The Role of MiR-29 in the Mechanism of Fibrosis

Min      Wang; Zhiying      Huo; Xiaoyan      He; Fuyou      Liu; Jingtao      Liang; Lijuan      Wu; Dongdong      Yang
doi:10.2174/1389557523666230328125031
Abstract

Fibrosis is a pathological process characterized by tissue scarring that can occur in various human body organs. The fibrosis of the organ is manifested as an increase in fibrous connective tissue and a decrease in parenchymal cells in the organ tissue, leading to structural damage and functional decline of the organ. At present, the incidence and medical burden of fibrosis are increasing worldwide, which has presented severe negative impacts on human health. Although many of the cellular and molecular processes for underlying fibrosis have been discerned, there are still gaps for effective therapies and target fibrogenesis specifically. Recent studies have shown that the microRNA- 29 family (miR-29a, b, c) plays an essential role in the process of multiorgan fibrosis. It is a class of highly conserved single-stranded noncoding RNAs composed of 20-26 nucleotides. Through its 5' untranslated region (UTR) pairing with the 3'UTR of the target mRNA, the mRNA of the target gene is degraded to complete the physiological process of inhibiting the transcription and translation of the target gene. Here, we summarize the interaction of miR-29 with multiple cytokines, describe the mechanism by which miR-29 regulates major fibrotic pathways such as TGF- β1/Smad, PI3K/Akt/mTOR, DNA methylation, and found that miR-29 is closely linked to epithelial- mesenchymal transition (EMT). These findings point to a common or similar regulatory mechanism by miR-29 in fibrogenesis. Finally, we review the antifibrotic activity of miR-29 mimicked in current studies and highlight miR-29 as a promising therapeutic reagent or target for the treatment of pulmonary fibrosis. Besides, there is an urgent need to screen and identify small compounds to modulate miR-29 expression in vivo.
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[1]
LagosQuintana. M.; Rauhut, R.; Lendeckel, W.; Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science,  2001, 294(5543), 853-858.

[2]
Jiang, X.; Tsitsiou, E.; Herrick, S.E.; Lindsay, M.A. MicroRNAs and the regulation of fibrosis. FEBS J.,  2010, 277(9), 2015-2021.
 [http://dx.doi.org/10.1111/j.1742-4658.2010.07632.x] [PMID:  20412055]

[3]
Bartel, D.P. MicroRNAs: Geomics, biogenesis, mechanism and function. Cell,  2004, 116(2), 281-297.
 [http://dx.doi.org/10.1016/S0092-8674(04)00045-5] [PMID:  14744438]

[4]
Shruti, K.; Shrey, K.; Vibha, R. Micro RNAs: Tiny sequences with enormous potential. Biochem. Biophys. Res. Commun.,  2011, 407(3), 445-449.
 [http://dx.doi.org/10.1016/j.bbrc.2011.03.058] [PMID:  21419103]

[5]
Patel, V.; Noureddine, L. MicroRNAs and fibrosis. Curr. Opin. Nephrol. Hypertens.,  2012, 21(4), 410-416.
 [http://dx.doi.org/10.1097/MNH.0b013e328354e559] [PMID:  22622653]

[6]
Ogawa, T.; Iizuka, M.; Sekiya, Y.; Yoshizato, K.; Ikeda, K.; Kawada, N. Suppression of type I collagen production by microRNA-29b in cultured human stellate cells. Biochem. Biophys. Res. Commun.,  2010, 391(1), 316-321.
 [http://dx.doi.org/10.1016/j.bbrc.2009.11.056] [PMID:  19913496]

[7]
Xiao, J.; Meng, X.M.; Huang, X.R.; Chung, A.C.K.; Feng, Y.L.; Hui, D.S.C.; Yu, C.M.; Sung, J.J.Y.; Lan, H.Y. miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice. Mol. Ther.,  2012, 20(6), 1251-1260.
 [http://dx.doi.org/10.1038/mt.2012.36] [PMID:  22395530]

[8]
Cushing, L.; Kuang, P.P.; Qian, J.; Shao, F.; Wu, J.; Little, F.; Thannickal, V.J.; Cardoso, W.V.; Lü, J. miR-29 is a major regulator of genes associated with pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol.,  2011, 45(2), 287-294.
 [http://dx.doi.org/10.1165/rcmb.2010-0323OC] [PMID:  20971881]

[9]
Abreu, J.G.; Ketpura, N.I.; Reversade, B.; De Robertis, E.M. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β. Nat. Cell Biol.,  2002, 4(8), 599-604.
 [http://dx.doi.org/10.1038/ncb826] [PMID:  12134160]

[10]
Weiskirchen, R.; Weiskirchen, S.; Tacke, F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol. Aspects Med.,  2019, 65, 2-15.
 [http://dx.doi.org/10.1016/j.mam.2018.06.003] [PMID:  29958900]

[11]
van Rooij, E.; Olson, E.N. MicroRNA therapeutics for cardiovascular disease: Opportunities and obstacles. Nat. Rev. Drug Discov.,  2012, 11(11), 860-872.
 [http://dx.doi.org/10.1038/nrd3864] [PMID:  23080337]

[12]
He, Y.; Huang, C.; Lin, X.; Li, J. MicroRNA-29 family, a crucial therapeutic target for fibrosis diseases. Biochimie,  2013, 95(7), 1355-1359.
 [http://dx.doi.org/10.1016/j.biochi.2013.03.010] [PMID:  23542596]

[13]
Pandit, K.V.; Milosevic, J.; Kaminski, N. MicroRNAs in idiopathic pulmonary fibrosis. Transl. Res.,  2011, 157(4), 191-199.
 [http://dx.doi.org/10.1016/j.trsl.2011.01.012] [PMID:  21420029]

[14]
Ho, J.; Ng, K.H.; Rosen, S.; Dostal, A.; Gregory, R.I.; Kreidberg, J.A. Podocyte-specific loss of functional microRNAs leads to rapid glomerular and tubular injury. J. Am. Soc. Nephrol.,  2008, 19(11), 2069-2075.
 [http://dx.doi.org/10.1681/ASN.2008020162] [PMID:  18832437]

[15]
Zhang, X.; Liao, C.; Sun, K.; Liu, L.; Xu, D. A soluble epoxide hydrolase inhibitor upregulated KCNJ12 and KCNIP2 by downregulating MicroRNA-29 in a mouse model of myocardial infarction. Heart Surg. Forum,  2020, 23(5), E579-E585.
 [http://dx.doi.org/10.1532/hsf.2999]

[16]
Montgomery, R.L.; Yu, G.; Latimer, P.A.; Stack, C.; Robinson, K.; Dalby, C.M.; Kaminski, N.; Rooij, E. Micro RNA mimicry blocks pulmonary fibrosis. EMBO Mol. Med.,  2014, 6(10), 1347-1356.
 [http://dx.doi.org/10.15252/emmm.201303604] [PMID:  25239947]

[17]
Rosenbloom, J.; Castro, S.V.; Jimenez, S.A. Narrative review: fibrotic diseases: Cellular and molecular mechanisms and novel therapies. Ann. Intern. Med.,  2010, 152(3), 159-166.
 [http://dx.doi.org/10.7326/0003-4819-152-3-201002020-00007] [PMID:  20124232]

[18]
Zhang, Y.; Huang, X.R.; Wei, L.H.; Chung, A.C.K.; Yu, C.M.; Lan, H.Y. miR-29b as a therapeutic agent for angiotensin ii-induced cardiac fibrosis by targeting TGF-β;/Smad3 signaling. Mol. Ther.,  2014, 22(5), 974-985.
 [http://dx.doi.org/10.1038/mt.2014.25] [PMID:  24569834]

[19]
Gondaliya, P.; P Dasare, A. Jash, K.; Tekade, R.K.; Srivastava, A.; Kalia, K. miR-29b attenuates histone deacetylase-4 mediated podocyte dysfunction and renal fibrosis in diabetic nephropathy. J. Diabetes Metab. Disord.,  2019, 19(1), 13-27.
 [http://dx.doi.org/10.1007/s40200-019-00469-0] [PMID:  32550152]

[20]
Khedr, L.H.; Rahmo, R.M.; Farag, D.B.; Schaalan, M.F.; El Magdoub, H.M. Crocin attenuates cisplatin-induced hepatotoxicity via TLR4/NF-κBp50 signaling and BAMBI modulation of TGF-β; activity: Involvement of miRNA-9 and miRNA-29. Food Chem. Toxicol.,  2020, 140, 111307.
 [http://dx.doi.org/10.1016/j.fct.2020.111307] [PMID:  32259551]

[21]
Bonner, J.C. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev.,  2004, 15(4), 255-273.

[22]
Klinkhammer, B.M.; Floege, J.; Boor, P. PDGF in organ fibrosis. Mol. Aspects Med.,  2018, 62, 44-62.
 [http://dx.doi.org/10.1016/j.mam.2017.11.008] [PMID:  29155002]

[23]
Nakamura, Y.; Tanaka, F.; Yoshikawa, Y.; Mimori, K.; Inoue, H.; Yanaga, K.; Mori, M. PDGF-BB is a novel prognostic factor in colorectal cancer. Ann. Surg. Oncol.,  2008, 15(8), 2129-2136.
 [http://dx.doi.org/10.1245/s10434-008-9943-9] [PMID:  18478301]

[24]
Corsinovi, D.; Giannetti, K.; Cericola, A.; Naef, V.; Ori, M. PDGFB: The missing piece in the mosaic of PDGF family role in craniofacial development. Dev. Dyn.,  2019, 248(7), 603-612.
 [http://dx.doi.org/10.1002/dvdy.47] [PMID:  31070827]

[25]
Yang, Y.; Dodbele, S.; Park, T.; Glass, R.; Bhat, K.; Sulman, E.P.; Zhang, Y.; Abounader, R. MicroRNA-29a inhibits glioblastoma stem cells and tumor growth by regulating the PDGF pathway. J. Neurooncol.,  2019, 145(1), 23-34.
 [http://dx.doi.org/10.1007/s11060-019-03275-z] [PMID:  31482267]

[26]
Sobrevals, L.; Rodriguez, C.; Romero Trevejo, J. Insulin-like growth factor I gene transfer to cirrhotic liver induces fibrolysis and reduces fibrogenesis leading to cirrhosis reversion in rats. Hepatology,  2010, 51(3), 912-921.
 [http://dx.doi.org/10.1002/hep.23412]

[27]
Sekiya, Y.; Ogawa, T.; Yoshizato, K.; Ikeda, K.; Kawada, N. Suppression of hepatic stellate cell activation by microRNA-29b. Biochem. Biophys. Res. Commun.,  2011, 412(1), 74-79.
 [http://dx.doi.org/10.1016/j.bbrc.2011.07.041] [PMID:  21798245]

[28]
Kwiecinski, M.; Elfimova, N.; Noetel, A.; Töx, U.; Steffen, H.M.; Hacker, U.; Nischt, R.; Dienes, H.P.; Odenthal, M. Expression of platelet-derived growth factor-C and insulin-like growth factor I in hepatic stellate cells is inhibited by miR-29. Lab. Invest.,  2012, 92(7), 978-987.
 [http://dx.doi.org/10.1038/labinvest.2012.70] [PMID:  22565577]

[29]
Yu, X.; Elfimova, N.; Müller, M.; Bachurski, D.; Koitzsch, U.; Drebber, U.; Mahabir, E.; Hansen, H.P.; Friedman, S.L.; Klein, S.; Dienes, H.P.; Hösel, M.; Buettner, R.; Trebicka, J.; Kondylis, V.; Mannaerts, I.; Odenthal, M. Autophagy-related activation of hepatic stellate cells reduces cellular mir-29a by promoting its vesicular secretion. Cell. Mol. Gastroenterol. Hepatol.,  2022, 13(6), 1701-1716.
 [http://dx.doi.org/10.1016/j.jcmgh.2022.02.013] [PMID:  35219894]

[30]
Wang, K.; Yu, J.; Wang, B.; Wang, H.; Shi, Z.; Li, G. miR-29a regulates the proliferation and migration of human arterial smooth muscle cells in arteriosclerosis obliterans of the lower extremities. Kidney Blood Press. Res.,  2019, 44(5), 1219-1232.
 [http://dx.doi.org/10.1159/000502649] [PMID:  31614351]

[31]
Parks, W.C.; Wilson, C.L.; López-Boado, Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol.,  2004, 4(8), 617-629.
 [http://dx.doi.org/10.1038/nri1418] [PMID:  15286728]

[32]
Aristorena, M.; Gallardo-Vara, E.; Vicen, M.; de Las Casas-Engel, M.; Ojeda-Fernandez, L.; Nieto, C.; Blanco, F.J.; Valbuena-Diez, A.C.; Botella, L.M.; Nachtigal, P.; Corbi, A.L.; Colmenares, M.; Bernabeu, C. MMP-12, Secreted by pro-inflammatory macrophages, targets endoglin in human macrophages and endothelial Cells. Int. J. Mol. Sci.,  2019, 20(12), 3107.
 [http://dx.doi.org/10.3390/ijms20123107] [PMID:  31242676]

[33]
Huang, D.; Xue, H.; Shao, W.; Wang, X.; Liao, H.; Ye, Y. Inhibiting effect of miR-29 on proliferation and migration of uterine leiomyoma via the STAT3 signaling pathway. Aging,  2022, 14(3), 1307-1320.
 [http://dx.doi.org/10.18632/aging.203873] [PMID:  35113040]

[34]
Shen, L.; Song, Y.; Fu, Y.; Li, P. MiR-29b mimics promotes cell apoptosis of smooth muscle cells via targeting on MMP-2. Cytotechnology,  2018, 70(1), 351-359.
 [http://dx.doi.org/10.1007/s10616-017-0150-z] [PMID:  28988362]

[35]
Cai, J.; Yin, G.; Lin, B.; Wang, X.; Liu, X.; Chen, X.; Yan, D.; Shan, G.; Qu, J.; Wu, S. Roles of NFκB-miR-29s-MMP-2 circuitry in experimental choroidal neovascularization. J. Neuroinflam.,  2014, 11(1), 88.
 [http://dx.doi.org/10.1186/1742-2094-11-88] [PMID:  24886609]

[36]
Feng, G.; Zha, Z.; Huang, Y.; Li, J.; Wang, Y.; Ke, W.; Chen, H.; Liu, L.; Song, Y.; Ge, Z. Sustained and bioresponsive two-stage delivery of therapeutic miRNA via polyplex micelle-loaded injectable hydrogels for inhibition of intervertebral disc fibrosis. Adv. Healthc. Mater.,  2018, 7(21), 1800623.
 [http://dx.doi.org/10.1002/adhm.201800623] [PMID:  30296017]

[37]
Chou, C.H.; Hung, C.S.; Liao, C.W.; Wei, L.H.; Chen, C.W.; Shun, C.T.; Wen, W.F.; Wan, C.H.; Wu, X.M.; Chang, Y.Y.; Wu, V.C.; Wu, K.D.; Lin, Y.H. IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis. Cardiovasc. Res.,  2018, 114(5), 690-702.
 [http://dx.doi.org/10.1093/cvr/cvy013] [PMID:  29360942]

[38]
Yang, Linglan; Engeland, Christopher G; Cheng, Bin Social isolation impairs oral palatal wound healing in sprague-dawley rats: A role for miR-29 and miR-203 via VEGF suppression. PLoS One,  2013, 8(8), e72359.

[39]
Hand, N.J.; Horner, A.M.; Master, Z.R.; Boateng, L.A.; LeGuen, C.; Uvaydova, M.; Friedman, J.R. MicroRNA profiling identifies miR-29 as a regulator of disease-associated pathways in experimental biliary atresia. J. Pediatr. Gastroenterol. Nutr.,  2012, 54(2), 186-192.
 [http://dx.doi.org/10.1097/MPG.0b013e318244148b] [PMID:  22167021]

[40]
Semik, Orzech A The roIe of interIeukin 17 cytokine famiIy in inducing aIIergic infIammation in the puImonary tract PneumonoI. AIergoI PoI,,  2006, 74(4), 409-413.

[41]
Zhang, Y.; Wang, J.H.; Zhang, Y.Y.; Wang, Y.Z.; Wang, J.; Zhao, Y.; Jin, X.X.; Xue, G.L.; Li, P.H.; Sun, Y.L.; Huang, Q.H.; Song, X.T.; Zhang, Z.R.; Gao, X.; Yang, B.F.; Du, Z.M.; Pan, Z.W. Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFβ;1 and miR-29 pathways. Sci. Rep.,  2016, 6(1), 23010.
 [http://dx.doi.org/10.1038/srep23010] [PMID:  26972749]

[42]
Yang, Y.L.; Kuo, H-C.; Wang, F-S.; Huang, Y-H. MicroRNA-29a Disrupts DNMT3b to ameliorate diet-induced non-alcoholic steatohepatitis in mice. Int. J. Mol. Sci.,  2019, 20(6), 1499.
 [http://dx.doi.org/10.3390/ijms20061499]

[43]
Ortega, P.A.S.; Saulle, I.; Mercurio, V.; Ibba, S.V.; Lori, E.M.; Fenizia, C.; Masetti, M.; Trabattoni, D.; Caputo, S.L.; Vichi, F.; Mazzotta, F.; Clerici, M.; Biasin, M. Interleukin 21 (IL-21)/microRNA-29 (miR-29) axis is associated with natural resistance to HIV-1 infection. AIDS,  2018, 32(17), 2453-2461.
 [http://dx.doi.org/10.1097/QAD.0000000000001938] [PMID:  30005016]

[44]
Adoro, S.; Cubillos-Ruiz, J.R.; Chen, X.; Deruaz, M.; Vrbanac, V.D.; Song, M.; Park, S.; Murooka, T.T.; Dudek, T.E.; Luster, A.D.; Tager, A.M.; Streeck, H.; Bowman, B.; Walker, B.D.; Kwon, D.S.; Lazarevic, V.; Glimcher, L.H. IL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection. Nat. Commun.,  2015, 6(1), 7562.
 [http://dx.doi.org/10.1038/ncomms8562] [PMID:  26108174]

[45]
Dubois-Camacho, K.; Diaz-Jimenez, D.; De la Fuente, M.; Quera, R.; Simian, D.; Martínez, M.; Landskron, G.; Olivares-Morales, M.; Cidlowski, J.A.; Xu, X.; Gao, G.; Xie, J.; Chnaiderman, J.; Soto-Rifo, R.; González, M.J.; Calixto, A.; Hermoso, M.A. Inhibition of miR-378a-3p by Inflammation Enhances IL-33 Levels: A novel mechanism of alarmin modulation in ulcerative colitis. Front. Immunol.,  2019, 10, 2449.
 [http://dx.doi.org/10.3389/fimmu.2019.02449] [PMID:  31824476]

[46]
Millar, N.L.; Gilchrist, D.S.; Akbar, M.; Reilly, J.H.; Kerr, S.C.; Campbell, A.L.; Murrell, G.A.C.; Liew, F.Y.; Kurowska-Stolarska, M.; McInnes, I.B. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat. Commun.,  2015, 6(1), 6774.
 [http://dx.doi.org/10.1038/ncomms7774] [PMID:  25857925]

[47]
Hinz, M.; Scheidereit, C. The IκB kinase complex in NF ‐κB regulation and beyond. EMBO Rep.,  2014, 15(1), 46-61.
 [http://dx.doi.org/10.1002/embr.201337983] [PMID:  24375677]

[48]
Sun, S.C. The non-canonical NF-κB pathway in immunity and inflammation. Nat. Rev. Immunol.,  2017, 17(9), 545-558.
 [http://dx.doi.org/10.1038/nri.2017.52] [PMID:  28580957]

[49]
Taniguchi, K. Karin, M. NF-κB, inflammation, immunity and cancer: Coming of age. Nat. Rev. Immunol.,  2018, 18(5), 309-324.
 [http://dx.doi.org/10.1038/nri.2017.142] [PMID:  29379212]

[50]
Fan, Z.; Qi, X.; Yang, W.; Xia, L.; Wu, Y. Melatonin Ameliorates Renal Fibrosis Through the Inhibition of NF-κB and TGF-β1/Smad3 Pathways in db/db Diabetic Mice. Arch. Med. Res.,  2020, 51(6), 524-534.
 [http://dx.doi.org/10.1016/j.arcmed.2020.05.008] [PMID:  32473749]

[51]
Feng, X.J.; Liu, S.X.; Wu, C.; Kang, P.P.; Liu, Q.J.; Hao, J.; Li, H.B.; Li, F.; Zhang, Y.J.; Fu, X.H.; Zhang, S.B.; Zuo, L.F. The PTEN/PI3K/Akt signaling pathway mediates HMGB1-induced cell proliferation by regulating the NF-κB/cyclin D1 pathway in mouse mesangial cells. Am. J. Physiol. Cell Physiol.,  2014, 306(12), C1119-C1128.
 [http://dx.doi.org/10.1152/ajpcell.00385.2013] [PMID:  24760979]

[52]
Wang, H.; Garzon, R.; Sun, H.; Ladner, K.J.; Singh, R.; Dahlman, J.; Cheng, A.; Hall, B.M.; Qualman, S.J.; Chandler, D.S.; Croce, C.M.; Guttridge, D.C. NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell,  2008, 14(5), 369-381.
 [http://dx.doi.org/10.1016/j.ccr.2008.10.006] [PMID:  18977326]

[53]
Mannaerts, I.; Eysackers, N.; Onyema, O.O.; Van Beneden, K.; Valente, S.; Mai, A.; Odenthal, M.; van Grunsven, L.A. Class II HDAC inhibition hampers hepatic stellate cell activation by induction of microRNA-29. PLoS One,  2013, 8(1), e55786.
 [http://dx.doi.org/10.1371/journal.pone.0055786] [PMID:  23383282]

[54]
Mott, J.L.; Kurita, S.; Cazanave, S.C.; Bronk, S.F.; Werneburg, N.W.; Fernandez-Zapico, M.E. Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, hedgehog, and NF-kappaB. J. Cell. Biochem.,  2010, 110(5), 1155-1164.
 [http://dx.doi.org/10.1002/jcb.22630] [PMID:  20564213]

[55]
Hu, N.; Guo, C.; Dai, X.; Wang, C.; Gong, L.; Yu, L.; Peng, C.; Li, Y. Forsythiae Fructuse water extract attenuates liver fibrosis via TLR4/MyD88/NF-κB and TGF-β/smads signaling pathways. J. Ethnopharmacol.,  2020, 262, 113275.
 [http://dx.doi.org/10.1016/j.jep.2020.113275] [PMID:  32810620]

[56]
Liu, C.; Chen, X.; Yang, L.; Kisseleva, T.; Brenner, D.A.; Seki, E. Transcriptional repression of the transforming growth factor β (TGF-β) Pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 enhances TGF-β signaling in hepatic stellate cells. J. Biol. Chem.,  2014, 289(10), 7082-7091.
 [http://dx.doi.org/10.1074/jbc.M113.543769] [PMID:  24448807]

[57]
Qiang, Jian; Dan, Li; Wei, CHENG Tiantian, TANG Mechanismof Mir-29a-3p reducing airway inflammation in children with asthma by targeting HMGB1/TLR4/NF-kB signaling axis Int. J. Lab.Med.,  43(18), 2201-2206.

[58]
Huexia, Qu; Xiaofeng, Yuan Xin, Qu LncRNA NEAT1 regulatesTLR4/NF-kB signaling pathway by targeting Mir-29B-3p to inhibit hippocampal neuron apoptosis in epilepsy model Chin. J. Child.Health,,  2022, 1-6.

[59]
Murphy, K.M.; Reiner, S.L. The lineage decisions of helper T cells. Nat. Rev. Immunol.,  2002, 2(12), 933-944.
 [http://dx.doi.org/10.1038/nri954] [PMID:  12461566]

[60]
Aikaterini, S. Papadopoulou, James Dooley, Michelle A Linterman. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-alpha receptor. Nat. Immunol.,  2012, 13(2), 181-187.

[61]
Roderick, J.E.; Gonzalez-Perez, G.; Kuksin, C.A.; Dongre, A.; Roberts, E.R.; Srinivasan, J.; Andrzejewski, C., Jr; Fauq, A.H.; Golde, T.E.; Miele, L.; Minter, L.M. Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia. J. Exp. Med.,  2013, 210(7), 1311-1329.
 [http://dx.doi.org/10.1084/jem.20112615] [PMID:  23733784]

[62]
Romina, Dieli-Crimi; Martínez-Gallo, Mónica; Franco-Jarava,
Clara; Antolin, Maria; Blasco, Laura; Paramonov, Ida; Semidey,
Maria E; Molero, Antoni Álvarez; Velásquez, Julio; Martín-Nalda,
Andrea; Pujol-Borrell, Ricardo; Colobran, Roger Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1- deficient patient with CVID and severe gastrointestinal manifestations. Clin. Immunol.,  2018, 195, 49-58.

[63]
Chandiran, K.; Lawlor, R.; Pannuti, A.; Perez, G.G.; Srinivasan, J.; Golde, T.E.; Miele, L.; Osborne, B.A.; Minter, L.M. Notch1 primes CD4 T cells for T helper type I differentiation through its early effects on miR-29. Mol. Immunol.,  2018, 99, 191-198.
 [http://dx.doi.org/10.1016/j.molimm.2018.05.002] [PMID:  29807327]

[64]
Ma, F.; Xu, S.; Liu, X.; Zhang, Q.; Xu, X.; Liu, M.; Hua, M.; Li, N.; Yao, H.; Cao, X. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nat. Immunol.,  2011, 12(9), 861-869.
 [http://dx.doi.org/10.1038/ni.2073] [PMID:  21785411]

[65]
Yu, X.; Li, R.; He, L.; Ding, X.; Liang, Y.; Peng, W.; Shi, H.; Lin, H.; Zhang, Y.; Lu, D. MicroRNA-29b modulates the innate immune response by suppressing IFNγs production in orange-spotted grouper (Epinephelus coioides). Fish Shellfish Immunol.,  2020, 104, 537-544.
 [http://dx.doi.org/10.1016/j.fsi.2020.05.057]

[66]
Matsubara, H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ. Res.,  1998, 83(12), 1182-1191.
 [http://dx.doi.org/10.1161/01.RES.83.12.1182] [PMID:  9851935]

[67]
Ruiz-Ortega, M.; Lorenzo, O.; Rupérez, M.; König, S.; Wittig, B.; Egido, J. Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms. Circ. Res.,  2000, 86(12), 1266-1272.
 [http://dx.doi.org/10.1161/01.RES.86.12.1266] [PMID:  10864918]

[68]
Dobaczewski, M.; Chen, W.; Frangogiannis, N.G. Transforming growth factor (TGF)-β signaling in cardiac remodeling. J. Mol. Cell. Cardiol.,  2011, 51(4), 600-606.
 [http://dx.doi.org/10.1016/j.yjmcc.2010.10.033] [PMID:  21059352]

[69]
Ma, F.; Li, Y.; Jia, L.; Han, Y.; Cheng, J.; Li, H.; Qi, Y.; Du, J. Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II. PLoS One,  2012, 7(5), e35144.
 [http://dx.doi.org/10.1371/journal.pone.0035144] [PMID:  22574112]

[70]
Wei, L.H.; Huang, X.R.; Zhang, Y.; Li, Y.Q.; Chen, H.; Heuchel, R.; Yan, B.P.; Yu, C.M.; Lan, H.Y. Deficiency of Smad7 enhances cardiac remodeling induced by angiotensin II infusion in a mouse model of hypertension. PLoS One,  2013, 8(7), e70195.
 [http://dx.doi.org/10.1371/journal.pone.0070195] [PMID:  23894614]

[71]
Nives, Pećina-Slaus Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int.,  2003, 3, 17.

[72]
Hu, H.; Hu, S.; Xu, S.; Gao, Y.; Zeng, F.; Shui, H. miR-29b regulates Ang II-induced EMT of rat renal tubular epithelial cells via targeting PI3K/AKT signaling pathway. Int. J. Mol. Med.,  2018, 42(1), 453-460.
 [http://dx.doi.org/10.3892/ijmm.2018.3579] [PMID:  29568897]

[73]
Sun, L.; Zhang, J.; Li, Y. Chronic central miR-29b antagonism alleviates angiotensin II-induced hypertension and vascular endothelial dysfunction. Life Sci.,  2019, 235, 116862.
 [http://dx.doi.org/10.1016/j.lfs.2019.116862] [PMID:  31513814]

[74]
Miyazawa, K.; Miyazono, K. Regulation of TGF-β Family Signaling by Inhibitory Smads. Cold Spring Harb. Perspect. Biol.,  2017, 9(3), a022095.
 [http://dx.doi.org/10.1101/cshperspect.a022095] [PMID:  27920040]

[75]
Chen, L.; Yang, T.; Lu, D.W.; Zhao, H.; Feng, Y.L.; Chen, H.; Chen, D.Q.; Vaziri, N.D.; Zhao, Y.Y. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. The EMBO
journal,  1998, 17(11), 3091-3100.

[76]
Chen, L.; Yang, T.; Lu, D.W. Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment. Biomed. Pharmacother.,  2018, 101, 670-681.
 [http://dx.doi.org/10.1016/j.biopha.2018.02.090]

[77]
Ma, T.T.; Meng, X.M. TGF-β/smad and renal fibrosis. Adv. Exp. Med. Biol.,  2019, 1165, 347-364.
 [http://dx.doi.org/10.1007/978-981-13-8871-2_16] [PMID:  31399973]

[78]
Lan, H.Y. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation. Int. J. Biol. Sci.,  2011, 7(7), 1056-1067.
 [http://dx.doi.org/10.7150/ijbs.7.1056] [PMID:  21927575]

[79]
Meng, X.M.; Huang, X.R.; Chung, A.C.K.; Qin, W.; Shao, X.; Igarashi, P.; Ju, W.; Bottinger, E.P.; Lan, H.Y. Smad2 protects against TGF-beta/Smad3-mediated renal fibrosis. J. Am. Soc. Nephrol.,  2010, 21(9), 1477-1487.
 [http://dx.doi.org/10.1681/ASN.2009121244] [PMID:  20595680]

[80]
Qin, W.; Chung, A.C.K.; Huang, X.R.; Meng, X.M.; Hui, D.S.C.; Yu, C.M.; Sung, J.J.Y.; Lan, H.Y. TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J. Am. Soc. Nephrol.,  2011, 22(8), 1462-1474.
 [http://dx.doi.org/10.1681/ASN.2010121308] [PMID:  21784902]

[81]
Luo, X.; Lin, H.; Pan, Z.; Xiao, J.; Zhang, Y.; Lu, Y.; Yang, B.; Wang, Z. Down-regulation of miR-1/miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart. J. Biol. Chem.,  2008, 283(29), 20045-20052.
 [http://dx.doi.org/10.1074/jbc.M801035200] [PMID:  18458081]

[82]
Fabregat, I.; Moreno-Càceres, J.; Sánchez, A.; Dooley, S.; Dewidar, B.; Giannelli, G.; ten Dijke, P. TGF-β signalling and liver disease. FEBS J.,  2016, 283(12), 2219-2232.
 [http://dx.doi.org/10.1111/febs.13665] [PMID:  26807763]

[83]
Liang, C.; Bu, S.; Fan, X. Suppressive effect of microRNA‐29b on hepatic stellate cell activation and its crosstalk with TGF‐β1/Smad3. Cell Biochem. Funct.,  2016, 34(5), 326-333.
 [http://dx.doi.org/10.1002/cbf.3193] [PMID:  27273381]

[84]
Kerr, L.D.; Miller, D.B.; Matrisian, L.M. TGF-β;1 inhibition of transin/stromelysin gene expression is mediated through a fos binding sequence. Cell,  1990, 61(2), 267-278.
 [http://dx.doi.org/10.1016/0092-8674(90)90807-Q] [PMID:  2110031]

[85]
Fedele, C.G.; Ooms, L.M.; Ho, M.; Vieusseux, J.; O’Toole, S.A.; Millar, E.K.; Lopez-Knowles, E.; Sriratana, A.; Gurung, R.; Baglietto, L.; Giles, G.G.; Bailey, C.G.; Rasko, J.E.J.; Shields, B.J.; Price, J.T.; Majerus, P.W.; Sutherland, R.L.; Tiganis, T.; McLean, C.A.; Mitchell, C.A. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc. Natl. Acad. Sci.,  2010, 107(51), 22231-22236.
 [http://dx.doi.org/10.1073/pnas.1015245107] [PMID:  21127264]

[86]
Cornu, M.; Albert, V.; Hall, M.N. mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev.,  2013, 23(1), 53-62.
 [http://dx.doi.org/10.1016/j.gde.2012.12.005] [PMID:  23317514]

[87]
Zhang, L.; Zhou, F.; ten Dijke, P. Signaling interplay between transforming growth factor-β; receptor and PI3K/AKT pathways in cancer. Trends Biochem. Sci.,  2013, 38(12), 612-620.
 [http://dx.doi.org/10.1016/j.tibs.2013.10.001] [PMID:  24239264]

[88]
Tao, Y.; Ying, L.; Lin, Q.; Liu, J.; Luo, F.; Li, X.; Hui, Z.; Sheng, Z.; Zhang, H. miR-29 mediates TGFβ; 1-induced extracellular matrix synthesis through activation of PI3K-AKT pathway in human lung fibroblasts. J. Cell. Biochem.,  2013, 114(6), 1336-1342.

[89]
Wang, P.; Liu, S.; Chao, Z.; Duan, Q.; Yue, J.; Gao, K.; Bu, Q.; Cao, B. An Xiaopeng. MiR-29 regulates the function of goat granulosa cell by targeting PTX3 via the PI3K/AKT/mTOR and Erk1/2 signaling pathways. J. Steroid Biochem. Mol. Biol.,  2020, 202, 105722.

[90]
Yang, Y.; Zhou, X.; Xiao, M.; Hong, Z.; Gong, Q.; Jiang, L.; Zhou, J. Erratum to: Discovery of chrysoeriol, a PI3K-AKT-mTOR pathway inhibitor with potent antitumor activity against human multiple myeloma cells in vitro. Curr. Med. Sci.,  2020, 40(6), 1203.
 [http://dx.doi.org/10.1007/s11596-020-2309-7] [PMID:  33428150]

[91]
Jia, W.; Chu Eagle, S.H.; Chen, H-Y. Kwan, Man; Minnie Y Y, Go; Huang, Xiao Ru; Lan, Hui Yao; Sung, Joseph J Y; Yu, Jun microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway. Oncotarget,  2015, 6(9), 7325-7338.

[92]
Yan, B.; Guo, Q.; Fu, F.J.; Wang, Z.; Yin, Z.; Wei, Y.B.; Yang, J.R. The role of miR-29b in cancer: Regulation, function, and signaling. OncoTargets Therapy.,  2015, 2015, 539-548.

[93]
Wang, Y.; Han, X.; Zang, T.; Kang, P.; Jiang, W.; Niu, N. miR 29b enhances the proliferation and migration of bone marrow mesenchymal stem cells in rats with castration induced osteoporosis through the PI3K/AKT and TGF β;/Smad signaling pathways. Exp. Ther. Med.,  2020, 20(4), 3185-3195.
 [http://dx.doi.org/10.3892/etm.2020.9045] [PMID:  32855687]

[94]
Hines, M.J.; Coffre, M.; Mudianto, T.; Panduro, M.; Wigton, E.J.; Tegla, C.; Osorio-Vasquez, V.; Kageyama, R.; Benhamou, D.; Perez, O.; Bajwa, S.; McManus, M.T.; Ansel, K.M.; Melamed, D.; Koralov, S.B. miR-29 Sustains B Cell Survival and Controls Terminal
Differentiation via Regulation of PI3K Signaling. Cell Rep.,  2020, 33(9), 108436.
 [http://dx.doi.org/10.1016/j.celrep.2020.108436] [PMID:  33264610]

[95]
Zaytseva, ekaterina Y.; Valentino, Joseph D.; Gulhati, Pat; Evers, B. Mark mTOR inhibitors in cancer therapy. Cancer Lett.,  2012, 319(1), 1-7.

[96]
Zeisberg, M.; Neilson, E.G. Biomarkers for epithelial-mesenchymal transitions. J. Clin. Invest.,  2009, 119(6), 1429-1437.
 [http://dx.doi.org/10.1172/JCI36183] [PMID:  19487819]

[97]
Cicchini, Carla; de Nonno, Valeria; Battistelli, Cecilia; Cozzolino, Angela Maria; Puzzonia, Marco De Santis; Ciafrè, Silvia Anna; Brocker, Chad; Gonzalez, Frank J.; Amicone, Laura; Tripodi, Marco Epigenetic control of EMT/MET dynamics: HNF4α impacts1858 Mini-Reviews in Medicinal Chemistry, 2023, Vol. 23, No. 19 Wang et al.DNMT3s through miRs-29. BBA. Gene Regula Mecha,  2015, 1849(8), 919-929.

[98]
Kristina, Kapinas.; Catherine, Kessler.; Tinisha, Rcks.; Gloria, Gronowicz.; Anne, M. Delany miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. J. Biol. Chem.,  2010, 285(33), 25221-25231.

[99]
Shin, J.; Shin, Y.; Oh, S-M.; Yang, H.; Yu, W-J.; Lee, J-P.; Huh, S-O.; Lee, S.H.; Suh, Y-H.; Chung, S.; Kim, H-S. MiR-29b controls fetal mouse neurogenesis by regulating ICAT-mediated Wnt/β;-catenin signaling. Cell Death Dis.,  2014, 5(10), e1473.
 [http://dx.doi.org/10.1038/cddis.2014.439] [PMID:  25321480]

[100]
Hou, J.; Jiang, S.; Zhao, J.; Dong, Z.; Zhao, X.; Cai, J-C. Zhang Si Qing. N-Myc-Interacting Protein Negatively Regulates TNF-α-Induced NF-kB Transcriptional Activity by Sequestering NF-kB/p65 in the Cytoplasm. Sci. Rep.,  2017, 7, 14579.
 [http://dx.doi.org/10.1038/s41598-017-15074-5]

[101]
Rostas Jack, W.; Pruitt Hawley, C.; Metge Brandon, J. Mitra, Aparna; Bailey, Sarah K; Bae, Sejong; Singh, Karan P; Devine, Daniel J; Dyess, Donna L; Richards, William O; Tucker, J Allan; Shevde, Lalita A; Samant, Rajeev S microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer. Mol. Cancer,  2014, 13(1), 200.

[102]
Gebeshuber, C.A.; Zatloukal, K.; Martinez, J. miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep.,  2009, 10(4), 400-405.
 [http://dx.doi.org/10.1038/embor.2009.9] [PMID:  19247375]

[103]
Bedi, U.; Mishra, V.K.; Wasilewski, D.; Scheel, C.; Johnsen, S.A. Epigenetic plasticity: A central regulator of epithelial-to-mesenchymal transition in cancer. Oncotarget,  2014, 5(8), 2016-2029.
 [http://dx.doi.org/10.18632/oncotarget.1875] [PMID:  24840099]

[104]
Carmona, F.J.; Davalos, V.; Vidal, E.; Gomez, A.; Heyn, H.; Hashimoto, Y.; Vizoso, M.; Martinez-Cardus, A.; Sayols, S.; Ferreira, H.J.; Sánchez-Mut, J.V.; Morán, S.; Margelí, M.; Castella, E.; Berdasco, M.; Stefansson, O.A.; Eyfjord, J.E.; Gonzalez-Suarez, E.; Dopazo, J.; Orozco, M.; Gut, I.G.; Esteller, M. A comprehensive DNA methylation profile of epithelial-to-mesenchymal transition. Cancer Res.,  2014, 74(19), 5608-5619.
 [http://dx.doi.org/10.1158/0008-5472.CAN-13-3659] [PMID:  25106427]

[105]
Fabbri, M.; Garzon, R.; Cimmino, A.; Liu, Z.; Zanesi, N.; Callegari, E.; Liu, S.; Alder, H.; Costinean, S.; Fernandez-Cymering, C.; Volinia, S.; Guler, G.; Morrison, C.D.; Chan, K.K.; Marcucci, G.; Calin, G.A.; Huebner, K.; Croce, C.M. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc. Natl. Acad. Sci. USA,  2007, 104(40), 15805-15810.
 [http://dx.doi.org/10.1073/pnas.0707628104] [PMID:  17890317]

[106]
Cheung, Hoi-Hung; Lee, Tin-Lap; Rennert, Owen M.; Chan, Wai-
Yee DNA methylation of cancer genome. Birth Defects Res. C Embryo Today,  2009, 87(4), 335-350.

[107]
Bian, E.B.; Huang, C.; Ma, T.T.; Tao, H.; Zhang, H.; Cheng, C.; Lv, X.W.; Li, J. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol. Appl. Pharmacol.,  2012, 264(1), 13-22.
 [http://dx.doi.org/10.1016/j.taap.2012.06.022] [PMID:  22841775]

[108]
Zheng, J.; Wu, C.; Lin, Z.; Guo, Y.; Shi, L.; Dong, P.; Lu, Z.; Gao, S.; Liao, Y.; Chen, B.; Yu, F. Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA-mediated control of DNA methylation - a novel mechanism suppressing liver fibrosis. FEBS J.,  2014, 281(1), 88-103.
 [http://dx.doi.org/10.1111/febs.12574] [PMID:  24138392]

[109]
Hysolli, E.; Tanaka, Y.; Su, J.; Kim, K.Y.; Zhong, T.; Janknecht, R.; Zhou, X.L.; Geng, L.; Qiu, C.; Pan, X.; Jung, Y.W.; Cheng, J.; Lu, J.; Zhong, M.; Weissman, S.M.; Park, I.H. Regulation of the DNA methylation landscape in human somatic cell reprogramming by the mir-29 family. Stem Cell Reports,  2016, 7(1), 43-54.
 [http://dx.doi.org/10.1016/j.stemcr.2016.05.014] [PMID:  27373925]

[110]
Luna, C; Li, G Qiu, J Role of miR-29b on the regulation of the extracellular matrix in human trabecular meshwork cells under	chronic oxidative stress Molecular Vision.,  2009, 15(263-67), 2488-2497.

[111]
Chen, J.Q.; Papp, G.; Póliska, S.; Szabó, K.; Tarr, T.; Bálint, B.L.; Szodoray, P.; Zeher, M. MicroRNA expression profiles identify disease-specific alterations in systemic lupus erythematosus and primary Sjögren’s syndrome. PLoS One,  2017, 12(3), e0174585.
 [http://dx.doi.org/10.1371/journal.pone.0174585]

[112]
Babak, O.; Mehdi, A. Gorgani, Habib-o-Lah; Farahini, Hossein; Moghtadaei, Mehdi; Boddouhi, Bahram; Kaghazian, Peyman; Hosseinzadeh, Shayan; Alaee, Atefe MicroRNAs signatures, bioinformatics analysis of miRNAs, miRNA mimics and antagonists, and miRNA therapeutics in osteosarcoma. Cancer Cell Int.,  2020, 20(18), 1-18.

[113]
Peacock, H.; Kannan, A.; Beal, P.A.; Burrows, C.J. Chemical modification of siRNA bases to probe and enhance RNA interference. J. Org. Chem.,  2011, 76(18), 7295-7300.
 [http://dx.doi.org/10.1021/jo2012225] [PMID:  21834582]

[114]
Masayuki, Matsui.; Thazha, P. Prakash; David R, MCoreyatsui Argonaute 2-dependent regulation of gene expression by single-stranded miRNA mimics. Molecular therapy.,  2016, 24(5), 946-955.
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DOI https://dx.doi.org/10.2174/1389557523666230328125031	Print ISSN 1389-5575
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Mini-Reviews in Medicinal Chemistry

The Role of MiR-29 in the Mechanism of Fibrosis

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