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肝纤维化中上皮间质转化的调控及靶向治疗的研究进展
DOI: 10.3969/j.issn.1001-5256.2021.01.035
作者贡献声明：王永娟负责课题设计，资料分析，撰写论文；谢肖立参与收集数据，修改论文；姜慧卿负责拟定写作思路，指导撰写文章并最后定稿。
Research advances in the regulation of epithelial-mesenchymal transition and targeted therapy for liver fibrosis
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摘要: 肝纤维化的病理基础是细胞外基质沉积，肌成纤维细胞是细胞外基质的主要来源。上皮间质转化(EMT)是肌成纤维细胞的产生机制之一。目前大量研究表明，以EMT关键分子及信号通路为靶点进行干预，可减轻肝纤维化。回顾了相关文献，对EMT相关的信号通路、重要调控分子和以EMT为靶点治疗肝纤维化的药物进行综述，以期为治疗肝纤维化提供新思路。Abstract: The pathological basis of liver fibrosis is the deposition of extracellular matrix (ECM), and myofibroblasts are the main source of ECM. Epithelial-mesenchymal transition (EMT) is one of production mechanisms of myofibroblasts. At present, a large number of studies have shown that intervention of key EMT molecules and signaling pathways as targets can reduce liver fibrosis. Based on literature review, this article summarizes the signaling pathways associated with EMT, important regulatory molecules, and drugs targeting EMT in the treatment of liver fibrosis, so as to provide new ideas for the treatment of liver fibrosis.
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Key words:
- Liver Cirrhosis /
- Epithelial-Mesenchymal Transition /
- Therapeutics
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[1] GUANHUA X, ANNA MAE D. Evidence for and against epithelial-to-mesenchymal[J]. Am J Physiol Gastrointest Liver Physiol, 2013, 305(12): G881-90. DOI: 10.1152/ajpgi.00289.2013 [2] KALLURI R, WEINBERG RA. The basics of epithelial-mesenchymal transition[J]. J Clin Invest, 2009, 119(6): 1420-1428. DOI: 10.1172/JCI39104 [3] GREENBURG G, HAY ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells[J]. J Cell Biol, 1982, 95(1): 333-339. DOI: 10.1083/jcb.95.1.333 [4] LEE JM, DEDHAR S, KALLURI R, et al. The epithelial-mesenchymal transition: New insights in signaling, development, and disease[J]. J Cell Biol, 2006, 172(7): 973-981. DOI: 10.1083/jcb.200601018 [5] THIERY JP, ACLOQUE H, HUANG RY, et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell, 2009, 139(5): 871-890. DOI: 10.1016/j.cell.2009.11.007 [6] KRIZ W, KAISSLING B, LE HIR M. Epithelial-mesenchymal transition (EMT) in kidney fibrosis: Fact or fantasy?[J]. J Clin Invest, 2011, 121(2): 468-474. DOI: 10.1172/JCI44595 [7] MIZUTANI A, KOINUMA D, TSUTSUMI S, et al. Cell type-specific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte nuclear factor 4alpha in HepG2 cells[J]. J Biol Chem, 2011, 286(34): 29848-29860. DOI: 10.1074/jbc.M110.217745 [8] XU J, LAMOUILLE S, DERYNCK R. TGF-beta-induced epithelial to mesenchymal transition[J]. Cell Res, 2009, 19(2): 156-172. DOI: 10.1038/cr.2009.5 [9] SYN WK, CHOI SS, LIASKOU E, et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis[J]. Hepatology, 2011, 53(1): 106-115. DOI: 10.1002/hep.23998 [10] XIE G, KARACA G, SWIDERSKA-SYN M, et al. Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice[J]. Hepatology, 2013, 58(5): 1801-1813. DOI: 10.1002/hep.26511 [11] SEN S, LANGIEWICZ M, JUMAA H, et al. Hassan deletion of splicing factor SRSF3 in hepatocytes predisposes to hepatocellular carcinoma in mice[J]. Hepatology, 2015, 1(61): 171-183. DOI: 10.1002/hep.27380/abstract [12] ZHANG K, ZHANG M, YAO Q, 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. DOI: 10.7150/thno.36942 [13] CHEN T, LIN H, CHEN X, et al. LncRNA Meg8 suppresses activation of hepatic stellate cells and epithelial-mesenchymal transition of hepatocytes via the Notch pathway[J]. Biochem Biophys Res Commun, 2020, 521(4): 921-927. DOI: 10.1016/j.bbrc.2019.11.015 [14] 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. DOI: 10.1016/j.bbadis.2014.08.015 [15] ZHU J, LUO Z, PAN Y, 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. DOI: 10.1002/jcp.27656 [16] ZHANG K, HAN X, 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. DOI: 10.1038/s41467-017-00204-4 [17] ZOU Y, LI S, LI Z, et al. MiR-146a attenuates liver fibrosis by inhibiting transforming growth factor-β1 mediated epithelial-mesenchymal transition in hepatocytes[J]. Cell Signal, 2019, 58: 1-8. DOI: 10.1016/j.cellsig.2019.01.012 [18] WU K, YE C, LIN L, et al. Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT[J]. Clin Sci (Lond), 2016, 130(16): 1469-1480. DOI: 10.1042/CS20160334 [19] YU F, ZHENG Y, HONG W, et al. MicroRNA-200a suppresses epithelial-to-mesenchymal transition in rat hepatic stellate cells via GLI family zinc finger 2[J]. Mol Med Rep, 2015, 12(6): 8121-8128. DOI: 10.3892/mmr.2015.4452 [20] 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. DOI: 10.1111/liv.12660 [21] GWON MG, AN HJ, KIM JY, et al. Anti-fibrotic effects of synthetic TGF-β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial-mesenchymal transitions[J]. FASEB J, 2020, 34(1): 333-349. DOI: 10.1096/fj.201901307RR [22] GWON MG, KIM JY, AN HJ, et al. Antifibrotic effect of smad decoy oligodeoxynucleotide in a CCl (4)-induced hepatic fibrosis animal model[J]. Molecules, 2018, 23(8): 1991. DOI: 10.3390/molecules23081991 [23] KIM KH, LEE WR, KANG YN, et al. Inhibitory effect of nuclear factor-κB decoy oligodeoxynucleotide on liver fibrosis through regulation of the epithelial-mesenchymal transition[J]. Hum Gene Ther, 2014, 25(8): 721-729. DOI: 10.1089/hum.2013.106 [24] HAO H, ZHANG D, SHI J, et al. Sorafenib induces autophagic cell death and apoptosis in hepatic stellate cell through the JNK and Akt signaling pathways[J]. Anticancer Drugs, 2016, 27(3): 192-203. DOI: 10.1097/CAD.0000000000000316 [25] CHENG Y, ZHENG H, WANG B, et al. Sorafenib and fluvastatin synergistically alleviate hepatic fibrosis via inhibiting the TGFβ1/Smad3 pathway[J]. Dig Liver Dis, 2018, 50(4): 381-388. DOI: 10.1016/j.dld.2017.12.015 [26] PRATAP A, SINGH S, MUNDRA V, et al. Attenuation of early liver fibrosis by pharmacological inhibition of smoothened receptor signaling[J]. J Drug Target, 2012, 20(9): 770-782. DOI: 10.3109/1061186X.2012.719900 [27] ZHAO H, WANG Z, TANG F, et al. Carnosol-mediated Sirtuin 1 activation inhibits Enhancer of Zeste Homolog 2 to attenuate liver fibrosis[J]. Pharmacol Res, 2018, 128: 327-337. DOI: 10.1016/j.phrs.2017.10.013 [28] PARK JH, PARK B, PARK KK. Suppression of hepatic epithelial-to-mesenchymal transition by melittin via blocking of TGFβ/Smad and MAPK-JNK signaling pathways[J]. Toxins (Basel), 2017, 9(4): 138. DOI: 10.3390/toxins9040138 [29] CHUANG HM, HO LI, HUANG MH, et al. Non-canonical regulation of type I collagen through promoter binding of SOX2 and its contribution to ameliorating pulmonary fibrosis by butylidenephthalide[J]. Int J Mol Sci, 2018, 19(10): 3024. DOI: 10.3390/ijms19103024 [30] TAI CJ, CHOONG CY, LIN YC, et al. The anti-hepatic fibrosis activity of ergosterol depended on upregulation of PPARgamma in HSC-T6 cells[J]. Food Funct, 2016, 7(4): 1915-1923. DOI: 10.1039/C6FO00117C [31] SONG YN, SUN JJ, LU YY, et al. Therapeutic efficacy of fuzheng-huayu tablet based traditional chinese medicine syndrome differentiation on hepatitis-B-caused cirrhosis: A multicenter double-blind randomized controlled trail[J]. Evid Based Complement Alternat Med, 2013, 2013: 709305. [32] 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. DOI: 10.1111/jcmm.12655 [33] REN S, YUE Q, WANG Q, et al. Cryptotanshinone suppresses liver fibrosis by attenuating epithelial-mesenchymal transition through targeting hedgehog pathway[J]. Anticancer Agents Med Chem, 2020.[Online ahead of print] [34] YANG YZ, ZHAO XJ, XU HJ, et al. Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling[J]. Acta Pharmacol Sin, 2019, 40(7): 879-894. http://www.cqvip.com/QK/95561A/20197/7002551626.html -
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