Advertisement

siRNA- and miRNA-based therapeutics for liver fibrosis

  • Zhen Zhao
    Affiliations
    Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
    Search for articles by this author
  • Chien-Yu Lin
    Affiliations
    Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
    Search for articles by this author
  • Kun Cheng
    Correspondence
    Reprint requests: Kun Cheng, Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108.
    Affiliations
    Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
    Search for articles by this author
Published:August 13, 2019DOI:https://doi.org/10.1016/j.trsl.2019.07.007
      Liver fibrosis is a wound-healing process induced by chronic liver injuries, such as nonalcoholic steatohepatitis, hepatitis, alcohol abuse, and metal poisoning. The accumulation of excessive extracellular matrix (ECM) in the liver is a key characteristic of liver fibrosis. Activated hepatic stellate cells (HSCs) are the major producers of ECM and therefore play irreplaceably important roles during the progression of liver fibrosis. Liver fibrogenesis is highly correlated with the activation of HSCs, which is regulated by numerous profibrotic cytokines. Using RNA interference to downregulate these cytokines in activated HSCs is a promising strategy to reverse liver fibrosis. Meanwhile, microRNAs (miRNAs) have also been exploited for the treatment of liver fibrosis. This review focuses on the current siRNA- and miRNA-based liver fibrosis treatment strategies by targeting activated HSCs in the liver.

      Abbreviations:

      ECM (extracellular matrix), HSC (hepatic stellate cell), RNAi (Ribonucleic acid interference), PDGF (platelet-derived growth factor), TNF-α (tumor necrosis factor alpha), α-SMA (α-smooth muscle actin), siRNA (interfering RNA), shRNA (short-hairpin RNA), miRNA (micro RNA), ATP (Adenosine triphosphate), RISC (RNA-induced silencing complex), IGFIIR (insulin-like growth factor II receptor), MMP (matrix metalloproteinases), COL1A1 (Type I collagen, alpha 1), COL1A2 (Type I collagen, alpha 2), COL3A1 (Type III collagen, alpha 1), COL5A2 (Type V collagen, alpha 1), COL6A1 (Type VI collagen, alpha 1), COL6A3 (Type VI collagen, alpha 3), COL7A1 (Type VII collagen, alpha 1), TGF-β (transforming growth factor beta), IL-4 (interleukin 4), IL-13 (interleukin 13), TIMP (Tissue inhibitors of matrix metalloproteinase), CCl4 (carbon tetrachloride), TANGO1 (transport and Golgi organization 1), HSP47 (heat shock protein 47), αCP2 (α-complex protein 2), PCBP2 (Poly(RC) Binding Protein 2), UTR (untranslated region), EGF (epidermal growth factor), DMN (dimethylnitrosamine), UPR (unfolded protein response), BMP (bone morphogenetic protein), TβR1 (transforming growth factor beta receptor 1), TβR2 (transforming growth factor beta receptor 2), ALK3 (activin-like kinase 3), TRPM7 (transient receptor potential melastatin 7), 2-APB (2-aminoethoxydiphenyl borate), HDAC2 (Histone deacetylase 2), NLRC5 (Nucleotide oligomerization domain-like receptors CARD domain containing 5), MKL1 (megakaryoblastic leukemia 1), Hic-5 (hydrogen peroxide-inducible clone-5), PDGFR (platelet-derived growth factor receptor), RTK (receptor tyrosine kinase), PI3Ks (phosphoinositide 3-kinases), PIP2 (phosphatidylinositol-3,4-bisphosphate), PIP3 (phosphatidylinositol-3,4,5-trisphosphate), PDK1 (phosphoinositide-dependent kinase 1), Tβ4 (thymosin β4), ELF (embryonic liver fordin), VEGF (vascular endothelial growth factor), PlGF (placental growth factor), HIF-1a (hypoxia-dependent factor-1a), GRB2 (growth factor receptor-bound 2), HMGB1 (high mobility group protein box1), PTPRO (receptor-type tyrosine-protein phosphatase O), NF-κB (nuclear factor-kappa B), RAGE (receptor for advanced glycation end products), FGFR1 (fibroblast growth factor receptor 1), Hh (hedgehog), Smo (smoothened), Gli (glioblastoma), CP-MSCs (chorionic plate-derived mesenchymal stem cells), CHB (chronic hepatitis B), CHC (chronic hepatitis C), RT-qPCR (Real Time-quantitative polymerase chain reaction)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Friedman S.L.
        Liver fibrosis—from bench to bedside.
        J Hepatol. 2003; 38: S38-S53
        • Lee Y.A.
        • Wallace M.C.
        • Friedman S.L.
        Pathobiology of liver fibrosis: a translational success story.
        Gut. 2015; 64: 830-841
        • Scaglione S.
        • Kliethermes S.
        • Cao G.
        • Shoham D.
        • Durazo R.
        • Luke A.
        • et al.
        The epidemiology of cirrhosis in the United States: a population-based study.
        J Clin Gastroenterol. 2015; 49: 690-696
        • Sun M.
        • Kisseleva T.
        Reversibility of liver fibrosis.
        Clin Res Hepatol Gastroenterol. 2015; 39: S60-S63
        • Tacke F.
        Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis.
        Expert Opin Investig Drugs. 2018; 27: 301-311
        • Sanyal A.
        • Charles E.D.
        • Neuschwander-Tetri B.A.
        • Loomba R.
        • Harrison S.A.
        • Abdelmalek M.F.
        • et al.
        Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial.
        Lancet. 2019; 392: 2705-2717
        • Tully D.C.
        • Rucker P.V.
        • Chianelli D.
        • Williams J.
        • Vidal A.
        • Alper P.B.
        • et al.
        Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH).
        J Med Chem. 2017; 60: 9960-9973
        • Geerts A.
        History heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.
        Semin Liver Dis. 2001; 21: 311-335
        • Marra F.
        • Pinzani M.
        Role of hepatic stellate cells in the pathogenesis of portal hypertension.
        Nefrologia. 2002; 22: 34-40
        • Higashi T.
        • Friedman S.L.
        • Hoshida Y.
        Hepatic stellate cells as key target in liver fibrosis.
        Adv Drug Deliv Rev. 2017; 121: 27-42
        • Liu H.
        • Chen Z.
        • Jin W.
        • Barve A.
        • Wan Y.Y.
        • Cheng K.
        Silencing of alpha-complex protein-2 reverses alcohol- and cytokine-induced fibrogenesis in hepatic stellate cells.
        Liver Res. 2017; 1: 70-79
        • Issa R.
        • Williams E.
        • Trim N.
        • Kendall T.
        • Arthur M.J.
        • Reichen J.
        • et al.
        Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors.
        Gut. 2001; 48: 548-557
        • Saile B.
        • Matthes N.
        • Knittel T.
        • Ramadori G.
        Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells.
        Hepatology. 1999; 30: 196-202
        • Cheng K.
        • Mahato R.I.
        Gene modulation for treating liver fibrosis.
        Crit Rev Ther Drug Carrier Syst. 2007; 24: 93-146
        • Raghow R.
        The role of extracellular matrix in postinflammatory wound healing and fibrosis.
        FASEB J. 1994; 8: 823-831
        • Senoo H.
        • Imai K.
        • Matano Y.
        • Sato M.
        Molecular mechanisms in the reversible regulation of morphology, proliferation and collagen metabolism in hepatic stellate cells by the three-dimensional structure of the extracellular matrix.
        J Gastroenterol Hepatol. 1998; 13: S19-S32
        • Omar R.
        • Yang J.
        • Liu H.
        • Davies N.M.
        • Gong Y.
        Hepatic stellate cells in liver fibrosis and siRNA-based therapy.
        Rev Physiol Biochem Pharmacol. 2016; 172: 1-37
        • Zhao Z.
        • Li Y.
        • Jain A.
        • Chen Z.
        • Liu H.
        • Jin W.
        • et al.
        Development of a peptide-modified siRNA nanocomplex for hepatic stellate cells.
        Nanomedicine. 2018; 14: 51-61
        • Shukla R.S.
        • Qin B.
        • Cheng K.
        Peptides used in the delivery of small noncoding RNA.
        Mol Pharm. 2014; 11: 3395-3408
        • Aagaard L.
        • Rossi J.J.
        RNAi therapeutics: principles, prospects and challenges.
        Adv Drug Deliv Rev. 2007; 59: 75-86
        • Zhao Z.
        • Li Y.
        • Shukla R.
        • Liu H.
        • Jain A.
        • Barve A.
        • et al.
        Development of a biocompatible copolymer nanocomplex to deliver VEGF siRNA for triple negative breast cancer.
        Theranostics. 2019; 9: 4508
        • Cheng K.
        • Mahato R.I.
        Biological and therapeutic applications of small RNAs.
        Pharm Res. 2011; 28: 2961-2965
        • Kulkarni J.A.
        • Cullis P.R.
        • van der Meel R.
        Lipid nanoparticles enabling gene therapies: from concepts to clinical utility.
        Nucleic Acid Ther. 2018; 28: 146-157
        • Stoff J.A.
        Selected office based anticancer treatment strategies.
        J Oncol. 2019; 20197462513
        • Wittrup A.
        • Lieberman J.
        Knocking down disease: a progress report on siRNA therapeutics.
        Nat Rev Genet. 2015; 16: 543-552
        • Chen Z.
        • Jain A.
        • Liu H.
        • Zhao Z.
        • Cheng K.
        Targeted drug delivery to hepatic stellate cells for the treatment of liver fibrosis.
        J Pharmacol Exp Ther. 2019; 370: 695-702
        • Chen Z.
        • Jin W.
        • Liu H.
        • Zhao Z.
        • Cheng K.
        Discovery of peptide ligands for hepatic stellate cells using phage display.
        Mol Pharm. 2015; 12: 2180-2188
        • Bhogal R.K.
        • Stoica C.M.
        • McGaha T.L.
        • Bona C.A.
        Molecular aspects of regulation of collagen gene expression in fibrosis.
        J Clin Immunol. 2005; 25: 592-603
        • Tsukada S.
        • Westwick J.K.
        • Ikejima K.
        • Sato N.
        • Rippe R.A.
        SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta-stimulated hepatic stellate cells.
        J Biol Chem. 2005; 280: 10055-10064
        • Jimenez Calvente C.
        • Sehgal A.
        • Popov Y.
        • Kim Y.O.
        • Zevallos V.
        • Sahin U.
        • et al.
        Specific hepatic delivery of procollagen alpha1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis.
        Hepatology. 2015; 62: 1285-1297
        • Toriyabe N.
        • Sakurai Y.
        • Kato A.
        • Yamamoto S.
        • Tange K.
        • Nakai Y.
        • et al.
        The delivery of small interfering RNA to hepatic stellate cells using a lipid nanoparticle composed of a vitamin A-scaffold lipid-like material.
        J Pharm Sci. 2017; 106: 2046-2052
        • Kaps L.
        • Nuhn L.
        • Aslam M.
        • Brose A.
        • Foerster F.
        • Rosigkeit S.
        • et al.
        In vivo gene-silencing in fibrotic liver by siRNA-loaded cationic nanohydrogel particles.
        Adv Healthc Mater. 2015; 4: 2809-2815
        • Maiers J.L.
        • Kostallari E.
        • Mushref M.
        • deAssuncao T.M.
        • Li H.
        • Jalan-Sakrikar N.
        • et al.
        The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice.
        Hepatology. 2017; 65: 983-998
        • Sato Y.
        • Murase K.
        • Kato J.
        • Kobune M.
        • Sato T.
        • Kawano Y.
        • et al.
        Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone.
        Nat Biotechnol. 2008; 26: 431-442
        • Lindquist J.N.
        • Stefanovic B.
        • Brenner D.A.
        Regulation of collagen alpha1(I) expression in hepatic stellate cells.
        J Gastroenterol. 2000; 35: 80-83
        • Sato M.
        • Suzuki S.
        • Senoo H.
        Hepatic stellate cells: unique characteristics in cell biology and phenotype.
        Cell Struct Funct. 2003; 28: 105-112
        • Shukla R.S.
        • Qin B.
        • Wan Y.J.
        • Cheng K.
        PCBP2 siRNA reverses the alcohol-induced pro-fibrogenic effects in hepatic stellate cells.
        Pharm Res. 2011; 28: 3058-3068
        • Jain A.
        • Barve A.
        • Zhao Z.
        • Fetse J.
        • Liu H.
        • Li Y.
        Targeted delivery of an siRNA-PNA hybrid nanocomplex reverses carbon tetrachloride-induced liver fibrosis.
        Adv Ther. 2019;
        • Nagata K.
        Expression and function of heat shock protein 47: a collagen-specific molecular chaperone in the endoplasmic reticulum.
        Matrix Biol. 1998; 16: 379-386
        • Xu F.
        • Liu C.
        • Zhou D.
        • Zhang L.
        TGF-beta/SMAD pathway and its regulation in hepatic fibrosis.
        J Histochem Cytochem. 2016; 64: 157-167
        • Yang J.H.
        • Kim S.C.
        • Kim K.M.
        • Jang C.H.
        • Cho S.S.
        • Kim S.J.
        • et al.
        Isorhamnetin attenuates liver fibrosis by inhibiting TGF-beta/Smad signaling and relieving oxidative stress.
        Eur J Pharmacol. 2016; 783: 92-102
        • Lang Q.
        • Liu Q.
        • Xu N.
        • Qian K.L.
        • Qi J.H.
        • Sun Y.C.
        • et al.
        The antifibrotic effects of TGF-beta1 siRNA on hepatic fibrosis in rats.
        Biochem Biophys Res Commun. 2011; 409: 448-453
        • Fabregat I.
        • Moreno-Caceres J.
        • Sanchez A.
        • Dooley S.
        • Dewidar B.
        • Giannelli G.
        • et al.
        TGF-beta signalling and liver disease.
        FEBS J. 2016; 283: 2219-2232
        • De Bleser P.J.
        • Niki T.
        • Rogiers V.
        • Geerts A.
        Transforming growth factor-beta gene expression in normal and fibrotic rat liver.
        J Hepatol. 1997; 26: 886-893
        • Meyer C.
        • Meindl-Beinker N.M.
        • Dooley S.
        TGF-beta signaling in alcohol induced hepatic injury.
        Front Biosci (Landmark Ed). 2010; 15: 740-749
        • Li L.
        • Wang J.Y.
        • Yang C.Q.
        • Jiang W.
        Effect of RhoA on transforming growth factor beta1-induced rat hepatic stellate cell migration.
        Liver Int. 2012; 32: 1093-1102
        • Fu M.Y.
        • He Y.J.
        • Lv X.
        • Liu Z.H.
        • Shen Y.
        • Ye G.R.
        • et al.
        Transforming growth factorbeta1 reduces apoptosis via autophagy activation in hepatic stellate cells.
        Mol Med Rep. 2014; 10: 1282-1288
        • Verrecchia F.
        • Chu M.L.
        • Mauviel A.
        Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach.
        J Biol Chem. 2001; 276: 17058-17062
        • Walton K.L.
        • Johnson K.E.
        • Harrison C.A.
        Targeting TGF-beta Mediated SMAD signaling for the prevention of fibrosis.
        Front Pharmacol. 2017; 8: 461
        • Wang S.
        • Hirschberg R.
        BMP7 antagonizes TGF-beta-dependent fibrogenesis in mesangial cells.
        Am J Physiol Renal Physiol. 2003; 284: F1006-F10013
        • Taipale J.
        • Saharinen J.
        • Hedman K.
        • Keski-Oja J.
        Latent transforming growth factor-beta 1 and its binding protein are components of extracellular matrix microfibrils.
        J Histochem Cytochem. 1996; 44: 875-889
        • Wordinger R.J.
        • Sharma T.
        • Clark A.F.
        The role of TGF-beta2 and bone morphogenetic proteins in the trabecular meshwork and glaucoma.
        J Ocul Pharmacol Ther. 2014; 30: 154-162
        • Yamashita S.
        • Maeshima A.
        • Kojima I.
        • Nojima Y.
        Activin A is a potent activator of renal interstitial fibroblasts.
        J Am Soc Nephrol. 2004; 15: 91-101
        • Deng L.
        • Huang L.
        • Guo Q.
        • Shi X.
        • Xu K.
        CREB1 and Smad3 mediate TGF-beta3-induced Smad7 expression in rat hepatic stellate cells.
        Mol Med Rep. 2017; 16: 8455-8462
        • Cheng K.
        • Yang N.
        • Mahato R.I.
        TGF-beta1 gene silencing for treating liver fibrosis.
        Mol Pharm. 2009; 6: 772-779
        • Kim K.H.
        • Kim H.C.
        • Hwang M.Y.
        • Oh H.K.
        • Lee T.S.
        • Chang Y.C.
        • et al.
        The antifibrotic effect of TGF-beta1 siRNAs in murine model of liver cirrhosis.
        Biochem Biophys Res Commun. 2006; 343: 1072-1078
        • Fu R.
        • Wu J.
        • Ding J.
        • Sheng J.
        • Hong L.
        • Sun Q.
        • et al.
        Targeting transforming growth factor betaRII expression inhibits the activation of hepatic stellate cells and reduces collagen synthesis.
        Exp Biol Med (Maywood). 2011; 236: 291-297
        • Herrera B.
        • Addante A.
        • Sanchez A.
        BMP signalling at the crossroad of liver fibrosis and regeneration.
        Int J Mol Sci. 2017; 19: 1-25
        • Wozney J.M.
        • Rosen V.
        • Celeste A.J.
        • Mitsock L.M.
        • Whitters M.J.
        • Kriz R.W.
        • et al.
        Novel regulators of bone formation: molecular clones and activities.
        Science. 1988; 242: 1528-1534
        • Sugimoto H.
        • LeBleu V.S.
        • Bosukonda D.
        • Keck P.
        • Taduri G.
        • Bechtel W.
        • et al.
        Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis.
        Nat Med. 2012; 18: 396-404
        • Kinoshita K.
        • Iimuro Y.
        • Otogawa K.
        • Saika S.
        • Inagaki Y.
        • Nakajima Y.
        • et al.
        Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats.
        Gut. 2007; 56: 706-714
        • Zeng X.Y.
        • Zhang Y.Q.
        • He X.M.
        • Wan L.Y.
        • Wang H.
        • Ni Y.R.
        • et al.
        Suppression of hepatic stellate cell activation through downregulation of gremlin1 expression by the miR-23b/27b cluster.
        Oncotarget. 2016; 7: 86198-86210
        • Li P.
        • Li Y.
        • Zhu L.
        • Yang Z.
        • He J.
        • Wang L.
        • et al.
        Targeting secreted cytokine BMP9 gates the attenuation of hepatic fibrosis.
        Biochim Biophys Acta Mol Basis Dis. 2018; 1864: 709-720
        • Fang L.
        • Huang C.
        • Meng X.
        • Wu B.
        • Ma T.
        • Liu X.
        • et al.
        TGF-beta1-elevated TRPM7 channel regulates collagen expression in hepatic stellate cells via TGF-beta1/Smad pathway.
        Toxicol Appl Pharmacol. 2014; 280: 335-344
        • Li X.
        • Wu X.Q.
        • Xu T.
        • Li X.F.
        • Yang Y.
        • Li W.X.
        • et al.
        Role of histone deacetylases (HDACs) in progression and reversal of liver fibrosis.
        Toxicol Appl Pharmacol. 2016; 306: 58-68
        • Xu T.
        • Ni M.M.
        • Xing L.
        • Li X.F.
        • Meng X.M.
        • Huang C.
        • et al.
        NLRC5 regulates TGF-beta1-induced proliferation and activation of hepatic stellate cells during hepatic fibrosis.
        Int J Biochem Cell Biol. 2016; 70: 92-104
        • Shang H.
        • Liu X.
        • Guo H.
        Knockdown of Fstl1 attenuates hepatic stellate cell activation through the TGFbeta1/Smad3 signaling pathway.
        Mol Med Rep. 2017; 16: 7119-7123
        • Fan Z.
        • Hao C.
        • Li M.
        • Dai X.
        • Qin H.
        • Li J.
        • et al.
        MKL1 is an epigenetic modulator of TGF-beta induced fibrogenesis.
        Biochim Biophys Acta. 2015; 1849: 1219-1228
        • Lei X.F.
        • Fu W.
        • Kim-Kaneyama J.R.
        • Omoto T.
        • Miyazaki T.
        • Li B.
        • et al.
        Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice.
        J Hepatol. 2016; 64: 110-117
        • Breitkopf K.
        • Roeyen C.
        • Sawitza I.
        • Wickert L.
        • Floege J.
        • Gressner A.M.
        Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC).
        Cytokine. 2005; 31: 349-357
        • Ying H.Z.
        • Chen Q.
        • Zhang W.Y.
        • Zhang H.H.
        • Ma Y.
        • Zhang S.Z.
        • et al.
        PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (Review).
        Mol Med Rep. 2017; 16: 7879-7889
        • Heldin C.H.
        • Lennartsson J.
        • Westermark B.
        Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis.
        J Intern Med. 2018; 283: 16-44
        • Heldin C.H.
        • Westermark B.
        Mechanism of action and in vivo role of platelet-derived growth factor.
        Physiol Rev. 1999; 79: 1283-1316
        • Cao Y.
        Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis.
        Trends Mol Med. 2013; 19: 460-473
        • Park H.J.
        • Kim H.G.
        • Wang J.H.
        • Choi M.K.
        • Han J.M.
        • Lee J.S.
        • et al.
        Comparison of TGF-beta, PDGF, and CTGF in hepatic fibrosis models using DMN, CCl4, and TAA.
        Drug Chem Toxicol. 2016; 39: 111-118
        • Matsumoto Y.
        • Itami S.
        • Kuroda M.
        • Yoshizato K.
        • Kawada N.
        • Murakami Y.
        MiR-29a assists in preventing the activation of human stellate cells and promotes recovery from liver fibrosis in mice.
        Mol Ther. 2016; 24: 1848-1859
        • Andrae J.
        • Gallini R.
        • Betsholtz C.
        Role of platelet-derived growth factors in physiology and medicine.
        Genes Dev. 2008; 22: 1276-1312
        • Borkham-Kamphorst E.
        • Meurer S.K.
        • Van de Leur E.
        • Haas U.
        • Tihaa L.
        • Weiskirchen R.
        PDGF-D signaling in portal myofibroblasts and hepatic stellate cells proves identical to PDGF-B via both PDGF receptor type alpha and beta.
        Cell Signal. 2015; 27: 1305-1314
        • Wang X.
        • Wu X.
        • Zhang A.
        • Wang S.
        • Hu C.
        • Chen W.
        • et al.
        Targeting the PDGF-B/PDGFR-beta Interface with destruxin A5 to selectively block PDGF-BB/PDGFR-ββ signaling and attenuate liver fibrosis.
        EBioMedicine. 2016; 7: 146-156
        • Majumder S.
        • Piguet A.C.
        • Dufour J.F.
        • Chatterjee S.
        Study of the cellular mechanism of sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis.
        Eur J Pharmacol. 2013; 705: 86-95
        • Westra I.M.
        • Oosterhuis D.
        • Groothuis G.M.
        • Olinga P.
        Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs.
        Toxicol Appl Pharmacol. 2014; 274: 328-338
        • Ehnman M.
        • Ostman A.
        Therapeutic targeting of platelet-derived growth factor receptors in solid tumors.
        Expert Opin Investig Drugs. 2014; 23: 211-226
        • Kumar V.
        • Mondal G.
        • Dutta R.
        • Mahato R.I.
        Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis.
        Biomaterials. 2016; 76: 144-156
        • Chen S.W.
        • Zhang X.R.
        • Wang C.Z.
        • Chen W.Z.
        • Xie W.F.
        • Chen Y.X.
        RNA interference targeting the platelet-derived growth factor receptor beta subunit ameliorates experimental hepatic fibrosis in rats.
        Liver Int. 2008; 28: 1446-1457
        • Lim B.J.
        • Lee W.K.
        • Lee H.W.
        • Lee K.S.
        • Kim J.K.
        • Chang H.Y.
        • et al.
        Selective deletion of hepatocyte platelet-derived growth factor receptor alpha and development of liver fibrosis in mice.
        Cell Commun Signal. 2018; 16: 93
        • Roderfeld M.
        Matrix metalloproteinase functions in hepatic injury and fibrosis.
        Matrix Biol. 2018; 68–69: 452-462
        • Campana L.
        • Iredale J.P.
        Regression of liver fibrosis.
        Semin Liver Dis. 2017; 37: 1-10
        • Li Y.
        • Liu F.
        • Ding F.
        • Chen P.
        • Tang M.
        Inhibition of liver fibrosis using vitamin A-coupled liposomes to deliver matrix metalloproteinase-2 siRNA in vitro.
        Mol Med Rep. 2015; 12: 3453-3461
        • Fowell A.J.
        • Collins J.E.
        • Duncombe D.R.
        • Pickering J.A.
        • Rosenberg W.M.
        • Benyon R.C.
        Silencing tissue inhibitors of metalloproteinases (TIMPs) with short interfering RNA reveals a role for TIMP-1 in hepatic stellate cell proliferation.
        Biochem Biophys Res Commun. 2011; 407: 277-282
        • Zhu Y.
        • Miao Z.
        • Gong L.
        • Chen W.
        Transplantation of mesenchymal stem cells expressing TIMP-1-shRNA improves hepatic fibrosis in CCl(4)-treated rats.
        Int J Clin Exp Pathol. 2015; 8: 8912-8920
        • Cong M.
        • Liu T.
        • Wang P.
        • Xu Y.
        • Tang S.
        • Wang B.
        • et al.
        Suppression of tissue inhibitor of metalloproteinase-1 by recombinant adeno-associated viruses carrying siRNAs in hepatic stellate cells.
        Int J Mol Med. 2009; 24: 685-692
        • Cong M.
        • Liu T.
        • Wang P.
        • Fan X.
        • Yang A.
        • Bai Y.
        • et al.
        Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis.
        Am J Pathol. 2013; 182: 1607-1616
        • Zhang Q.
        • Shu F.L.
        • Jiang Y.F.
        • Huang X.E.
        Influence of expression plasmid of connective tissue growth factor and tissue inhibitor of metalloproteinase-1 shRNA on hepatic precancerous fibrosis in rats.
        Asian Pac J Cancer Prev. 2015; 16: 7205-7210
        • Murphy F.R.
        • Issa R.
        • Zhou X.
        • Ratnarajah S.
        • Nagase H.
        • Arthur M.J.
        • et al.
        Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis.
        J Biol Chem. 2002; 277: 11069-11076
        • Arthur M.J.
        • Mann D.A.
        • Iredale J.P.
        Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis.
        J Gastroenterol Hepatol. 1998; 13: S33-S38
        • Hu Y.B.
        • Li D.G.
        • Lu H.M.
        Modified synthetic siRNA targeting tissue inhibitor of metalloproteinase-2 inhibits hepatic fibrogenesis in rats.
        J Gene Med. 2007; 9: 217-229
        • Paez J.
        • Sellers W.R.
        PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling.
        Cancer Treat Res. 2003; 115: 145-167
        • Peng Y.
        • Yang H.
        • Wang N.
        • Ouyang Y.
        • Yi Y.
        • Liao L.
        • et al.
        Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells.
        Am J Physiol Gastrointest Liver Physiol. 2014; 306: G253-G263
        • Xiao Y.
        • Qu C.
        • Ge W.
        • Wang B.
        • Wu J.
        • Xu L.
        • et al.
        Depletion of thymosin beta4 promotes the proliferation, migration, and activation of human hepatic stellate cells.
        Cell Physiol Biochem. 2014; 34: 356-367
        • Tu W.
        • Ye J.
        • Wang Z.J.
        Embryonic liver fordin is involved in glucose glycolysis of hepatic stellate cell by regulating PI3K/Akt signaling.
        World J Gastroenterol. 2016; 22: 8519-8527
        • Li X.
        • Yao Q.Y.
        • Liu H.C.
        • Jin Q.W.
        • Xu B.L.
        • Zhang S.C.
        • et al.
        Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease.
        J Cell Mol Med. 2017; 21: 2370-2385
        • Ge S.
        • Xiong Y.
        • Wu X.
        • Xie J.
        • Liu F.
        • He J.
        • et al.
        Role of growth factor receptor-bound 2 in CCl4-induced hepatic fibrosis.
        Biomed Pharmacother. 2017; 92: 942-951
        • Zhang X.
        • Tan Z.
        • Wang Y.
        • Tang J.
        • Jiang R.
        • Hou J.
        • et al.
        PTPRO-associated hepatic stellate cell activation plays a critical role in liver fibrosis.
        Cell Physiol Biochem. 2015; 35: 885-898
        • Xiao Y.
        • Wang J.
        • Chen Y.
        • Zhou K.
        • Wen J.
        • Wang 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.
        Cell Signal. 2014; 26: 925-932
        • Gilmore T.D.
        Introduction to NF-kappaB: players, pathways, perspectives.
        Oncogene. 2006; 25: 6680-6684
        • Hayden M.S.
        • Ghosh S.
        Signaling to NF-kappaB.
        Genes Dev. 2004; 18: 2195-2224
        • Mohamed A.K.
        • Bierhaus A.
        • Schiekofer S.
        • Tritschler H.
        • Ziegler R.
        • Nawroth P.P.
        The role of oxidative stress and NF-kappaB activation in late diabetic complications.
        Biofactors. 1999; 10: 157-167
        • Lohwasser C.
        • Neureiter D.
        • Popov Y.
        • Bauer M.
        • Schuppan D.
        Role of the receptor for advanced glycation end products in hepatic fibrosis.
        World J Gastroenterol. 2009; 15: 5789-5798
        • Cai X.G.
        • Xia J.R.
        • Li W.D.
        • Lu F.L.
        • Liu J.
        • Lu Q.
        • et al.
        Anti-fibrotic effects of specific-siRNA targeting of the receptor for advanced glycation end products in a rat model of experimental hepatic fibrosis.
        Mol Med Rep. 2014; 10: 306-314
        • Liu X.
        • Wu Y.
        • Yang Y.
        • Li W.
        • Huang C.
        • Meng X.
        • et al.
        Role of NLRC5 in progression and reversal of hepatic fibrosis.
        Toxicol Appl Pharmacol. 2016; 294: 43-53
        • Lou D.
        • Han J.
        • Zhou L.
        • Ma H.
        • Xv J.
        • Shou J.
        • et al.
        Fibroblast growth factor receptor 1 antagonism attenuates lipopolysaccharide-induced activation of hepatic stellate cells via suppressing inflammation.
        Exp Ther Med. 2018; 16: 2909-2916
        • Hyun J.
        • Jung Y.
        MicroRNAs in liver fibrosis: focusing on the interaction with hedgehog signaling.
        World J Gastroenterol. 2016; 22: 6652-6662
        • Ha M.
        • Kim V.N.
        Regulation of microRNA biogenesis.
        Nat Rev Mol Cell Biol. 2014; 15: 509-524
        • Bartel D.P.
        MicroRNAs: target recognition and regulatory functions.
        Cell. 2009; 136: 215-233
        • Ji F.
        • Wang K.
        • Zhang Y.
        • Mao X.L.
        • Huang Q.
        • Wang J.
        • et al.
        MiR-542-3p controls hepatic stellate cell activation and fibrosis via targeting BMP-7.
        J Cell Biochem. 2019; 120: 4573-4581
        • Murakami Y.
        • Toyoda H.
        • Tanaka M.
        • Kuroda M.
        • Harada Y.
        • Matsuda F.
        • et al.
        The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families.
        PLoS One. 2011; 6: e16081
        • Kitano M.
        • Bloomston P.M.
        Hepatic stellate cells and microRNAs in pathogenesis of liver fibrosis.
        J Clin Med. 2016; 5
        • Czech M.P.
        MicroRNAs as therapeutic targets.
        N Engl J Med. 2006; 354: 1194-1195
        • Krutzfeldt J.
        • Rajewsky N.
        • Braich R.
        • Rajeev K.G.
        • Tuschl T.
        • Manoharan M.
        • et al.
        Silencing of microRNAs in vivo with ‘antagomirs’.
        Nature. 2005; 438: 685-689
        • Janssen H.L.
        • Reesink H.W.
        • Lawitz E.J.
        • Zeuzem S.
        • Rodriguez-Torres M.
        • Patel K.
        • et al.
        Treatment of HCV infection by targeting microRNA.
        N Engl J Med. 2013; 368: 1685-1694
        • Thakral S.
        • Ghoshal K.
        miR-122 is a unique molecule with great potential in diagnosis, prognosis of liver disease, and therapy both as miRNA mimic and antimir.
        Curr Gene Ther. 2015; 15: 142-150
        • Ning Z.W.
        • Luo X.Y.
        • Wang G.Z.
        • Li Y.
        • Pan M.X.
        • Yang R.Q.
        • et al.
        MicroRNA-21 mediates angiotensin II-induced liver fibrosis by activating NLRP3 inflammasome/IL-1beta axis via targeting Smad7 and Spry1.
        Antioxid Redox Signal. 2017; 27: 1-20
        • Caviglia J.M.
        • Yan J.
        • Jang M.K.
        • Gwak G.Y.
        • Affo S.
        • Yu L.
        • et al.
        MicroRNA-21 and Dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis.
        Hepatology. 2018; 67: 2414-2429
        • You K.
        • Li S.Y.
        • Gong J.
        • Fang J.H.
        • Zhang C.
        • Zhang M.
        • et al.
        MicroRNA-125b promotes hepatic stellate cell activation and liver fibrosis by activating RhoA signaling.
        Mol Ther Nucleic Acids. 2018; 12: 57-66
        • Chen Y.
        • Ou Y.
        • Dong J.
        • Yang G.
        • Zeng Z.
        • Liu Y.
        • et al.
        Osteopontin promotes collagen I synthesis in hepatic stellate cells by miRNA-129-5p inhibition.
        Exp Cell Res. 2018; 362: 343-348
        • Wang Y.Z.
        • Zhang W.
        • Wang Y.H.
        • Fu X.L.
        • Xue C.Q.
        Repression of liver cirrhosis achieved by inhibitory effect of miR-454 on hepatic stellate cells activation and proliferation via Wnt10a.
        J Biochem. 2019; 165: 361-367
        • Zhu D.
        • He X.
        • Duan Y.
        • Chen J.
        • Wang J.
        • Sun X.
        • et al.
        Expression of microRNA-454 in TGF-beta1-stimulated hepatic stellate cells and in mouse livers infected with Schistosoma japonicum.
        Parasit Vectors. 2014; 7: 148
        • Sicklick J.K.
        • Li Y.X.
        • Choi S.S.
        • Qi Y.
        • Chen W.
        • Bustamante M.
        • et al.
        Role for hedgehog signaling in hepatic stellate cell activation and viability.
        Lab Invest. 2005; 85: 1368-1380
        • Hyun J.
        • Wang S.
        • Kim J.
        • Rao K.M.
        • Park S.Y.
        • Chung I.
        • et al.
        MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression.
        Nat Commun. 2016; 7: 10993
        • Yang L.
        • Wang Y.
        • Mao H.
        • Fleig S.
        • Omenetti A.
        • Brown K.D.
        • et al.
        Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells.
        J Hepatol. 2008; 48: 98-106
        • Hyun J.
        • Wang S.
        • Kim J.
        • Kim G.J.
        • Jung Y.
        MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells.
        Sci Rep. 2015; 5: 14135
        • Zeng C.
        • Wang Y.L.
        • Xie C.
        • Sang Y.
        • Li T.J.
        • Zhang M.
        • et al.
        Identification of a novel TGF-beta-miR-122-fibronectin 1/serum response factor signaling cascade and its implication in hepatic fibrogenesis.
        Oncotarget. 2015; 6: 12224-12233
        • Li J.
        • Ghazwani M.
        • Zhang Y.
        • Lu J.
        • Fan J.
        • Gandhi C.R.
        • et al.
        miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression.
        J Hepatol. 2013; 58: 522-528
        • Lou G.
        • Yang Y.
        • Liu F.
        • Ye B.
        • Chen Z.
        • Zheng M.
        • et al.
        MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis.
        J Cell Mol Med. 2017; 21: 2963-2973
        • Catela Ivkovic T.
        • Voss G.
        • Cornella H.
        • Ceder Y.
        microRNAs as cancer therapeutics: a step closer to clinical application.
        Cancer Lett. 2017; 407: 113-122
        • Hayes C.N.
        • Chayama K.
        MicroRNAs as biomarkers for liver disease and hepatocellular carcinoma.
        Int J Mol Sci. 2016; 17: 280
        • Mokdad A.A.
        • Lopez A.D.
        • Shahraz S.
        • Lozano R.
        • Mokdad A.H.
        • Stanaway J.
        • et al.
        Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis.
        BMC Med. 2014; 12: 145
        • de Martel C.
        • Maucort-Boulch D.
        • Plummer M.
        • Franceschi S.
        World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma.
        Hepatology. 2015; 62: 1190-1200
        • Waidmann O.
        • Koberle V.
        • Brunner F.
        • Zeuzem S.
        • Piiper A.
        • Kronenberger B.
        Serum microRNA-122 predicts survival in patients with liver cirrhosis.
        PLoS One. 2012; 7: e45652
        • Appourchaux K.
        • Dokmak S.
        • Resche-Rigon M.
        • Treton X.
        • Lapalus M.
        • Gattolliat C.H.
        • et al.
        MicroRNA-based diagnostic tools for advanced fibrosis and cirrhosis in patients with chronic hepatitis B and C.
        Sci Rep. 2016; 6: 34935
        • Nakamura M.
        • Kanda T.
        • Jiang X.
        • Haga Y.
        • Takahashi K.
        • Wu S.
        • et al.
        Serum microRNA-122 and Wisteria floribunda agglutinin-positive Mac-2 binding protein are useful tools for liquid biopsy of the patients with hepatitis B virus and advanced liver fibrosis.
        PLoS One. 2017; 12e0177302
        • Roderburg C.
        • Mollnow T.
        • Bongaerts B.
        • Elfimova N.
        • Vargas Cardenas D.
        • Berger K.
        • et al.
        Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis.
        PLoS One. 2012; 7: e32999
        • Jansen C.
        • Eischeid H.
        • Goertzen J.
        • Schierwagen R.
        • Anadol E.
        • Strassburg C.P.
        • et al.
        The role of miRNA-34a as a prognostic biomarker for cirrhotic patients with portal hypertension receiving TIPS.
        PLoS One. 2014; 9e103779
        • Li B.B.
        • Li D.L.
        • Chen C.
        • Liu B.H.
        • Xia C.Y.
        • Wu H.J.
        • et al.
        Potentials of the elevated circulating miR-185 level as a biomarker for early diagnosis of HBV-related liver fibrosis.
        Sci Rep. 2016; 6: 34157