摘要
肝脏疾病的发病率逐年上升,由于肝脏疾病发病诱因复杂和发病机制尚未阐明,治愈率不够理想,迫切需要明确其作用机制以找到更有效的治疗靶点与药物。长链非编码RNA( long non-coding RNA,lncRNA)作为一种长度超过200 nt的非编码RNA,是近年来肝脏疾病的研究热点。本文以肝脏疾病中主要的信号转导通路为主线,对近年来lncRNA调控肝脏疾病相关信号通路的最新研究进展进行归纳总结,详细阐述lncRNA通过调节肝脏疾病中关键的信号通路,参与细胞增殖、凋亡、侵袭、迁移等多种生理过程,从而促进肝脏疾病的发生发展,为肝脏疾病的机制研究提供新的思路,为寻找治疗肝脏疾病的新靶点及生物标志物提供新的研究方向。
肝脏是人体最大的实质性脏器,具有多种功能,被称为“物质代谢中枢”、人体内最大的“化工厂”和“清洁器”。肝脏是一个很容易受损的器官,各种损肝因素如病毒、酗酒、脂代谢异常、药物、自身免疫等,均会造成肝脏炎症损伤,这时肝内的物质代谢就会出现障碍,身体的多种功能也会受到影响,如果炎症持续发展就会发展为肝硬化、肝纤维化、肝癌
长链非编码RNA(long non-coding RNA,lncRNA)是一类长度大于200个核苷酸,缺少特异完整的开放阅读框、无蛋白质编码功能的RNA分
LncRNA分布于细胞质、细胞核以及细胞器中,功能较为复杂,具有多样性,能够在表观遗传、转录、转录后水平调控基因表达,广泛参与机体几乎所有的生理和病理过

图1 长链非编码RNA(lncRNA)的调控机制
LncRNA作为生物标记物在肝脏疾病的诊断和预后中发挥了重要作用。例如Liu
转化生长因子-β(TGF-β)信号通路是细胞内重要的信号转导通路,参与调控众多细胞生长发育过程,包括细胞生长、分化、凋亡以及细胞动态平衡等其他细胞功
TGF-β在肿瘤中发挥双相调节作用。在肿瘤的早期阶段,TGF-β通过诱导细胞周期停滞和细胞凋亡发挥肿瘤抑制作用;随着肿瘤的恶性进展,TGF-β通过诱导细胞发生上皮-间质转化(epithelial-mesenchymal transition,EMT)进而诱导细胞增殖,迁移和侵袭来发挥促肿瘤转移作用。EMT已被证明有助于肿瘤细胞的迁移与侵袭。肝细胞癌(hepatocellular carcinoma,HCC)作为全球第六大常见肿瘤,具有高复发率和预后差的特
2.1.2 LncRNA调控肝纤维化中的TGF-β信号通路 肝纤维化作为肝内结缔组织异常增生的过程,其主要特征是细胞外基质(extracellular matrix,ECM)蛋白的产生和沉积增加。肝星状细胞 (hepatic stellate cells,HSC)是影响纤维化产生的最主要细胞,在其活化的过程中会产生大量的Ⅰ型胶原α1(collagen type I collagenα1,COL1α1),ɑ平滑肌动蛋白(ɑ-smooth actin,ɑ-SMA)以及促纤维化因子。TGF-β信号通路是肝纤维化过程中重要的参与者,可以通过诱导细胞损伤,促进炎症因子和促纤维化因子表达增加,进而加重肝纤维化,其中TGF-β/Smad是调控肝纤维化的典型信号通路。TGF-β1作为最主要的促纤维化细胞因子,与其受体TGF-βR1和TGF-βRII结合导致异四聚体复合物的形成和Smad2的磷酸化;磷酸化Smads易位进入细胞核从而促进HSC活化和胶原合成。近年来,研究发现lncRNA通过介导TGF-β/Smad信号通路进而调控肝纤维化。例如lncRNA-ATB通过与miR-425-5p竞争性结合来上调TGF-βRII和Smad2的表达,从而促进HSC的活化和增殖,发挥促纤维化作
Notch信号通路是一个高度保守的信号通路,参与调控多种生物进程,包括细胞增殖、分化、上皮-间质转化和血管生成等。在哺乳动物中,Notch信号通路有4个受体(Notch1-4)和5个Notch配体(Delta-like 1,Dll1;Delta-like 3,Dll3;Delta-like 4,Dll4;Jagged-1 and Jagged-2)。当Notch受体与相邻细胞上的相应配体相互结合时,ADAM家族对Notch受体进行两步蛋白水解,释放Notch细胞内结构域(notch intracellular domain,NICD);NICD易位至细胞核并与DNA结合蛋白CSL作用以促进靶基因的转录,包括Hes和与Hes相关转录因
肝癌细胞的高转移是肝癌预后差和术后复发率高的重要原因。大量研究表明,Notch通路在肿瘤中异常激活并与肿瘤的侵袭转移密切相关,例如已证实Notch1的激活有助于肝癌细胞的生长与增殖,但Notch通路如何介导肝癌细胞的侵袭机制仍不明确,目前研究报道lncRNA可能通过调控Notch通路进而介导这一过程。例如:在肝癌组织和细胞系中显著下调的lincRNA-p21被认为在肝癌中发挥抗肿瘤作用,其可以抑制肝癌细胞的增殖和迁移;对lincRNA-p21的作用机制进行探究,发现过表达的lincRNA-p21通过介导Notch信号通路诱导的EMT进程来抑制肝癌细胞的转移;激活Notch通路可以逆转pcDNA-lincRNA-p21的肝癌细胞抑制作用,提示Notch通路参与lincRNA-p21的抑癌作
Notch通路已被报道通过各种途径与方式参与肝纤维化的发生发展。例如:敲低Notch3可以抑制ɑ-SMA和COL1α1的表达,进而介导HSCs活
Zhang
PI3K/AKT信号通路是蛋白质合成的重要通路,可以调控细胞增殖、分化、凋亡等多种生物进程。磷脂酰肌醇-3羟基激酶(phosphatidylinositol 3-kinase, PI3K)可以被G蛋白偶联受体、蛋白酪氨酸激酶受体或Ras蛋白激活;激活的PI3K通过激活蛋白激酶 B(protein kinase B,PKB)即AKT,进而激活下游信号分子mTOR。mTOR作为丝氨酸/苏氨酸蛋白激酶,负责对氨基酸、营养物质、葡萄糖等刺激产生应答,进而调控细胞周期,促进细胞增殖和存活等生物进程。
PI3K/AKT信号通路已被报道通过抑制细胞凋亡,促进肿瘤细胞的侵袭和迁移进而参与肿瘤的发生发展,是肿瘤机制研究的热
PI3K/AKT信号通路在肝纤维化中发挥着重要作用,可以通过调节ECM的合成与降解,促纤维化因子的表达以及HSC的活化参与肝纤维化的形成。激活的PI3K/AKT信号通路促进HSC的增殖,也可以通过调控c-FLIPL的表达,抑制HSC的凋亡。PTEN作为PI3K/AKT信号通路的主要负向调节因子,可以抑制PI3K和AKT磷酸化进而抑制HSC活化与增殖,是治疗肝纤维化的有效靶
非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是慢性肝病的最常见病因,后期可能发展为肝硬化或肝癌,是世界性的健康问
Wnt/β-catenin信号通路与肝癌的增殖、转移及侵袭密切相关。β-catenin 作为该通路的关键调节因子,其表达水平与肿瘤细胞的迁移侵袭能力呈正相关;β-catenin 可以促进肿瘤血管生成等方式参与肝癌的浸润和转移;Wnt/β-catenin信号通路还可通过介导细胞凋亡参与恶性肿瘤的发展。LncRNA已被报道参与调控肝癌细胞的生长、增殖、迁移、侵袭、凋亡等过程。越来越多的证据表明,lncRNA可能通过作用于Wnt/β-catenin信号通路来调节肝癌。例如:Liang
Wnt信号通路在肝纤维化中发挥着重要作用,可以通过经典β-catenin依赖信号通路和非经典β-catenin独立通路调节HSCs的活化与增殖。当Wnt受体激活时,与相应受体结合,活化胞内Dishevelled 蛋白,促使Axin 结合LRP,抑制糖原合成激酶3β (glycogen synthase kinase 3β,GSK-3β)活性,胞浆内β-catenin积累;持续激增的β-catenin入核与转录因子家族TCF/LEF结合形成转录复合物,激活下游纤维化相关基因,促进HSC活化,进而调节肝纤维化。LncRNA在肝纤维化中异常表达,可以通过多种机制作用于肝纤维化。目前研究表明,lncRNA主要以充当ceRNA的方式调节Wnt信号通路介导肝纤维化。近来研究发现,沉默SNHG7可以抑制HSC活化和细胞增殖,减少胶原蛋白生成。机制研究表明,SNHG7通过竞争性结合miR-378a-3p,增加DVL2胞内含量,提高TCF活性,减少磷酸化β-catenin和GSK-3β表达,从而激活Wnt/β-catenin信号通路,诱导HSC活化,调节肝纤维
丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路是细胞内重要的信号通路,参与调控细胞的增殖、分化、侵袭与迁移等多种生理过程,其主要的MAPK成员包括:细胞外信号调节激酶(ERK)、c-Jun氨基末端激酶(JNK)和p38 丝裂原活化蛋白激酶(p38 MAPK
MAPK信号通路除了在肝癌中发挥作用,在NAFLD的形成、发展中所起的作用也受到越来越多的关注。已报道游离脂肪酸(free fatty acid,FFA)、炎症因子、细胞内的高氧化应激水平均可激活JNK信号通路,活化的JNK通路通过调节肥胖,IR以及细胞凋亡介导NAFLD的病程;JNK1能加重NAFLD中的肝损伤,且与IR水平呈正相关;过表达AMPKa1抑制p38 MAPK的激活,进而可能作为治疗NAFLD的新靶点。研究表明lncRNA调控MAPK信号通路参与NAFLD的发生发展。Shen
综上,肝脏疾病中涉及的信号通路众多,lncRNA通过多种方式调控相关信号通路进而参与调控细胞增殖、迁移、侵袭、凋亡等多种生物学进程,介导肝脏疾病的发生发展(
肝脏疾病涉及的信号通路众多,通路之间的调控关系比较复杂,对肝脏疾病中的信号通路进行研究,有助于阐明肝脏疾病的发病机制,找到新的作用靶点。近年来lncRNA是肝脏疾病的研究热点,也取得了一定的进展。例如研究发现在H19调控序列的控制下,构建表达白喉毒素A链基因的单启动子载体可以治疗膀胱癌,并完成了Ⅰ/Ⅱa期临床试验,这可能同样适用于高表达H19的肝癌治疗;促进肝细胞增殖的lncRNA LALR1在肝损伤后的肝再生过程中发挥治疗优势;人肝纤维化中显著下调的MEG3在HSCs活化和肝纤维化发展中起重要作用,有望成为逆转肝纤维化的新潜在靶点。由此可见,靶向lncRNA治疗肝脏疾病为研究者提供了新方向,需要进一步明确lncRNA作用肝脏疾病的分子机制。目前研究证实lncRNA通过多种作用机制包括调控各种信号转导通路参与肝脏疾病的发生发展,但是目前对lncRNA调控信号通路的研究尚在起步阶段,尤其在肝癌和肝纤维化中,研究还较为深入,但在非酒精性脂肪性肝病,肝硬化等其他疾病中的研究较少。在未来分析技术和实验条件发展的基础上,需要进一步探究lncRNA调控各种信号通路的机制以及不同信号通路之间的复杂调控关系,以阐明lncRNA作用肝脏疾病的分子机制,为临床诊断治疗肝脏疾病提供新的理论基础。
参考文献
Shimizu Y. Liver in systemic disease[J]. World J Gastroenterol, 2008, 14(26): 4111-4119. [百度学术]
Xu LC, Chen QN, Liu XQ, et al. Erratum: Up-regulation of LINC00161 correlates with tumor migration and invasion and poor prognosis of patients with hepatocellular carcinoma[J]. Oncotarget, 2019, 10(14): 1474. [百度学术]
Song YF, Liu CN, Liu X, et al. H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule[J]. Hepatology, 2017, 66(4): 1183-1196. [百度学术]
Tang SH, Gao JH, Wen SL, et al. Expression of cyclooxygenase-2 is correlated with lncRNA-COX-2 in cirrhotic mice induced by carbon tetrachloride[J]. Mol Med Rep, 2017, 15(4): 1507-1512. [百度学术]
Chen X, Tan XR, Li SJ, et al. LncRNA NEAT1 promotes hepatic lipid accumulation via regulating miR-146a-5p/ROCK1 in nonalcoholic fatty liver disease[J]. Life Sci, 2019, 235: 116829. [百度学术]
Pan XF, Zheng GB, Gao CF. LncRNA PVT1: a novel therapeutic target for cancers[J]. Clin Lab, 2018, 64(5):655-662. [百度学术]
Tang XW, Gao Y, Yu LX, et al. Correlations between lncRNA-SOX2OT polymorphism and susceptibility to breast cancer in a Chinese population[J]. Biomark Med, 2017, 11(3): 277-284. [百度学术]
Yoon JH, Abdelmohsen K, Gorospe M. Functional interactions among microRNAs and long noncoding RNAs[J]. Semin Cell Dev Biol, 2014, 34: 9-14. [百度学术]
Gong CG, Maquat LE. LncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements[J]. Nature, 2011, 470(7333): 284-288. [百度学术]
Long FQ, Su QJ, Zhou JX, et al. LncRNA SNHG12 ameliorates brain microvascular endothelial cell injury by targeting miR-199a[J]. Neural Regen Res, 2018, 13(11): 1919-1926. [百度学术]
Liu Y, Pan SD, Liu L, et al. A genetic variant in long non-coding RNA HULC contributes to risk of HBV-related hepatocellular carcinoma in a Chinese population[J]. PLoS One, 2012, 7(4): e35145. doi:10.1371/journal.pone.0035145. [百度学术]
Li J, Wang XC, Tang JW, et al. HULC and Linc00152 act as novel biomarkers in predicting diagnosis of hepatocellular carcinoma[J]. Cell Physiol Biochem, 2015, 37(2): 687-696. [百度学术]
Gao JZ, Li J, Du JL, et al. Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence[J]. Oncol Lett, 2016, 11(3): 1791-1798. [百度学术]
Liu RP, Li X, Zhu WW, et al. Cholangiocyte-derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis[J]. Hepatology, 2019, 70(4): 1317-1335. [百度学术]
Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling[J]. Sci Signal, 2019, 12(570): eaav5183. [百度学术]
Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma[J]. Semin Diagn Pathol, 2017, 34(2): 153-159. [百度学术]
Hu ML, Wang XY, Chen WM. TGF-β1 upregulates the expression of lncRNA UCA1 and its downstream HXK2 to promote the growth of hepatocellular carcinoma[J]. Eur Rev Med Pharmacol Sci, 2018, 22(15): 4846-4854. [百度学术]
Wang F, Yuan JH, Wang SB, et al. Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2[J]. Hepatology, 2014, 60(4): 1278-1290. [百度学术]
Yuan JH, Yang F, Wang F, et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma[J]. Cancer Cell, 2014, 25(5): 666-681. [百度学术]
Shi ZT, Wei D, Wu HM, et al. Long non-coding RNA snaR is involved in the metastasis of liver cancer possibly through TGF-β1[J]. Oncol Lett, 2019, 17(6): 5565-5571. [百度学术]
Yang X, Cai JB, Peng R, et al. The long noncoding RNA NORAD enhances the TGF-β pathway to promote hepatocellular carcinoma progression by targeting miR-202-5p[J]. J Cell Physiol, 2019, 234(7): 12051-12060. [百度学术]
Zhang JQ, Han C, Ungerleider N, et al. A transforming growth factor-β and H19 signaling Axis in tumor-initiating hepatocytes that regulates hepatic carcinogenesis[J]. Hepatology, 2019, 69(4): 1549-1563. [百度学术]
Fu N, Niu XM, Wang Y, et al. Role of lncRNA-activated by transforming growth factor beta in the progression of hepatitis C virus-related liver fibrosis[J]. Discov Med, 2016, 22(119): 29-42. [百度学术]
Zhang K, Han XH, Zhang Z, et al. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways[J]. Nat Commun, 2017, 8(1): 144. [百度学术]
Zhu J, Luo ZG, Pan YD, et al. H19/miR-148a/USP4 Axis facilitates liver fibrosis by enhancing TGF-β signaling in both hepatic stellate cells and hepatocytes[J]. J Cell Physiol, 2019, 234(6): 9698-9710. [百度学术]
Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling[J]. Science, 1995, 268(5208): 225-232. [百度学术]
Jia M, Jiang L, Wang YD, et al. LincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through Notch signaling-induced epithelial-mesenchymal transition[J]. Hepatol Res, 2016, 46(11): 1137-1144. [百度学术]
Zhang HF, Li W, Han YD. LINC00261 suppresses cell proliferation, invasion and Notch signaling pathway in hepatocellular carcinoma[J]. Cancer Biomark, 2018, 21(3): 575-582. [百度学术]
Hao L,Xing YC,Chun MW,et al.A Notch1-regulated lncRNA,AK022798,contributes to the baicalein-induced apoptosis in hepatocellular carcinoma[J].Int J Clin Exp Pathol,2017,10(4):4303-4311. [百度学术]
Chen YX, Weng ZH, Qi D, et al. Effect of Notch signaling on the activation of hepatic stellate cells[J]. Chin J Hepatol(中华肝脏病杂志), 2012, 20(9): 677-682. [百度学术]
Li CY, Song GR, Zhang SY, et al. Wnt3a increases the metastatic potential of non-small cell lung cancer cells in vitro in part via its upregulation of Notch3[J]. Oncol Rep, 2015, 33(3): 1207-1214. [百度学术]
Zhang K, Zhang MX, Yao QB, et al. The hepatocyte-specifically expressed lnc-HSER alleviates hepatic fibrosis by inhibiting hepatocyte apoptosis and epithelial-mesenchymal transition[J]. Theranostics, 2019, 9(25): 7566-7582. [百度学术]
Noorolyai S, Shajari N, Baghbani E, et al. The relation between PI3K/AKT signalling pathway and cancer[J]. Gene, 2019, 698: 120-128. [百度学术]
Han YD, Chen MZ, Wang AL, et al. STAT3-induced upregulation of lncRNA CASC11 promotes the cell migration, invasion and epithelial-mesenchymal transition in hepatocellular carcinoma by epigenetically silencing PTEN and activating PI3K/AKT signaling pathway[J]. Biochem Biophys Res Commun, 2019, 508(2): 472-479. [百度学术]
Wang X, Dong K, Jin QZ, et al. Upregulation of lncRNA FER1L4 suppresses the proliferation and migration of the hepatocellular carcinoma via regulating PI3K/AKT signal pathway[J]. J Cell Biochem, 2019, 120(4): 6781-6788. [百度学术]
Wei HM, Hu J, Pu J, et al. Long noncoding RNA HAGLROS promotes cell proliferation, inhibits apoptosis and enhances autophagy via regulating miR-5095/ATG12 Axis in hepatocellular carcinoma cells[J]. Int Immunopharmacol, 2019, 73: 72-80. [百度学术]
Huang JL, Cao SW, Ou QS, et al. The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma[J]. Mol Cancer, 2018, 17(1): 93. [百度学术]
Wu SM, Li TH, Yun H, et al. MiR-140-3p knockdown suppresses cell proliferation and fibrogenesis in hepatic stellate cells via PTEN-mediated AKT/mTOR signaling[J]. Yonsei Med J, 2019, 60(6): 561-569. [百度学术]
Dong ZH, Li S, Wang XH, et al. LncRNA GAS5 restrains CCl4-induced hepatic fibrosis by targeting miR-23a through the PTEN/PI3K/Akt signaling pathway[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 316(4): G539-G550. [百度学术]
Yu FJ, Chen BC, Dong PH, et al. HOTAIR epigenetically modulates PTEN expression via MicroRNA-29b: a novel mechanism in regulation of liver fibrosis[J]. Mol Ther, 2017, 25(1): 205-217. [百度学术]
Huang TJ, Ren JJ, Zhang QQ, et al. IGFBPrP1 accelerates autophagy and activation of hepatic stellate cells via mutual regulation between H19 and PI3K/AKT/mTOR pathway[J]. Biomedecine Pharmacother, 2019, 116: 109034. [百度学术]
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the american association for the study of liver diseases[J]. Hepatology, 2018, 67(1): 328-357. [百度学术]
Wang X. Down-regulation of lncRNA-NEAT1 alleviated the non-alcoholic fatty liver disease via mTOR/S6K1 signaling pathway[J]. J Cell Biochem, 2018, 119(2): 1567-1574. [百度学术]
Huang P, Huang FZ, Liu HZ, et al. LncRNA MEG3 functions as a Cerna in regulating hepatic lipogenesis by competitively binding to miR-21 with LRP6[J]. Metab Clin Exp, 2019, 94: 1-8. [百度学术]
Liang WC, Ren JL, Wong CW, et al. LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via Cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling[J]. Oncogene, 2018, 37(11): 1445-1456. [百度学术]
Zhang Y, Mi L, Xuan Y, et al. LncRNA HOTAIRM1 inhibits the progression of hepatocellular carcinoma by inhibiting the Wnt signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2018, 22(15): 4861-4868. [百度学术]
Zhu LY, Yang NH, Du GQ, et al. LncRNA CRNDE promotes the epithelial-mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/β-catenin signaling pathway[J]. J Cell Biochem, 2018. doi:10.1002/jcb.26762. [百度学术]
Fu XM, Zhu XY, Qin FJ, et al. Linc00210 drives Wnt/β-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner[J]. Mol Cancer, 2018, 17(1): 73. [百度学术]
Yu FJ, Dong PH, Mao YF, et al. Loss of lncRNA-SNHG7 promotes the suppression of hepatic stellate cell activation via miR-378a-3p and DVL2[J]. Mol Ther Nucleic Acids, 2019, 17: 235-244. [百度学术]
Fu N, Zhao SX, Kong LB, et al. LncRNA-ATB/microRNA-200a/β-catenin regulatory Axis involved in the progression of HCV-related hepatic fibrosis[J]. Gene, 2017, 618: 1-7. [百度学术]
Yu FJ, Guo Y, Chen BC, et al. LincRNA-p21 inhibits the wnt/β-catenin pathway in activated hepatic stellate cells via sponging MicroRNA-17-5p[J]. Cell Physiol Biochem, 2017, 41(5): 1970-1980. [百度学术]
Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions[J]. Microbiol Mol Biol Rev, 2004, 68(2): 320-344. [百度学术]
Bao H, Guo CG, Qiu PC, et al. Long non-coding RNA Igf2as controls hepatocellular carcinoma progression through the ERK/MAPK signaling pathway[J]. Oncol Lett, 2017, 14(3): 2831-2837. [百度学术]
Peng W, Fan H. Long noncoding RNA CCHE1 indicates a poor prognosis of hepatocellular carcinoma and promotes carcinogenesis via activation of the ERK/MAPK pathway[J]. Biomedecine Pharmacother, 2016, 83: 450-455. [百度学术]
Shen XT, Guo HY, Xu JJ, et al. Inhibition of lncRNA HULC improves hepatic fibrosis and hepatocyte apoptosis by inhibiting the MAPK signaling pathway in rats with nonalcoholic fatty liver disease[J]. J Cell Physiol, 2019, 234(10):18169-18179. [百度学术]