设为首页 加入收藏 期刊导航 网站地图

Advances in Clinical Medicine
Vol. 10  No. 11 ( 2020 ), Article ID: 38932 , 12 pages
10.12677/ACM.2020.1011424

非编码RNA在肝脏相关疾病中的 表达探析

刘艳云1，张娟2*，马莹1，张心想1，余家明1，韩辉2

1安徽中医药大学研究生院，安徽 合肥

2安徽中医药大学第一附属医院脑病中心，安徽 合肥

收稿日期：2020年11月2日；录用日期：2020年11月23日；发布日期：2020年11月30日

摘要

非编码RNA (noncoding RNA, ncRNA)是一类不编码蛋白，但在基因的复制、转录、翻译、表达等多个水平对细胞的生长凋零以及疾病的发生与进展过程中发挥重要作用的RNA。在肝脏疾病的发生进展中，病毒性肝炎、酒精性或非酒精性肝病、自身免疫疾性肝病、胆道疾病等慢性肝脏疾病均可缓慢发展为肝纤维化、肝硬化，甚至是肝细胞癌。而在这整个过程中，多种ncRNA参与调节，其表达水平发生明显改变，并且在疾病的发生发展中处于核心调控地位。所以，进一步加强研究ncRNA与肝脏疾病之间的关系，明确其作用机制，有助于我们日后临床中肝脏疾病的精准诊断、治疗与预后。本文综述了长链非编码RNA (long noncoding RNA, lncRNA)及环状RNA (circular RNA, circRNA)在不同肝脏疾病时的表达情况、作用机制、临床展望等。

关键词

非编码RNA，LncRNA，circRNA，肝脏疾病

Expression of Noncoding RNA in Liver Related Disease

Yanyun Liu1, Juan Zhang2*, Ying Ma1, Xinxiang Zhang1, Jiaming Yu1, Hui Han2

1Graduate School, Anhui University of Traditional Chinese Medicine, Hefei Anhui

2Encephalopathy Center, First Affiliated Hospital, Anhui University of Traditional Chinese Medicine, Hefei Anhui

Received: Nov. 2nd, 2020; accepted: Nov. 23rd, 2020; published: Nov. 30th, 2020

ABSTRACT

Noncoding RNAs (ncRNAs) are a kind of RNA that do not encode proteins, but play an important role in the process of cell growth and apoptosis, as well as in the process of disease occurrence and progression at multiple levels such as gene replication, transcription, translation and expression. In the development of liver diseases, chronic liver diseases such as viral hepatitis, alcoholic or nonalcoholic liver disease, autoimmune liver disease and biliary tract disease can develop slowly into hepatic fibrosis, cirrhosis and even hepatocellular carcinoma (HCC). However, in this whole process, varieties of ncRNA participate in the regulation, its expression level changes significantly, and it is in the core regulatory position in the occurrence and development of the disease. Therefore, further study on the relationship between ncRNA and liver diseases and its mechanism of action will be helpful for the accurate diagnosis, treatment and prognosis of liver diseases in the future. This paper reviews the expression, mechanism and clinical prospect of long noncoding RNA (lncRNA) and circular RNA (circRNA) in different liver diseases.

Keywords:Noncoding RNAs, Long Noncoding RNA, Circular RNA, Hepatic Disease

Copyright © 2020 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

非编码RNA (noncoding RNAs, ncRNA)起初被认为是基因组的废弃物，对基因的表达并无实质作用，直到后来随着现代科学技术的进步和人类对医学的艰苦钻研，才逐渐发现，人类基因组中的大部分都被转录成了各种ncRNA [1]。这些RNA由基因组转录而来，然而不编码蛋白，在RNA水平就可行使生物学功能 [2]。肝脏作为人体重要的代谢和解毒器官，承担着分泌和合成各种因素的任务，然而我国仍是肝病大国，根据《2019年全国法定传染病疫情概况》，病毒性肝炎是我国法定传染病中报告病例数第一、死亡数第三的乙类传染病；且在我国癌症致死原因中，肝细胞癌位居第二 [3]。可见我国民众的肝脏疾病问题依旧值得重点关注，非编码RNA的发现与深入研究极大的开拓了临床治疗思维，更为预防肝脏疾病的发生及延缓肝脏疾病的进展提供了极大可能。本文主要从lncRNA和circRNA这两个方面论述其在不同肝脏损害中的表达及临床意义。

2. 非编码RNA的作用机制

2.1. lncRNA的作用机制

21世纪初，lncRNA首次由日本学者Okazaki [4] 发现，即一种长度大于200 nt的非编码RNA，并认为没有重要的生物学功能。而后Rinn [5] 等人于2007年报道了一条功能性长链非编码RNA (HOTAIR)，可通过修饰染色质，参与HOX基因的转录。这一重要发现表明lncRNA不再仅仅是编码RNA的垃圾，反而却有很大程度的可能对整个基因的表达起到十分重要的作用。自此之后，lncRNA逐渐成为基因学的研究热点。根据目前的研究，lncRNA的作用机制并不是十分完善，主要的机制有：靶向作用于转录因子、RNA聚合酶等影响基因的转录过程，调节基因的转录和表达 [6]；结合PRC1 (polycomb repressive complex 1)、PRC2 (polycomb repressive complex 2)和染色质修饰蛋白，引导染色质修饰复合物发挥改变表观遗传的特异性效应 [7]；通过与蛋白质和蛋白复合体直接相互作用作为支架、变构激活剂或抑制剂发挥致癌作用 [8]；通过结合miRNA作为竞争性内源RNA (ceRNA)机制发挥海绵吸附作用，进一步调控下游靶基因 [9]。lncRNA通过以上机制影响基因的转录过程，调节基因的转录和表达，甚至发挥改变表观遗传的特异性效应。转移到生物效应层面来看，总结为信号、诱饵、指导和支架4种功能 [10]，即标记空间、时间、发育阶段和基因调控表达的信号；结合蛋白质靶标，并使其失活的诱饵；使RNA结合蛋白复合物定位到特定目标的指导物；多种效应器配体的支架。

2.2. circRNA的作用机制

1976年，Sanger [11] 等首次在植物感染的病毒中观察到了共价闭合环状RNA分子。但是这些RNA仅仅被当作是异常剪接的产物，并没有引起广泛重视。2012年，Salzman [12] 等通过小儿急性淋巴细胞白血病样品的RNA测序数据库，发现了circRNA在人类细胞的普遍表达，基于此数据库发现人体内大约有10万个circRNA。人们才开始重新认识并深入研究circRNA。circRNA由于其环状结构的特异性，具有更稳定和高度保守的特点，除此之外还具有组织细胞特异性表达的特点。circRNA在生物体内的作用机制主要包括以下几点：作为miRNA的海绵体吸附miRNA，进而影响下游靶基因；与RNA结合蛋白相互作用并发挥生物功能，即作为蛋白的海绵；形成转录或转录后调控因子，直接参与调控基因的表达；翻译蛋白质。circRNA的海绵吸附的作用、结合蛋白的作用以及调控转录等作用毋庸置疑，但对于circRNA可以翻译蛋白质这一功能的提出，既是一个非常重要的新发现同时又质疑了我们对非编码RNA的传统认识。

3. 非编码RNA与病毒性肝炎

病毒性肝炎严重威胁人类健康与生活品质，在我国的各类传染病中发病率最高，尤其是乙型肝炎。病毒性肝炎是慢性肝脏炎症、肝纤维化、肝硬化，乃至肝癌的重要因素。非编码RNA在病毒性肝炎的复制、抗病毒方面发挥关键作用，但其作用机制尚需进一步研究。

3.1. lncRNA与病毒性肝炎

Samaloty [13] 等表明，在尚未予以治疗手段的病毒性肝炎患者中，血清LncRNA GAS5和LncRNA BISPR上调，而LncRNA HEIH下调，其中GAS5和BISPR与病毒载量以及ALT呈正相关(P < 0.001)，更有意思的是，HEIH与AFP亦呈显著正相关(P < 0.001)。Hu [14] 等人证实在HCV感染后早期LncR-8 (Lnc-ITM2C-1/LOC151484)上调，并表明LncR-8表达与HCV复制呈正相关，HCV诱导LncR-8表达，而LncR-8通过刺激其邻近基因GPR55的表达间接促进HCV复制。Fan [15] 等人发现Lnc ATV基因敲除显著抑制了丙型病毒肝炎、寨卡病毒、新城疫病毒和仙台病毒等多种RNA病毒的复制，其机制为通过限制RIG-I介导的先天免疫来促进病毒的复制。上述研究提示LncRNA通过影响肝炎病毒的复制进而调控病毒性肝炎的发展，可作为生物诊断分子或治疗分子。而某些LncRNA在病毒性肝炎中的表达尚存在争议,如LncRNA-Dreh，Huang [16] 等首次发现在HBx转基因小鼠中LncRNA-Dreh表达显著下调，并发现其在HBV相关的肝癌组织中的表达水平与邻近的非癌肝组织相比经常下调，其降低与肝癌患者的生存率低显著相关；但潘延凤 [17] 等人在小鼠乙型肝炎病毒模型的肝组织中LncRNA-Dreh较正常组织表达量升高。

3.2. circRNA与病毒性肝炎

目前来讲，关于circRNA和病毒性肝炎的研究尚处于匮乏阶段，其研究结果也乏善可陈，但无论是人体自身存在的还是人工外体合成的，circRNA都因其结构的独特性和稳定性，有望为病毒性肝炎的诊疗提供新的方向。

4. 非编码RNA与肝纤维化

肝纤维化是由炎症、药物等多种因素引起的肝内结缔组织的异常增生，主要病理表现有肝星状细胞的活化增生和胶原蛋白的沉积，目前临床上尚缺乏有效治疗肝纤维化的措施，而非编码RNA的发现与研究则为肝纤维化的治疗指明了另一途径。

4.1. lncRNA与肝纤维化

Zhang [18] 等人发现LncRNA SCARNA10在小鼠纤维化肝脏中表达显著上调，并证明SCARNA10通过抑制PRC2与细胞外基质(extracellularmatrix; ECM)和转化生长因子(TGFβ)途径相关基因启动子的结合，在肝纤维化的发生中起到了一种新的TGFβ信号阳性调节因子的作用，促进了肝细胞(hepatic cells; HCs)的凋亡和肝星状细胞(hepatic stellate cell; HSC)的活化，在体内外均促进了肝纤维化。Kong [19] 等人证实Lnc-NEAT1通过NEAT1/miR-29b/Atg9a调控轴参与胰岛素样生长因子结合蛋白相关蛋白1 (IGFBPrP1)促进HSC的自噬和活化过程。上述两项研究提示LncRNA SCARNA10和Lnc-NEAT1可能是肝纤维化的一种破坏因子，我们可通过抑制其表达而延缓纤维化的进展。又有研究表明Lnc-HSER为一种肝细胞特异性表达的LncRNA，在人和小鼠的纤维化肝脏以及发生肝纤维化的小鼠的原发性肝细胞中减少，可通过5AR1-Hippo-YAP途径抑制肝细胞凋亡、通过Notch信号抑制肝细胞的上皮细胞-间充质转化(EMT)过程 [20]。LncRNA-Meg8在活化的肝星状细胞、损伤的肝细胞以及纤维化的肝脏中过度表达，并提出LncRNA-Meg8可能通过抑制Notch途径抑制HSC活化和EMT过程 [21]。LncRNA Gm5091在酒精性肝纤维化(alcoholic hepatic fibrosis; AHF)小鼠HSC中被下调，可能通过吸附miR-27b、miR-23b和miR-24减轻小鼠AHF，且对细胞迁移、ROS含量、IL-1β分泌、Ⅰ型胶原表达及а-SMA等HSC活化标志物均有负调控作用 [22]。这几项重要研究提示Lnc-Hser、Meg8、LncRNA Gm5091可能是肝纤维化的保护因子和潜在治疗靶点。

H19在肝纤维化中的表达尚存在争议，Yang [23] 等人发现在活化的HSC和大鼠肝纤维化组织中，LncRNA H19表达降低，并证实H19 siRNA处理HSC可增加HSC中p-ERK1/2的表达。而Song [24] 等人的研究却表明在肝纤维化小鼠肝组织中LncRNA H19的表达显著上升，其机制可能是，肝LncRNA H19的激活下调肝锌指电子盒结合同源盒1 (ZEB1)、上调上皮细胞黏附分子(EpCAM)和SRY (性别决定区Y)盒9的表达。

4.2. circRNA与肝纤维化

Chen [25] 等发现CircRNA-RSF1 (circRSF1)在照射LX2细胞中表达上调，并证实circRSF1是通过充当miR-146a-5p的海绵，抑制miR-146a-5p的表达而增加了Ras相关的C3肉毒杆菌毒素底物1 (RAC1)的表达，从而提高细胞活力，促进LX-2细胞的炎症和纤维化表型。Zhou [26] 等人提出mmu-circ-34116可能通过miR-22-3p/BMP7轴参与HSC的激活调控肝纤维化。Zhu [27] 等发现circRNA-0067835作为miR-155的海绵促进FOXO3a的表达进而参与肝纤维化过程，并证实circRNA-0067835基因的敲除通过引起G1期阻滞和促进细胞凋亡而显著降低LX-2细胞的增殖。Chen [28] 等人发现抑制has-circ-0071410可增加miR-9-5p的表达，从而减弱辐射诱导的HSC活化。另，mmu-circ-33594、mmu-circ-35216、mmu-circ-42398等也参与肝星状细胞的活化 [29]。上述研究提示这些circRNA通过circRNA/miRNA/靶基因这一信号轴作为肝纤维化的保护因子亦或是破坏因子，可成为肝纤维化的潜在治疗生物分子，为肝纤维化的治疗开拓了新的思维。

5. 非编码RNA与肝细胞癌

原发性肝癌大多为肝细胞癌(hepatocellular carcinoma, HCC)，我国的肝癌患者多由慢性乙型肝炎发展而来，经历肝纤维化、肝硬化的过程，最终发展成为肝癌。在肝癌的治疗方面，放射性治疗敏感性差，药物化疗不良反应严重，手术治疗的复发率高，且疗效均不是特别可观。但是近些年来人们对非编码RNA的认识逐渐显露，发现非编码RNA与肿瘤的发生密切相关，对于肿瘤细胞的增殖、侵袭和转移有非常重要的调控功能，这对肝癌的治疗提供了另一研究方向。非编码RNA在HCC的进程中一般作为抑癌基因或者致癌基因来调控HCC，抑癌基因的低表达和致癌基因的高表达促进了肝癌细胞的增殖、侵入和迁移等；且常通过调控Wnt、NOTCH2、PIK3-AKT、MAPK等多条信号通路影响HCC的进展。

5.1. lncRNA与肝细胞癌

病毒性肝炎是HCC的重要发病因素之一，Hu [30] 等首次发现LncRNA WEE2-AS1在HCC中高表达，促进了肝癌细胞的增殖、迁移、侵袭和细胞周期的进展，同时抑制了肝癌细胞的凋亡，且与HBV感染、肝血管侵犯、肿瘤分化不良及患者预后不良呈正相关，提出HBV/HBx-WEE2-AS1-FERMT3轴可作为HBV相关肝癌的治疗靶点。Zuo [31] 等发现在HBV阳性HCC中LncRNA AX800134的表达高于HBV阴性HCC，siRNA干扰沉默AX800134显著抑制HBx表达的HepG2细胞的生长和侵袭，并表明高表达的AX800134在肝癌中起致癌作用，其上调与病毒产物HBx和慢性炎症有关。说明LncRNA AX800134可作为HBV相关性肝细胞癌的生物治疗分子。另有研究表明LncRNA-BC017743和LncRNA-BC043430在乙型/丙型/丁型肝炎相关性肝癌组织中上调；LINC01152在此三种肝炎相关性肝癌组织中均下调；TMEVPG1在丙型/丁型肝炎相关性肝癌组织中下调；而一些LncRNA主要在特定的肝炎病毒相关的HCC中显著失调，比如HBV相关的HCC中的PCAT-29下调、HCV相关的HCC中的aHIF、PAR5下调以及HDV相关的HCC中的Y3下调 [32]。提示lncRNA在病毒性肝炎相关性肝细胞癌的发展中起重要调控作用，可作为潜在治疗靶点。也有些lncRNA在HCC中的异常表达不受病毒性肝炎的影响，如Zhong [33] 等发现肝癌组织中的SEMA3B-AS1表达下调，不受HBV和HCV感染的影响，并表明SEMA3B-AS1的高表达通过下调miR-178促进PTEN的表达而抑制肝癌细胞的增殖，且低水平的SEMA3B-AS1与低生存率密切相关。LncRNA在HCC中的生物作用调控轴日渐清晰，如Fan [34] 等人证明在HBV阳性的HCC组织和细胞中，LncRNA n335586的表达显著增加，并证明n335586通过竞争性结合miR-924促进宿主基因CKMT1A的表达，继而促进肝癌细胞的迁移和侵袭、EMT及体内转移。即LncRNA n335586/ miR-924/CKMT1A轴。此外，Unigene56159/miR-140-5p/Slug轴能有效地抑制靶基因片段的表达，从而显著促进了肝癌细胞的迁移、侵袭和上皮-间质转化 [35]。Lnc-HULC也可通过miR-107/E2F1/SPHK1信号通路促进肿瘤血管生成 [36]。还有研究表明一种LncRNA不仅通过一条调控轴控制HCC的进展，如MALAT1作为miR-125a-3p的海绵继而调节FOXM1 [37] 或作为miR-3064-5p的海绵通过FOXA1/CD24/Src途径 [38] 参与肝癌的进展，GAS5通过miR-1323/TP53INP1轴 [39] 或miR-182/ANGPTL1 [40] 轴抑制肝癌细胞的侵袭和转移，PVT1通过miR-365/AGT3途径参与肝癌细胞的自噬 [41] 或通过miR-150/HIG2轴 [42] 参与HCC (具体见表2)。

5.2. circRNA与肝细胞癌

随着对非编码RNA 研究的逐渐丰富，circRNA对疾病的调控轴越来越受到关注，如circ-PRMT5/ miR-188-5P/HK2轴在肝癌细胞的增殖、迁移和糖酵解中发挥重要作 [43]，circ-14723/miR-16-5p/CCND1和circ-14723/miR-16-5p/CCNE1轴在大鼠LR细胞G1/S期阻滞中起到促进细胞增殖的关键作用 [44]，circ-0001498/miR-122/MAPK3K2轴参与HCV核心蛋白致癌的过程 [45]，circ PVT1/miR-3666/SIRT7轴 [46]，circ-104268/miR-214-3p/E2F2轴 [47]、circ-104168/miR-139-5p/HRAS轴 [47]、circ-104769/miR-93-5p/ JUN轴 [47] 等对肝癌细胞的生长亦起到重要调控作用。这些调控轴在自己的基因节点上控制着肝细胞癌的发生与进展，有望作为HCC的潜在生物治疗靶点。更有趣的是，众多circRNA的表达量与临床相关因素存在关联，如circCDYL [48]、circDYNC1H1 [49]、circHIPK3 [50]、circ-103809 [51]、circ-0001445 [52]、circ-0005986 [53] 的表达量与HCC肿瘤的大小数目、分化的程度、有无转移或分期相关，提示可作为辅助分级、分期以及诊断的生物分子；circMTO1 [54]、circ-100338 [55]、circ-000673 [56] 的表达量均与生存期相关，有助于预后评估； circ-000673 [56]、circC3P1 [57] 既与肿瘤的大小数目、分期相关，又与患者的生存期相关，便可做辅助诊断分子又可做预后分子(具体见表1)。此外，单纯某个基因的异常表达无法非常全面和准确的作为疾病的诊断分子，故提出联合检测两种或两种以上circRNA协助临床诊断，如吴光辉 [58] 等人发现在AFP阴性肝癌(AFP-NHCC)患者血清中circRNA PTENP1水平降低，而circRNA HIPK3和GP73水平显著高于肝良性病变患者和健康人群(P < 0.05)，并最终提出联合检测circRNA PTENP1、circRNA HIPK3、GP73对AFP-NHCC具有较高的诊断和发病风险评估价值。

Table 1. Relationship between circRNA and HCC

表1. circRNA与HCC的关系

6. 总结与展望

在肝脏的损伤进程中，病毒性肝炎→肝纤维化→肝硬化→肝癌，是一个十分重要的疾病链，查阅文献发现，有些LncRNA在肝脏损伤的发生与进展中贯穿始终，在病毒性肝炎、肝纤维化、肝细胞癌中均异常表达，其作用机制也不完全相同，可通过不同的调控轴影响不同的肝脏损伤，具体见表2。这就为延缓肝脏的损伤、预防肝癌的发生提供了可能。而circRNA与肝脏相关疾病的研究目前尚处于起步阶段，且研究的重点放在了HCC上，对于病毒性肝炎和肝纤维化的研究相对较少。关于circRNA在HCC中的表达，其表达量常与临床病理参数相关，如肿瘤的大小、数目，肝硬化的程度，MVI (microvascular invasion，微血管浸润)，血清AFP (alpha fetoprotein，甲胎蛋白)，TNM分期，BCLC分期等，故circRNA根据相关性因素可作为诊断分子或预后分子。

Table 2. Relationship between lncRNA and hepatic disease

表2. lncRNA与肝脏疾病的关系

综上所述，非编码RNA在转录、转录后以及蛋白等多个水平影响并参与几乎所有疾病的生理和病理过程，在肝脏疾病的发生与进展中处于重要调控地位，可作为特异性生物标记物、诊断标记物、潜在的治疗靶点以及预后的生物分子。如基于ncRNA介导的RNA干扰技术在疾病的治疗方面具有良好的前景，但就目前来讲，非编码RNA功能复杂繁琐，我们的研究目前尚处于起步阶段，很多作用机制还不清楚，并不能充分地应用于临床。LncRNA、miRNA与circRNA三者之间相互作用、相互影响、相互调节，逐渐明确和完善ceRNA调控网(ceRNA-miRNA-mRNA)是基础研究中的核心问题，亟需解决。并且随着基因学、生物信息学以及基因芯片技术的发展，我们对非编码RNA的研究将会更加全面和透彻。

基金项目

1) 国家自然科学基金资助项目(编号No. 81774299)； 2) 安徽省自然科学基金项目(编号No. 170805mh199)； 3) 安徽省重点研究与开发计划项目(编号No. 1804h08020244)。

文章引用

刘艳云,张 娟,马 莹,张心想,余家明,韩 辉. 非编码RNA在肝脏相关疾病中的表达探析
Expression of Noncoding RNA in Liver Related Disease[J]. 临床医学进展, 2020, 10(11): 2787-2798. https://doi.org/10.12677/ACM.2020.1011424

参考文献

  1. 1. Zhang, R.K., Zhang, L. and Yu, W.Q. (2012) Genome-Wide Expression of Non-Coding RNA and Global Chromatin Modification. Acta Biochimica et Biophysica Sinica, 44, 40-47. https://doi.org/10.1093/abbs/gmr112

  2. 2. Esteller, M. (2011) Non-Coding RNAs in Human Disease. Nature Reviews Genetics, 12, 861-874. https://doi.org/10.1038/nrg3074

  3. 3. Kulik, L. and El-Serag, H.B. (2019) Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology, 156, 477-491. https://doi.org/10.1053/j.gastro.2018.08.065

  4. 4. Okazaki, Y., Furuno, M., Kasukawa, T., et al. (2002) Analysis of the Mouse Transcriptome Based on Functional Annotation of 60,770 Full-Length cDNAs. Nature, 420, 563-573. https://doi.org/10.1038/nature01266

  5. 5. Rinn, J.R., Kertesz, M., Wang, J.K., et al. (2007) Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs. Cell, 129, 1311-1323. https://doi.org/10.1016/j.cell.2007.05.022

  6. 6. Xu, W.-H., Zhang, J.-B., Dang, Z., et al. (2014) Long Non-Coding RNA URHC Regulates Cell Proliferation and Apoptosis via ZAK through the ERK/MAPK Signaling Pathway in Hepatocellular Carcinoma. International Journal of Biological Sciences, 10, 664-676. https://doi.org/10.7150/ijbs.8232

  7. 7. Huang, M.-D., Chen, W.-M., Qi, F.-Z., et al. (2015) Long Non-Coding RNA TUG1 Is Up-Regulated in Hepatocellular Carcinoma and Promotes Cell Growth and Apoptosis by Epigenetically Silencing of KLF2. Molecular Cancer, 14, 165-174. https://doi.org/10.1186/s12943-015-0431-0

  8. 8. Yang, X., Xie, X., Xiao, Y.F., et al. (2015) The Emergence of Long Non-Coding RNAs in the Tumorigenesis of Hepatocellular Carcinoma. Cancer Letters, 360, 119-124. https://doi.org/10.1016/j.canlet.2015.02.035

  9. 9. Yuan, J.H., Yang, F., Wang, F., et al. (2014) A Long Noncoding RNA Activated by TGF-β Promotes the Invasion- Metastasis Cascade in Hepatocellular Carcinoma. Cancer Cell, 25, 666-681. https://doi.org/10.1016/j.ccr.2014.03.010

  10. 10. Wang, K.C. and Chang, H.Y. (2011) Molecular Mechanisms of Long Noncoding RNAs. Molecular Cell, 43, 904-914. https://doi.org/10.1016/j.molcel.2011.08.018

  11. 11. Sanger, H.L., Klotz, G., Riesner, D., et al. (1976) Viroids Are Single-Stranded Covalently Closed Circular RNA Molecules Existing as Highly Base-Paired Rod-Like Structures. Proceedings of the National Academy of Sciences of the United States of America, 73, 3852-3856. https://doi.org/10.1073/pnas.73.11.3852

  12. 12. Salzman, J., Gawad, C., Wang, P.L., et al. (2012) Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types. PLoS ONE, 7, e30733. https://doi.org/10.1371/journal.pone.0030733

  13. 13. El Samaloty, N.M., Shabayek, M.I., Ghait, R.S., et al. (2020) Assessment of lncRNA GAS5, lncRNA HEIH, lncRNA BISPR and Its mRNA BST2 as Serum Innovative Non-Invasive Biomarkers: Recent Insights into Egyptian Patients with Hepatitis C Virus Type 4. World Journal of Gastroenterology, 26, 168-183. https://doi.org/10.3748/wjg.v26.i2.168

  14. 14. Hu, P., Wilhelm, J., Gerresheim, G.K., et al. (2019) Lnc-ITM2C-1 and GPR55 Are Proviral Host Factors for Hepatitis C Virus. Viruses, 11, 549-577. https://doi.org/10.3390/v11060549

  15. 15. Fan, J.J., Cheng, M., Chi, X.J., et al. (2019) A Human Long Non-Coding RNA LncATV Promotes Virus Replication through Restricting RIG-I-Mediated Innate Immunity. Frontiers in Immunology, 10, 1711-1718. https://doi.org/10.3389/fimmu.2019.01711

  16. 16. Huang, J.F., Guo, Y.J., Zhao, C.X., et al. (2013) Hepatitis B Virus X Protein (HBx)-Related Long Noncoding RNA (lncRNA) Down-Regulated Expression by HBx (Dreh) Inhibits Hepatocellular Carcinoma Metastasis by Targeting the Intermediate Filament Protein Vimentin. Hepatology (Baltimore, Md.), 57, 1882-1892. https://doi.org/10.1002/hep.26195

  17. 17. Pan, Y.-F., Qin, T., Feng, L. and Yu, Z.-J. (2013) Expression Profile of Altered Long Non-Coding RNAs in Patients with HBV-Associated Hepatocellular Carcinoma. Journal of Huazhong University of Science and Technology (Medical Sciences), 33, 96-101. https://doi.org/10.1007/s11596-013-1078-y

  18. 18. Zhang, K., Han, Y.W., Hu, Z.M., et al. (2019) SCARNA10, a Nuclear-Retained Long Non-Coding RNA, Promotes Liver Fibrosis and Serves as a Potential Biomarker. Theranostics, 9, 3622-3638. https://doi.org/10.7150/thno.32935

  19. 19. Kong, Y.Y., Huang, T.J., et al. (2019) The lncRNA NEAT1/miR-29b/Atg9a Axis Regulates IGFBPrP1-Induced Autophagy and Activation of Mouse Hepatic Stellate Cells. Life Sciences, 237, Article ID: 116902. https://doi.org/10.1016/j.lfs.2019.116902

  20. 20. Zhang, K., Zhang, M.X., Yao, Q.B., et al. (2019) The Hepatocyte-Specifically Expressed lnc-HSER Alleviates Hepatic Fibrosis by Inhibiting Hepatocyte Apoptosis and Epithelial-Mesenchymal Transition. Theranostics, 9, 7566-7582. https://doi.org/10.7150/thno.36942

  21. 21. Chen, T., Lin, H.J., Chen, X., et al. (2020) LncRNA Meg8 Suppresses Activation of Hepatic Stellate Cells and Epithelial-Mesenchymal Transition of Hepatocytes via the Notch Pathway. Biochemical and Biophysical Research Communications, 521, 921-927. https://doi.org/10.1016/j.bbrc.2019.11.015

  22. 22. Zhou, B., Yuan, W.W. and Li, X.P. (2018) LncRNA Gm5091 Alleviates Alcoholic Hepatic Fibrosis by Sponging miR-27b/23b/24 in Mice. Cell Biology International, 42, 1330-1339. https://doi.org/10.1002/cbin.11021

  23. 23. Yang, J.J., She, Q., Yang, Y., et al. (2018) DNMT1 Controls LncRNA H19/ERK Signal Pathway in Hepatic Stellate Cell Activation and Fibrosis. Toxicology Letters, 295, 325-334. https://doi.org/10.1016/j.toxlet.2018.07.013

  24. 24. Song, Y.F., Liu, C.E., Liu, X., et al. (2017) H19 Promotes Cholestatic Liver Fibrosis by Preventing ZEB1-Mediated Inhibition of Epithelial Cell Adhesion Molecule. Hepatology, 66, 1183-1196. https://doi.org/10.1002/hep.29209

  25. 25. Chen, Y.H., Yuan, B.Y., Chen, G.W., et al. (2020) Circular RNA RSF1 Promotes Inflammatory and Fibrotic Phenotypes of Irradiated Hepatic Stellate Cell by Modulating miR-146a-5p. Journal of Cellular Physiology, 235, 8270-8282. https://doi.org/10.1002/jcp.29483

  26. 26. Zhou, Y.P., Lv, X.Y., Qu, H., et al. (2018) Preliminary Screening and Functional Analysis of Circular RNAs Associated with Hepatic Stellate Cell Activation. Gene, 677, 317-323. https://doi.org/10.1016/j.gene.2018.08.052

  27. 27. Zhu, L.L., Ren, T.T., Zhu, Z.X., et al. (2018) Thymosin-β4 Mediates Hepatic Stellate Cell Activation by Interfering with CircRNA-0067835/miR-155/FoxO3 Signaling Pathway. Cellular Physiology and Biochemistry, 51, 1389-1398. https://doi.org/10.1159/000495556

  28. 28. Chen, Y.H., Yuan, B.Y., Wu, Z.F., et al. (2017) Microarray Profiling of Circular RNAs and the Potential Regulatory Role of hsa_circ_0071410 in the Activated Human Hepatic Stellate Cell Induced by Irradiation. Gene, 629, 35-42. https://doi.org/10.1016/j.gene.2017.07.078

  29. 29. Zhou, Y.P., Lv, X.Y., Qu, H., et al. (2019) Differential Expression of Circular RNAs in Hepatic Tissue in a Model of Liver Fibrosis and Functional Analysis of Their Target Genes. Hepatology Research, 49, 324-334. https://doi.org/10.1111/hepr.13284

  30. 30. Hu, Z.G., Huang, P.B., Yan, Y.C., et al. (2018) Hepatitis B Virus X Protein Related lncRNA WEE2-AS1 Promotes Hepatocellular Carcinoma Proliferation and Invasion. Biochemical and Biophysical Research Communications, 508, 79-86. https://doi.org/10.1016/j.bbrc.2018.11.091

  31. 31. Zuo, K., Kong, L., Xue, D., et al. (2018) The Expression and Role of lncRNA AX800134 in Hepatitis B Virus-Related Hepatocellular Carcinoma. Virus Genes, 54, 475-483. https://doi.org/10.1007/s11262-018-1564-1

  32. 32. Zhang, Q., Matsuura, K., Kleiner, D.E., et al. (2016) Analysis of Long Noncoding RNA Expression in Hepatocellular Carcinoma of Different Viral Etiology. Journal of Translational Medicine, 14, 328-338. https://doi.org/10.1186/s12967-016-1085-4

  33. 33. Zhong, Y.C., Li, Y., Song, T., et al. (2019) MiR-718 Mediates the Indirect Interaction between lncRNA SEMA3B-AS1 and PTEN to Regulate the Proliferation of Hepatocellular Carcinoma Cells. Physiological Genomics, 51, 500-505. https://doi.org/10.1152/physiolgenomics.00019.2019

  34. 34. Fan, H.X., Lv, P., Mu, T., et al. (2018) LncRNA n335586/miR-924/CKMT1A Axis Contributes to Cell Migration and Invasion in Hepatocellular Carcinoma Cells. Cancer Letters, 429, 89-99. https://doi.org/10.1016/j.canlet.2018.05.010

  35. 35. Lv, J., Fan, H.X., Zhao, X.P., et al. (2016) Long Non-Coding RNA Unigene56159 Promotes Epithelial-Mesenchymal Transition by Acting as a ceRNA of miR-140-5p in Hepatocellular Carcinoma Cells. Cancer Letters, 382, 166-175. https://doi.org/10.1016/j.canlet.2016.08.029

  36. 36. Lu, Z.P., Xiao, Z.L., Liu, F.B., et al. (2016) Long Non-Coding RNA HULC Promotes Tumor Angiogenesis in Liver Cancer by Up-Regulating Sphingosine Kinase 1 (SPHK1). Oncotarget, 7, 241-254. https://doi.org/10.18632/oncotarget.6280

  37. 37. Liu, S.H., Qiu, J., He, G.F., et al. (2019) LncRNA MALAT1 Acts as a miR-125a-3p Sponge to Regulate FOXM1 Expression and Promote Hepatocellular Carcinoma Progression. Journal of Cancer, 10, 6649-6659. https://doi.org/10.7150/jca.29213

  38. 38. Zhang, P., Ha, M., Li, L.B., et al. (2020) MicroRNA-3064-5p Sponged by MALAT1 Suppresses Angiogenesis in Human Hepatocellular Carcinoma by Targeting the FOXA1/CD24/Src Pathway. FASEB Journal, 34, 66-81. https://doi.org/10.1096/fj.201901834R

  39. 39. Zhang, F.J., Yang, C., Xing, Z.Y., et al. (2019) LncRNA GAS5-Mediated miR-1323 Promotes Tumor Progression by Targeting TP53INP1 in Hepatocellular Carcinoma. OncoTargets and Therapy, 12, 4013-4023. https://doi.org/10.2147/OTT.S209439

  40. 40. Chen, F., Li, Y.H., Li, M.J., et al. (2019) Long Noncoding RNA GAS5 Inhibits Metastasis by Targeting miR-182/ ANGPTL1 in Hepatocellular Carcinoma. American Journal of Cancer Research, 9, 108-121.

  41. 41. Yang, L., Peng, X.Q., Jin, H.Y., et al. (2019) Long Non-Coding RNA PVT1 Promotes Autophagy as ceRNA to Target ATG3 by Sponging microRNA-365 in Hepatocellular Carcinoma. Gene, 697, 94-102. https://doi.org/10.1016/j.gene.2019.02.036

  42. 42. Xu, Y., Luo, X., He, W., et al. (2018) Long Non-Coding RNA PVT1/miR-150/HIG2 Axis Regulates the Proliferation, Invasion and the Balance of Iron Metabolism of Hepatocellular Carcinoma. Cellular Physiology and Biochemistry, 49, 1403-1419. https://doi.org/10.1159/000493445

  43. 43. Ding, Z.H., Guo, L., Deng, Z.M. and Li, P. (2020) Circ-PRMT5 Enhances the Proliferation, Migration and Glycolysis of Hepatoma Cells by Targeting miR-188-5p/HK2 Axis. Annals of Hepatology, 19, 269-279. https://doi.org/10.1016/j.aohep.2020.01.002

  44. 44. Guo, X.Q., Xi, L.L., Li, L.F., et al. (2020) circRNA-14723 Promotes Hepatocytes Proliferation in Rat Liver Regeneration by Sponging rno-miR-16-5p. Journal of Cellular Physiology, 235, 8176-8186. https://doi.org/10.1002/jcp.29473

  45. 45. Peng, J.F., et al. (2016) The Impact of HCV Core Protein on the Expression of lncRNA and circRNA in Human Huh7 Hepatoma Cell Line and the Preliminary Mechanism Study. 第十一届全国免疫学学术大会摘要汇编, 中国免疫学会, 122-123.

  46. 46. Li, Y., Shi, H.T., Yuan, J., et al. (2020) Downregulation of Circular RNA circPVT1 Restricts Cell Growth of Hepatocellular Carcinoma through Downregulation of Sirtuin 7 via microRNA-3666. Clinical and Experimental Pharmacology & Physiology, 47, 1291-1300. https://doi.org/10.1111/1440-1681.13273

  47. 47. Sun, X.J., Ge, X.F., Xu, Z.Y., et al. (2020) Identification of Circular RNA-microRNA-Messenger RNA Regulatory Network in Hepatocellular Carcinoma by Integrated Analysis. Journal of Gastroenterology and Hepatology, 35, 157-164. https://doi.org/10.1111/jgh.14762

  48. 48. Wei, Y.P., Chen, X., Liang, C., et al. (2020) A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma. Hepatology (Baltimore, Md.), 71, 130-147. https://doi.org/10.1002/hep.30795

  49. 49. Wang, Z.Y., Zhu, Z., Wang, H.F., et al. (2019) Downregulation of circDYNC1H1 Exhibits Inhibitor Effect on Cell Proliferation and Migration in Hepatocellular Carcinoma through miR-140-5p. Journal of Cellular Physiology, 234, 17775-17785. https://doi.org/10.1002/jcp.28403

  50. 50. Chen, G.W., Shi, Y.T., Liu, M.M., et al. (2018) circHIPK3 Regulates Cell Proliferation and Migration by Sponging miR-124 and Regulating AQP3 Expression in Hepatocellular Carcinoma. Cell Death & Disease, 9, 175-187. https://doi.org/10.1038/s41419-017-0204-3

  51. 51. Li, X. and Shen, M. (2019) Circular RNA has-circ-103809 Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Sponging miR-620. European Review for Medical and Pharmacological Sciences, 23, 555-566.

  52. 52. Yu, J., Xu, Q.G., Wang, Z.G., et al. (2018) Circular RNA cSMARCA5 Inhibits Growth and Metastasis in Hepatocellular Carcinoma. Journal of Hepatology, 68, 1214-1227. https://doi.org/10.1016/j.jhep.2018.01.012

  53. 53. Fu, L.Y., Chen, Q.Q., Yao, T., et al. (2017) Hsa_circ_0005986 Inhibits Carcinogenesis by Acting as a miR-129-5p Sponge and Is Used as a Novel Biomarker for Hepatocellular Carcinoma. Oncotarget, 8, 43878-43888. https://doi.org/10.18632/oncotarget.16709

  54. 54. Han, D., Li, J.X., Wang, H.M., et al. (2017) Circular RNA circMTO1 Acts as the Sponge of microRNA-9 to Suppress Hepatocellular Carcinoma Progression. Hepatology, 66, 1151-1164. https://doi.org/10.1002/hep.29270

  55. 55. Huang, X.Y., Huang, Z.L., Xu, Y.H., et al. (2017) Comprehensive Circular RNA Profiling Reveals the Regulatory Role of the circRNA-100338/miR-141-3p Pathway in Hepatitis B-Related Hepatocellular Carcinoma. Scientific Reports, 7, 5428-5439. https://doi.org/10.1038/s41598-017-05432-8

  56. 56. Jiang, W.D., Wen, D.C., Gong, L.L., et al. (2018) Circular RNA has-circ-0000673 Promotes Hepatocellular Carcinoma Malignance by Decreasing miR-767-3p Targeting SET. Biochemical and Biophysical Research Communications, 500, 211-216. https://doi.org/10.1016/j.bbrc.2018.04.041

  57. 57. Zhong, L.H., Wang, Y.Y., Cheng, Y., et al. (2018) Circular RNA circC3P1 Suppresses Hepatocellular Carcinoma Growth and Metastasis through miR-4641/PCK1 Pathway. Biochemical and Biophysical Research Communications, 499, 1044-1049. https://doi.org/10.1016/j.bbrc.2018.03.221

  58. 58. 吴光辉, 李伟. 环状RNA PTENP1、HIPK3联合高尔基体蛋白73对AFP阴性肝癌的诊断价值[J]. 肝脏, 2019, 24(5): 531-534.

  59. 59. Yang, X.Y., Song, H., Zi, Z.G., et al. (2019) Circ_0005075 Promotes Hepatocellular Carcinoma Progression by Suppression of microRNA-335. Journal of Cellular Physiology, 234, 21937-21946. https://doi.org/10.1002/jcp.28757

  60. 60. Shang, X.C., Li, G.Z., Liu, H., et al. (2016) Comprehensive Circular RNA Profiling Reveals That hsa_circ_0005075, a New Circular RNA Biomarker, Is Involved in Hepatocellular Crcinoma Development. Medicine, 95, e3811-e3817. https://doi.org/10.1097/MD.0000000000003811

  61. 61. Bai, N., Peng, E.M., Qiu, X.S., et al. (2018) circFBLIM1 Act as a ceRNA to Promote Hepatocellular Cancer Progression by Sponging miR-346. Journal of Experimental & Clinical Cancer Research, 37, 172-180. https://doi.org/10.1186/s13046-018-0838-8

  62. 62. Zhu, Q., Lu, G.Y., Luo, Z.H., et al. (2018) CircRNA circ_0067934 Promotes Tumor Growth and Metastasis in Hepatocellular Carcinoma through Regulation of miR-1324/FZD5/Wnt/β-Catenin Axis. Biochemical and Biophysical Research Communications, 497, 626-632. https://doi.org/10.1016/j.bbrc.2018.02.119

  63. 63. Yu, L., Gong, X.J., Sun, L., et al. (2017) The Circular RNA Cdr1as Act as an Oncogene in Hepatocellular Carcinoma through Targeting miR-7 Expression. PLoS ONE, 11, e0158347. https://doi.org/10.1371/journal.pone.0158347

  64. 64. Su, Y., Xu, C., Liu, Y.T., et al. (2019) Circular RNA hsa_circ_0001649 Inhibits Hepatocellular Carcinoma Progression via Multiple miRNAs Sponge. Aging, 11, 3362-3375. https://doi.org/10.18632/aging.101988

  65. 65. Qin, M.L., Liu, G., Huo, X.S., et al. (2016) Hsa_circ_0001649: A Circular RNA and Potential Novel Biomarker for Hepatocellular Carcinoma. Cancer Biomarkers, 16, 161-169. https://doi.org/10.3233/CBM-150552

  66. 66. Xu, L.L., Feng, X.F., Hao, X.Y., et al. (2019) CircSETD3 (Hsa_circ_0000567) Acts as a Sponge for microRNA-421 Inhibiting Hepatocellular Carcinoma Growth. Journal of Experimental & Clinical Cancer Research, 38, 98-112. https://doi.org/10.1186/s13046-019-1041-2

  67. 67. Sharma, G., Tripathi, S.K. and Das, S. (2019) lncRNA HULC Facilitates Efficient Loading of HCV-Core Protein onto Lipid Droplets and Subsequent Virus-Particle Release. Cellular Microbiology, 21, e13086-13095. https://doi.org/10.1111/cmi.13086

  68. 68. Shen, X.T., Guo, H.Y., Xu, J.J. and Wang, J.L. (2019) Inhibition of lncRNA HULC Improves Hepatic Fibrosis and Hepatocyte Apoptosis by Inhibiting the MAPK Signaling Pathway in Rats with Nonalcoholic Fatty Liver Disease. Journal of Cellular Physiology, 234, 18169-18179. https://doi.org/10.1002/jcp.28450

  69. 69. Li, Z.Q., Gu, X.Y., Hu, J.X., et al. (2016) Hepatitis C Virus Core Protein Impairs Metabolic Disorder of Liver Cell via HOTAIR-Sirt1 Signalling. Bioscience Reports, 36, e00336. https://doi.org/10.1042/BSR20160088

  70. 70. Zhi, S.-C., Chen, S.-Z., Li, Y.-Y., Li, J.-J., et al. (2019) Rosiglitazone Inhibits Activation of Hepatic Stellate Cells via Up-Regulating Micro-RNA-124-3p to Alleviate Hepatic Fibrosis. Digestive Diseases and Sciences, 64, 1560-1570. https://doi.org/10.1007/s10620-019-5462-8

  71. 71. Bian, E.-B., Wang, Y.-Y., Yang, Y., et al. (2017) Hotair Facilitates Hepatic Stellate Cells Activation and Fibrogenesis in the Liver. Biochimica et Biophysica Acta (BBA): Molecular Basis of Disease, 1863, 674-686. https://doi.org/10.1016/j.bbadis.2016.12.009

  72. 72. Gao, J.Z., Li, J., Du, J.L., et al. (2016) Long Non-Coding RNA HOTAIR Is a Marker for Hepatocellular Carcinoma Progression and Tumor Recurrence. Oncology Letters, 11, 1791-1798. https://doi.org/10.3892/ol.2016.4130

  73. 73. Peng, X.X., Wan, Y., Liu, W.J., et al. (2016) Protective Roles of Intra-Arterial Mild Hypothermia and Arterial Thrombolysis in Acute Cerebral Infarction. SpringerPlus, 5, 1988-1993. https://doi.org/10.1186/s40064-016-3654-7

  74. 74. Dong, Z.H., Li, S., Wang, X.H., et al. (2019) lncRNA GAS5 Restrains CCl4-Induced Hepatic Fibrosis by Targeting miR-23a through the PTEN/PI3K/Akt Signaling Pathway. American Journal of Physiology. Gastrointestinal and Liver Physiology, 316, G539-G550. https://doi.org/10.1152/ajpgi.00249.2018

  75. 75. He, Y., Wu, Y.T., Huang, C., et al. (2014) Inhibitory Effects of Long Noncoding RNA MEG3 on Hepatic Stellate Cells Activation and Liver Fibrogenesis. Biochimica et Biophysica Acta (BBA): Molecular Basis of Disease, 1842, 2204-2215. https://doi.org/10.1016/j.bbadis.2014.08.015

  76. 76. Chen, R.P., Huang, Z.L., Liu, L.X., et al. (2016) Involvement of Endoplasmic Reticulum Stress and p53 in lncRNA MEG3-Induced Human Hepatoma HepG2 Cell Apoptosis. Oncology Reports, 36, 1649-1657. https://doi.org/10.3892/or.2016.4919

  77. 77. Fu, N., Niu, X.M., Wang, Y., et al. (2016) Role of LncRNA-Activated by Transforming Growth Factor Beta in the Progression of Hepatitis C Virus-Related Liver Fibrosis. Discovery Medicine, 22, 29-42.

  78. 78. Wang, C.Z., Yan, G.X., Dong, D.S., et al. (2019) LncRNA-ATB Promotes Autophagy by Activating Yes-Associated Protein and Inducing Autophagy-Related Protein 5 Expression in Hepatocellular Carcinoma. World Journal of Gastroenterology, 25, 5310-5322. https://doi.org/10.3748/wjg.v25.i35.5310

  79. 79. Zheng, J.J., Yu, F.J., Dong, P.H., et al. (2016) Long Non-Coding RNA PVT1 Activates Hepatic Stellate Cells through Competitively Binding microRNA-152. Oncotarget, 7, 62886-62897. https://doi.org/10.18632/oncotarget.11709

    80. NOTES

    *通讯作者。

期刊菜单