)導(dǎo)通路及轉(zhuǎn)錄因子(c-Jun氨基末端激酶(JNK)，激活蛋白1(AP-1)及NF-κB上調(diào)肝纖維化相關(guān)基因(COL1A1、COL1A2、MCP1和TIMP1)的表達(dá)；第三，基質(zhì)金屬蛋白酶(MMP)和金屬蛋白酶組織抑制因子(TIMP)之間的平衡是細(xì)胞外基質(zhì)動(dòng)態(tài)穩(wěn)定的重要基礎(chǔ)。肝纖維化的早期二者之間的比例關(guān)系就已經(jīng)失衡。而活化的HSC可分泌MMP。研究顯示，肝損傷、炎癥、細(xì)胞凋亡、肝細(xì)胞再生過程中miRNAs表達(dá)譜發(fā)生顯著變化，miRNAs通過參與病毒致病過程、氧化應(yīng)激、細(xì)胞因子分泌及肝細(xì)胞脂類代謝，參與肝纖維化過程[14]。

2肝纖維化相關(guān)miRNAs

MiRNA是一種非編碼單鏈RNA，在進(jìn)化上高度保守。miRNAs可通過直接降解靶基因mRNA或是抑制其翻譯而發(fā)揮對(duì)目的基因的下調(diào)作用。因此，miRNAs既可通過下調(diào)促肝纖因子而發(fā)揮抑制肝纖維化的作用，也可通過下調(diào)肝纖抑制因子而發(fā)揮促肝纖維化作用。目前研究表明，miRNAs參與并調(diào)節(jié)肝纖維化進(jìn)程[15-17]，可作為肝纖維化的生物標(biāo)志物[18]。

Murakami等[19]在人和鼠中分別篩選了肝纖維化過程中變化的miRNAs，篩選出11個(gè)差異miRNAs與肝纖維化進(jìn)程密切相關(guān)的miRNAs(let-7e,miR-125-5p,miR-199a-5p，miR-199b，miR-199b*，miR-200a，miR-200b，miR-31，miR-34a，miR-497和miR-802)，并找到4個(gè)人和鼠共同表達(dá)的miRNAs(miR-199a,miR-199a*,miR-200a和miR-200b)，能夠促進(jìn)肝纖維化進(jìn)程。Li等[20]在小鼠CCl4誘導(dǎo)肝纖維化模型中篩選到10個(gè)上調(diào)miRNAs(miR-34b，miR-34c，miR-34a，miR-221，miR-146b，miR-214，miR-199a-5p，miR-199a-3p，miR-223和miR-324-5p)和7個(gè)下調(diào)miRNAs(miR-378，miR-193，miR-878等)[18]。其中，miR-34家族與脂肪代謝相關(guān)。

另有科學(xué)家在心肌纖維化、腎纖維化和肝纖維化過程中篩選出共有miRNAs，對(duì)纖維化有調(diào)控作用的，目前報(bào)道的最多的是miR-29家族。膽道結(jié)扎誘導(dǎo)肝纖維化小鼠模型中，miR-29a/b/c顯著下調(diào)，同時(shí)，低水平miR-29a提示肝纖維化進(jìn)展[21]。Zhang等[22]的研究發(fā)現(xiàn)，miR-29b可通過下調(diào)熱休克蛋白47(HSP47)和賴氨酰氧化酶的表達(dá)而抑制HSC中膠原蛋白的成熟，從而抑制肝纖維化的發(fā)生和發(fā)展。Kwiecinski等[23]發(fā)現(xiàn)miR-29b可通過直接抑制促肝纖生長(zhǎng)因子[血小板源生長(zhǎng)因子C和胰島素樣生長(zhǎng)因子1(IGF-1)]的表達(dá)而對(duì)機(jī)體起保護(hù)作用。同時(shí)，miR-29b也可通過表觀遺傳學(xué)調(diào)控的方式抑制肝纖維化的進(jìn)展[24]。

3MiRNAs參與HSC活化、增殖和凋亡

HSC是肝纖維化的主要效應(yīng)細(xì)胞，是Ⅰ型膠原沉積的主要來源，其激活因素主要包括病毒感染、肥胖和飲酒。HSC活化后分泌成纖維因子，包括轉(zhuǎn)化生長(zhǎng)因子-β(TGF-β)、纖維膠原蛋白、纖連蛋白和層粘連蛋白[25]。

最新研究表明，miRNAs參與HSC的分化。Chen等[26]比較了靜息狀態(tài)下人HSC和HSC激活后miRNAs表達(dá)差異，發(fā)現(xiàn)HSC激活后31個(gè)miRNAs表達(dá)有顯著性差異，包括17個(gè)miRNAs(miR-345-5p，miR-152，miR-199a-5p，miR-218，miR-125b-5p，miR-214，miR-34c，miR-34b，miR-199a-3p，miR-425，miR-221，miR-301a，miR-222，miR-193，miR-31，miR-143和miR-145)表達(dá)上調(diào)和14個(gè)miRNAs(miR-101a，miR-335，miR -877，miR -139-5p，miR-150，miR-126*，miR-192，miR-450a，miR-497，miR-338，miR-10a-5p，miR-378*,miR-195和miR-126) 表達(dá)下調(diào)。膽道結(jié)扎小鼠模型HSC活化后miR-150，miR-187，miR-194和miR-207顯著下調(diào)，Let7家族顯著上調(diào)，體外實(shí)驗(yàn)在人HSC LX-2細(xì)胞中高表達(dá)miR-150和miR-194能降低Ⅰ型膠原和α-SMA表達(dá)，抑制HSC活化[27]。Zhang等[28]的研究發(fā)現(xiàn)，miR-21可與程序性細(xì)胞死亡蛋白4(PDCD4)和活化蛋白1(AP1)共同形成一個(gè)自調(diào)節(jié)的反饋環(huán)路，激活HSC，是一個(gè)重要的肝纖始動(dòng)因素。Hassan等[29]在小鼠肝纖維化模型中使用姜黃素抗炎發(fā)現(xiàn)miR-199和miR-200b能夠促進(jìn)HSC活化和肝纖維化進(jìn)展。Ogawa等[30]提出并在人和鼠中驗(yàn)證了miR-221和miR-222作為HSC活化的生物標(biāo)志物。Ge等[31]通過體內(nèi)和體外試驗(yàn)驗(yàn)證了miR-19b通過靶定生長(zhǎng)因子受體結(jié)合蛋白(GRB2)抑制HSC的增殖，從而抑制肝纖維化進(jìn)展。Xiao等[32]發(fā)現(xiàn)miR-200b能夠顯著增強(qiáng)LX-2細(xì)胞的增殖和遷移。基因測(cè)序結(jié)果表明miR-15/16家族與HSC活化過程中抗凋亡細(xì)胞通路密切相關(guān)，其miRNA模擬物能夠抑制Bcl-2和細(xì)胞凋亡[33]。

4MiRNAs調(diào)控肝纖維化相關(guān)信號(hào)通路

肝纖維化過程受多種信號(hào)通路調(diào)控，主要為TGF-β/Smad、PI3K/Akt、p38 MAPK和Wnt/β-catenin信號(hào)通路。TGF-β參與細(xì)胞分化、生長(zhǎng)、凋亡、遷移、ECM沉積及ECM蛋白的生成和降解，是調(diào)控機(jī)體各個(gè)器官纖維化的核心信號(hào)通路[34-36]。TGF-β/Smad可以抑制正常肝細(xì)胞的增殖，激發(fā)肝星狀細(xì)胞的活化，促進(jìn)ECM的生成沉積，另一方面，TGF-β/Smad信號(hào)通路可以導(dǎo)致細(xì)胞MMPs和上調(diào)金屬蛋白酶組織抑制劑(tissue inhibitor of metalloproteinase TIMPs)，從而導(dǎo)致ECM低降解。在組織纖維化過程中，TGF-β/Smad信號(hào)通路的激活又可以促進(jìn)一些抗纖維化因子的表達(dá)，比如血管生長(zhǎng)因子(VEGF)、IGF-1和整合素等。因此肝纖維化進(jìn)程中miRNAs對(duì)TGF-β/Smad信號(hào)通路的調(diào)控成為近年的研究熱點(diǎn)。

研究顯示，miR-200在肝星狀細(xì)胞中過表達(dá)可以抑制其靶基因Keap1的表達(dá)[37]，從而促進(jìn)Nrf2的核遷移，進(jìn)而激活依賴Nrf2的NQO1表達(dá)。而Nrf2的激活可以阻止TGF-β/Smad信號(hào)通路的激活，減慢肝纖維化進(jìn)程。Zhang等[38]的研究顯示二吲哚甲烷(DIM)誘導(dǎo)的miR-21低表達(dá)可以阻止TGF-β信號(hào)通路的激活，從而減緩肝纖維化的進(jìn)程。Li等[39]的研究顯示miR-483的過表達(dá)通過抑制血小板生長(zhǎng)因子和金屬蛋白酶組織抑制因子調(diào)控TGF-β信號(hào)通路，進(jìn)而影響肝纖維化發(fā)展進(jìn)程。Tu等[40]的研究表明miR-101能夠靶定TβRI和KLF6，抑制TGF-β信號(hào)通路，抑制肝纖維化進(jìn)程。小鼠CCl4誘導(dǎo)肝纖維化模型中，miR-101能夠促進(jìn)活化的HSC恢復(fù)到靜止期，是逆轉(zhuǎn)肝纖維化的潛在靶點(diǎn)之一。Roderburg等[41]的研究揭示了miR-133a通過調(diào)控TGF-β/Smad信號(hào)通路，對(duì)肝纖維化發(fā)揮抑制作用。He等[42]的研究結(jié)果表明miR-146a過表達(dá)后抑制TGF-β誘導(dǎo)的HSC增殖和α-SMA的表達(dá)，降低Smad4表達(dá)水平，從而抑制肝纖維化進(jìn)程。

Li等[43]的研究發(fā)現(xiàn)，miR-33a可通過活化PI3K/Akt信號(hào)通路而促進(jìn)肝纖維化的進(jìn)展。Maubach等[44]發(fā)現(xiàn)HSC細(xì)胞(HSC-2)激活后與靜息期相比，16個(gè)miRNAs(miR-125b，miR-143，miR-214，miR-221等)上調(diào)，26個(gè)miRNAs(miR-122a，miR-126，miR-146a， miR-195，miR-30b等)下調(diào)，涉及MAPK，ERK/MAPK，PTEN和TGF-β等多種信號(hào)通路。其中，miR-146a過表達(dá)后抑制NF-κB 信號(hào)通路關(guān)鍵因子IRAK1和TRAF6 的表達(dá)，降低p38 MAPK信號(hào)通路關(guān)鍵因子TIMP-3表達(dá)。Tsukamoto等[45]的研究顯示體外激活HSC后Wnt/β-catenin信號(hào)通路激活，包括Wnt3a、Wnt10b、FzdR-1/2、LRP6、核內(nèi)β-catenin和TCF的表達(dá)上調(diào)。Sun等[46]發(fā)現(xiàn)Wnt/β-catenin和TGF-β信號(hào)通路同為miR-200a下游靶基因，miR-200a通過這兩個(gè)信號(hào)通路共同作用，抑制肝纖維化進(jìn)程。

5小結(jié)與展望

目前，越來越多的證據(jù)表明miRNAs參與調(diào)節(jié)肝纖維化進(jìn)展，HSC活化和細(xì)胞凋亡以及相關(guān)信號(hào)通路。對(duì)肝纖維化發(fā)生、發(fā)展的機(jī)制的深入理解，將為肝纖維化有效的診斷和治療提供靶點(diǎn)。令人高興的是，體外人工合成miRNA的方法和體系已經(jīng)建立，可以成功地生產(chǎn)抗TGF-β的miRNAs，實(shí)現(xiàn)體外抗肝纖維化進(jìn)程[47]。因此，對(duì)肝纖維化相關(guān)miRNAs作用機(jī)制和功能的理解將對(duì)未來的發(fā)展起至關(guān)重要的作用，預(yù)計(jì)miRNAs將參與肝纖維化治療策略，成為肝纖維化預(yù)警和診斷的生物標(biāo)志物。

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·綜述·

通訊作者

收稿日期：(2015-08-16)

文獻(xiàn)標(biāo)識(shí)碼：

DOI:10.3969/j.issn.1673-4130.2015.24.039A

文章編號(hào)：1673-4130(2015)24-3601-04

作者簡(jiǎn)介：張春燕，女，檢驗(yàn)技師，主要從事分子診斷學(xué)工作。 王娟，女，主治醫(yī)師，主要從事分子生物學(xué)研究?！鳎珽-mail：haoxkg@fmmu.edu.cn。