非编码RNA与肝纤维化的研究进展
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摘要
肝纤维化是一个病理生理过程,其中细胞外基质在肝组织中的过度沉积和结缔组织的异常增殖是由各种致病因子长期刺激引起的,肝纤维化的本质是一种炎症增生修复反应。许多非编码RNA(ncRNA)与肝纤维化的发生、发展关系密切,其在肝脏细胞的增殖、活化、凋亡、分解及信号通路调节等方面发挥重要作用,探索其在肝纤维化过程中的调控机制,不仅可以进一步熟悉和理解肝纤维化的病理生理过程,还可以寻找合适的分子靶点,为肝纤维化的诊断、治疗和预后提供新思路。
Hepatic fibrosis is a pathophysiological process,in which excessive deposition of extracellular matrix in liver tissue and abnormal proliferation of connective tissue are caused by long-term stimulation of various pathogenic factors,and its nature is an inflammatory proliferation repair response. Recent studies have shown that many non-coding RNAs( ncRNAs) are closely related to the occurrence and development of hepatic fibrosis,playing important roles in the proliferation and activation of hepatocytes,apoptotic decomposition and signal pathway regulation. Exploring the regulation mechanism of ncRNAs in the process of hepatic fibrosis can not only further familiarize and understand the physiology and pathology of hepatic fibrosis,but also bring new ideas for the diagnosis,treatment and prognosis of liver fibrosis through finding suitable molecular targets.
Hepatic fibrosis is a pathophysiological process,in which excessive deposition of extracellular matrix in liver tissue and abnormal proliferation of connective tissue are caused by long-term stimulation of various pathogenic factors,and its nature is an inflammatory proliferation repair response. Recent studies have shown that many non-coding RNAs( ncRNAs) are closely related to the occurrence and development of hepatic fibrosis,playing important roles in the proliferation and activation of hepatocytes,apoptotic decomposition and signal pathway regulation. Exploring the regulation mechanism of ncRNAs in the process of hepatic fibrosis can not only further familiarize and understand the physiology and pathology of hepatic fibrosis,but also bring new ideas for the diagnosis,treatment and prognosis of liver fibrosis through finding suitable molecular targets.
引文
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[15]He Y,Huang C,Sun X,et al.MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4[J].Cell Signal,2012,24(10):1923-1930.
[16]Wang B,Li W,Guo K,et al.MiR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients[J].Biochem Biophys Res Commun,2012,421(1):4-8.
[17]Iizuka M,Ogawa T,Enomoto M,et al.Inducton of microRNA-214-5p in human and rodent liver fibrosis[J].Fibrogenesis Tissue Repair,2012,5(1):12.
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[23]Du J,Niu X,Wang Y,et al.MiR-146a-5p suppresses activation and proliferation of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis through directly targeting Wnt1 and Wnt5a[J].Sci Rep,2015(5):16163.
[24]Zhou DD,Wang X,Wang Y,et al.MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/beta-catenin pathway[J].Mol Immunol,2016(75):151-160.
[25]Yu F,Fan X,Chen B,et al.Activation of hepatic stellate cells is inhibited by microRNA-378a-3p via Wnt10a[J].Cell Physiol Biochem,2016,39(6):2409-2420.
[26]潘澎,刘绍能.PI3K/AKT信号通路与肝纤维化[J].临床肝胆病杂志,2013,29(5):389-392.
[27]Bian EB,Huang C,Ma TT,et al.DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats[J].Toxicol Appl Pharmacol,2012,264(1):13-22.
[28]Garzon R,Liu S,Fabbri M,et al.MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3Band indirectly DNMT1[J].Blood,2009,113(25):6411-6418.
[29]Zheng J,Wu C,Lin Z,et al.Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through micro RNA-mediated control of DNA methylation--a novel mechanism suppressing liver fibrosis[J].FEBS J,2014,281(1):88-103.
[30]Wang J,Chu ES,Chen HY,et al.microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway[J].Oncotarget,2015,6(9):7325-7338.
[31]Wei J,Feng L,Li Z,et al.MicroRNA-21 activates hepatic stellate cells via PTEN/Akt signaling[J].Biomed Pharmacother,2013,67(5):387-392.
[32]Zheng J,Wu C,Xu Z,et al.Hepatic stellate cell is activated by microRNA-181b via PTEN/Akt pathway[J].Mol Cell Biochem,2015,398(1/2):1-9.
[33]Xiao Y,Wang J,Chen Y,et al.Up-regulation of miR-200b in biliary atresia patients accelerates proliferation and migration of hepatic stallate cells by activating PI3K/Akt signaling[J].Cell Signal,2014,26(5):925-932.
[34]Shen WJ,Dong R,Chen G,et al.microRNA-222 modulates liver fibrosis in a murine model of biliary atresia[J].Biochem Biophys Res Commun,2014,446(1):155-159.
[35]Dong R,Zheng Y,Chen G,et al.miR-222 overexpression may contribute to liver fibrosis in biliary atresia by targeting PPP2R2A[J].J Pediatr Gastroenterol Nutr,2015,60(1):84-90.
[36]Li ZJ,Ou-Yang PH,Han X.Profibrotic effect of miR-33a with Akt activation in hepatic stellate cells[J].Cell Signal,2014,26(1):141-148.
[37]Feng X,Tan W,Cheng S,et al.Upregulation of microRNA-126 in hepatic stellate cells may affect pathogenesis of liver fibrosis through the NF-κB pathway[J].DNA Cell Biol,2015,34(7):470-480.
[38]Dai W,Zhao J,Tang N,et al.MicroRNA-155 attenuates activation of hepatic stellate cell by simultaneously preventing EMT process and ERK1 signalling pathway[J].Liver Int,2015,35(4):1234-1243.
[39]Ye D,Dai L,Yao Y,et al.miR-155 inhibits nucleus pulposus cells'degeneration through targeting ERK 1/2[J].Dis Markers,2016,2016:6984270.
[40]Zhao J,Tang N,Wu K,et al.MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis[J].PLo S One,2014,9(10):e108005.
[41]Guo CJ,Pan Q,Li DG,et al.miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell:An essential role for apoptosis[J].J Hepatol,2009,50(4):766-778.
[42]Wu Y,Liu X,Zhou Q,et al.Silent information regulator 1(SIRT1)ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion[J].Toxicol Appl Pharmacol,2015,289(2):163-176.
[43]Zheng J,Yu F,Dong P,et al.Long non-coding RNA PVT1activates hepatic stellate cells through competitively binding microRNA-152[J].Oncotarget,2016,7(39):62886-62897.
[44]Zhang Z,Zhu Z,Watabe K,et al.Negative regulation of lncRNAGAS5 by miR-21[J].Cell Death Differ,2013,20(11):1558-1568.
[45]Yu F,Zheng J,Mao Y,et al.Long bon-coding RNA growth arrestspecific transcript 5(GAS5)inhibits liver fibrogenesis through a mechanism of competing endogenous RNA[J].J Biol Chem,2015,290(47):28286-28298.
[46]Zhou X,Ye F,Yin C,et al.The interaction between miR-141 and lncRNA-H19 in regulating cell proliferation and migration in gastric cancer[J].Cell Physiol Biochem,2015,36(4):1440-1452.
[47]Bian EB,Wang YY,Yang Y,et al.Hotair facilitates hepatic stellate cells activation and fibrogenesis in the liver[J].Biochim Biophys Acta Mol Basis Dis,2017,1863(3):674-686.
[48]He Y,Wu YT,Huang C,et al.Inhibitory effects of long noncoding RNA MEG3 on hepatic stellate cells activation and liver fibrogenesis[J].Biochim Biophys Acta,2014,1842(11):2204-2215.
[49]Fu N,Niu X,Wang Y,et al.Role of LncRNA-activated by transforming growth factor beta in the progression of hepatitis C virusrelated liver fibrosis[J].Discov Med,2016,22(119):29-42.
[50]Yu F,Zheng J,Mao Y,et al.Long non-coding RNA APTRpromotes the activation of hepatic stellate cells and the progression of liver fibrosis[J].Biochem Biophys Res Commun,2015,463(4):679-685.
[2]郭鑫昕,苏式兵,商嘉玮,等.MicroRNAs与肝纤维化及相关中医药研究的进展[J].世界科学技术-中医药现代化,2016,18(9):1515-1521.
[3]Murakami Y,Toyoda H,Tanaka M,et al.The progression of liver fibrosis is related with overexpression of the miR-199 and 200families[J].PLo S One,2011,6(1):e16081.
[4]Sun X,He Y,Ma TT,et al.Participation of miR-200a in TGF-β1-mediated hepatic stellate cell activation[J].Mol Cell Biochem,2014,388(1/2):11-23.
[5]Ji Y,Zhang J,Wang W,et al.Functional study of miR-27a in human hepatic stellate cells by proteomic analysis:Comprehensive view and a role in myogenic tans-differentiation[J].PLo S One,2014,9(9):e108351.
[6]Csak T,Bala S,Lippai D,et al.MicroRNA-155 deficiency attenuates liver steatosis and fibrosis without reducing inflammation in a mouse model of steatohepatitis[J].PLo S One,2015,10(6):e0129251.
[7]Zhu B,Wei XX,Wang TB,et al.Increased miR-16 expression induced by hepatitis C virus infection promotes liver fibrosis through downregulation of hepatocyte growth factor and Smad7[J].Arch Virol,2015,160(8):2043-2050.
[8]Roy S,Benz F,Vargas Cardenas D,et al.miR-30c and miR-193are a part of the TGF-β-dependent regulatory network controlling extracellular matrix genes in liver fibrosis[J].J Dig Dis,2015,16(9):513-524.
[9]Yu F,Guo Y,Chen B,et al.MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7[J].Lab Invest,2015,95(7):781-789.
[10]Zhao S,Zhang Y,Zheng X,et al.Loss of microRNA-101 promotes epithelial to mesenchymal transition in hepatocytes[J].J Cell Physiol,2015,230(11):2706-2717.
[11]Ogawa T,Iizuka M,Sekiya Y,et al.Suppression of typeⅠcollagen production by microRNA-29b in cultured human stellate cells[J].Biochem Biophys Res Commun,2010,391(1):316-321.
[12]Zhang Y,Huang XR,Wei LH,et al.miR-29b as a therapeutic agent for angiotensinⅡ-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling[J].Mol Ther,2014,22(5):974-985.
[13]Tu X,Zheng X,Li H,et al.MicroRNA-30 protects against carbon tetrachloride-induced liver fibrosis by attenuating transforming growth factorβsignaling in hepatic stellate cells[J].Toxicol Sci,2015,146(1):157-169.
[14]Lakner AM,Steuerwald NM,Walling TL,et al.Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis[J].Hepatology,2012,56(1):300-310.
[15]He Y,Huang C,Sun X,et al.MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4[J].Cell Signal,2012,24(10):1923-1930.
[16]Wang B,Li W,Guo K,et al.MiR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients[J].Biochem Biophys Res Commun,2012,421(1):4-8.
[17]Iizuka M,Ogawa T,Enomoto M,et al.Inducton of microRNA-214-5p in human and rodent liver fibrosis[J].Fibrogenesis Tissue Repair,2012,5(1):12.
[18]Yu F,Lu Z,Chen B,et al.Salvianolic acid B-induced microRNA-152 inhibits liver fibrosis by attenuating DNMT1-mediated Patched1 methylation[J].J Cell Mol Med,2015,19(11):2617-2632.
[19]Kumar V,Mondal G,Dutta R,et al.Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis[J].Biomaterials,2016,76:144-156.
[20]Yu F,Zheng Y,Hong W,et al.MicroRNA200a suppresses epithelial-to-mesenchymal transition in rat hepatic stellate cells via GLIfamily zinc finger 2[J].Mol Med Rep,2015,12(6):8121-8128.
[21]Hyun J,Wang S,Kim J,et al.MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression[J].Nat Commun,2016,7:10993.
[22]朱智杰,阮君山,李尧,等.Wnt信号通路诱导肿瘤细胞上皮间质转化的研究进展[J].中国药理学通报,2012,28(7):904-907.
[23]Du J,Niu X,Wang Y,et al.MiR-146a-5p suppresses activation and proliferation of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis through directly targeting Wnt1 and Wnt5a[J].Sci Rep,2015(5):16163.
[24]Zhou DD,Wang X,Wang Y,et al.MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/beta-catenin pathway[J].Mol Immunol,2016(75):151-160.
[25]Yu F,Fan X,Chen B,et al.Activation of hepatic stellate cells is inhibited by microRNA-378a-3p via Wnt10a[J].Cell Physiol Biochem,2016,39(6):2409-2420.
[26]潘澎,刘绍能.PI3K/AKT信号通路与肝纤维化[J].临床肝胆病杂志,2013,29(5):389-392.
[27]Bian EB,Huang C,Ma TT,et al.DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats[J].Toxicol Appl Pharmacol,2012,264(1):13-22.
[28]Garzon R,Liu S,Fabbri M,et al.MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3Band indirectly DNMT1[J].Blood,2009,113(25):6411-6418.
[29]Zheng J,Wu C,Lin Z,et al.Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through micro RNA-mediated control of DNA methylation--a novel mechanism suppressing liver fibrosis[J].FEBS J,2014,281(1):88-103.
[30]Wang J,Chu ES,Chen HY,et al.microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway[J].Oncotarget,2015,6(9):7325-7338.
[31]Wei J,Feng L,Li Z,et al.MicroRNA-21 activates hepatic stellate cells via PTEN/Akt signaling[J].Biomed Pharmacother,2013,67(5):387-392.
[32]Zheng J,Wu C,Xu Z,et al.Hepatic stellate cell is activated by microRNA-181b via PTEN/Akt pathway[J].Mol Cell Biochem,2015,398(1/2):1-9.
[33]Xiao Y,Wang J,Chen Y,et al.Up-regulation of miR-200b in biliary atresia patients accelerates proliferation and migration of hepatic stallate cells by activating PI3K/Akt signaling[J].Cell Signal,2014,26(5):925-932.
[34]Shen WJ,Dong R,Chen G,et al.microRNA-222 modulates liver fibrosis in a murine model of biliary atresia[J].Biochem Biophys Res Commun,2014,446(1):155-159.
[35]Dong R,Zheng Y,Chen G,et al.miR-222 overexpression may contribute to liver fibrosis in biliary atresia by targeting PPP2R2A[J].J Pediatr Gastroenterol Nutr,2015,60(1):84-90.
[36]Li ZJ,Ou-Yang PH,Han X.Profibrotic effect of miR-33a with Akt activation in hepatic stellate cells[J].Cell Signal,2014,26(1):141-148.
[37]Feng X,Tan W,Cheng S,et al.Upregulation of microRNA-126 in hepatic stellate cells may affect pathogenesis of liver fibrosis through the NF-κB pathway[J].DNA Cell Biol,2015,34(7):470-480.
[38]Dai W,Zhao J,Tang N,et al.MicroRNA-155 attenuates activation of hepatic stellate cell by simultaneously preventing EMT process and ERK1 signalling pathway[J].Liver Int,2015,35(4):1234-1243.
[39]Ye D,Dai L,Yao Y,et al.miR-155 inhibits nucleus pulposus cells'degeneration through targeting ERK 1/2[J].Dis Markers,2016,2016:6984270.
[40]Zhao J,Tang N,Wu K,et al.MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis[J].PLo S One,2014,9(10):e108005.
[41]Guo CJ,Pan Q,Li DG,et al.miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell:An essential role for apoptosis[J].J Hepatol,2009,50(4):766-778.
[42]Wu Y,Liu X,Zhou Q,et al.Silent information regulator 1(SIRT1)ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion[J].Toxicol Appl Pharmacol,2015,289(2):163-176.
[43]Zheng J,Yu F,Dong P,et al.Long non-coding RNA PVT1activates hepatic stellate cells through competitively binding microRNA-152[J].Oncotarget,2016,7(39):62886-62897.
[44]Zhang Z,Zhu Z,Watabe K,et al.Negative regulation of lncRNAGAS5 by miR-21[J].Cell Death Differ,2013,20(11):1558-1568.
[45]Yu F,Zheng J,Mao Y,et al.Long bon-coding RNA growth arrestspecific transcript 5(GAS5)inhibits liver fibrogenesis through a mechanism of competing endogenous RNA[J].J Biol Chem,2015,290(47):28286-28298.
[46]Zhou X,Ye F,Yin C,et al.The interaction between miR-141 and lncRNA-H19 in regulating cell proliferation and migration in gastric cancer[J].Cell Physiol Biochem,2015,36(4):1440-1452.
[47]Bian EB,Wang YY,Yang Y,et al.Hotair facilitates hepatic stellate cells activation and fibrogenesis in the liver[J].Biochim Biophys Acta Mol Basis Dis,2017,1863(3):674-686.
[48]He Y,Wu YT,Huang C,et al.Inhibitory effects of long noncoding RNA MEG3 on hepatic stellate cells activation and liver fibrogenesis[J].Biochim Biophys Acta,2014,1842(11):2204-2215.
[49]Fu N,Niu X,Wang Y,et al.Role of LncRNA-activated by transforming growth factor beta in the progression of hepatitis C virusrelated liver fibrosis[J].Discov Med,2016,22(119):29-42.
[50]Yu F,Zheng J,Mao Y,et al.Long non-coding RNA APTRpromotes the activation of hepatic stellate cells and the progression of liver fibrosis[J].Biochem Biophys Res Commun,2015,463(4):679-685.