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Review Article

Regulatory Mechanisms of the Molecular Pathways in Fibrosis Induced by MicroRNAs

Yang, Cui1; Zheng, Si-Dao2,; Wu, Hong-Jin3; Chen, Shao-Jun1

Author Information

1Department of Cardiology, Huairou Hospital of Traditional Chinese Medicine, Beijing 101400, China

2Department of Cardiology, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China

3Department of Cardiology, Beijing Haidian Hospital, Haidian Section of Peking University Third Hospital, Beijing 100191, China

Address for correspondence: Dr. Si-Dao Zheng, Department of Cardiology, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China E-Mail: [email protected]

Received June 16, 2016

doi: 10.4103/0366-6999.190677
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Abstract

INTRODUCTION

MicroRNAs (miRNAs or miRs) are a class of noncoding endogenous RNA molecules that are ~22 nucleotides in length and are produced by two RNase III proteins (Drosha and Dicer). miRNAs are discovered in 1993 in Caenorhabditis elegans and are pivotal regulatory agents for messenger RNA (mRNA) expression at the posttranscriptional level.[12] Different miRNA biogenesis pathways might exist, but the ultimate effect remains the same: The silencing of target mRNAs.[2] By base pairing with the 3' untranslated region (UTR) of the target mRNA, the miRNA induces translational repression and mRNA decay through the RNA-induced silencing complex, in which the Argonaute proteins function as RNA silencing effectors.

Tissue fibrosis driven by primary injury to organs might switch from its adaptive features in the short term to parenchymal scarring when the irritation remains for an excessively long period, eventually promoting cellular dysfunction and organ failure.[3] miRNAs have been suggested to play important roles in regulating fibrosis. For example, the regulatory effects on heart fibrosis of the miRNAs miR-21, miR-29, miR-30, andmiR-133, among others, have been studied.[4] Similarly, miR-29, miR-21, miR-433, miR-150, miR-let7, miR-324, and miR-200 affect kidney fibrosis,[5] andlet-7d, miR-15b, miR-19b, miR-21, miR-24, miR-29c, miR-145, and miR-155 affect radiation-induced fibrosis.[6] In this review, we have summarized the current knowledge of miRNA-induced regulatory effects on the molecular fibrosis pathways and uncovered their characteristics in different organs.

MICRORNA-RELATED CELL SIGNALING PATHWAYS IN FIBROSIS

Beyond the multiple cell types (inflammatory cells, epithelial cells, fibrogenic effector cells, endothelial cells, and others) involved in the fibrogenic response, three cellular signal transduction pathways play leading roles in the process of fibrosis: transforming growth factor-beta (TGF-β), mitogen-activated protein kinases (MAPKs) and integrins.[3]

MicroRNA-related transforming growth factor-beta pathway in fibrosis

Different ligands can bind to TGF-β receptors on the cell surface, allowing regulatory messages to be transferred into the cell by activating the signaling effectors and the Sma- and Mad-related proteins (Smads) and ultimately interacting with deoxyribonucleic acid.[7] Both Smad2 and Smad3 are activated by TGF-β, myostatin, or activin whereas Smad1, Smad5, and Smad8 are activated by bone morphogenetic proteins; the activation of these proteins results in the interaction with Smad4, leading to the modulation of target gene expression. Interestingly, activation of the TGF-β pathway also upregulates Smad6 and Smad7 expression, which can deactivate the pathway.[7] Evidence has also shown that Smad2 and Smad7 alleviate fibrosis whereas Smad3 promotes fibrosis.[8] Many miRNAs and their substrates are involved in regulating the TGF-β signal transduction pathway [Table 1].

T1-15
Table 1:
miRNA-related TGF-β pathway involved in fibrosis

MicroRNA-related mitogen-activated protein kinase pathways in fibrosis

The MAPKs, including p38 MAPK, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase in mammals, mediate signaling that is either triggered by extracellular stimuli, such as growth factors and cytokines, or intracellular stimuli.[48] The effector molecules of MAPKs play important roles in regulating cellular activities, including proliferation, differentiation, apoptosis, and survival. It is not surprising that the regulatory processes of MAPKs are induced by miRNAs, among which the roles of miR-29, miR-133, miR-146, miR-155, miR-350, miR-378, and miR-451 have been investigated [Table 2].

T2-15
Table 2:
miRNA-related MAPK pathway in fibrosis

MicroRNA-related integrin pathway in fibrosis

Integrins are composed of α and β subunits and act as surface receptors in all cell types except red blood cells.[59] In conjunction with extracellular receptors, integrins initiate the signal transduction pathways involved in the fibrotic process by coordinating with the intracellular integrin-linked kinase.[596061] Regulatory effects of miRNAs on integrin expression have been confirmed by studies on miR-29, miR-31, miR-17-92 cluster, miR-124, miR-126, miR-148b, and miR-184.[62] Here, we summarize the miRNAs involved in fibrosis, among which miR-21, miR-29, miR-133, miR-140, miR-146, miR-155, miR-199, miR-350, miR-378, and miR-451 play important roles [Table 3].

T3-15
Table 3:
miRNA-related integrin pathway in fibrosis

MICRORNA-RELATED SIGNALING PATHWAYS IN DIFFERENT TISSUES

Heart

Cardiac fibrosis is characterized by the aberrant proliferation of fibroblasts and excessive extracellular matrix (ECM) production in the myocardial interstitium, ultimately leading to heart failure. This process is regulated by many miRNAs and their targets.[1068]

MicroRNA-related transforming growth factor-beta pathway in cardiac fibrosis

By targeting the common ECM protein connective tissue growth factor (CTGF), miR-18a and miR-19b downregulated collagen (COL) 1A1 and COL3A1 expression, resulting in the alleviation of cardiac fibrosis in age-related heart failure induced by TGF-β activation.[69] A reciprocal loop has been identified between miR-21 and its target TGF receptor III, leading to ECM remodeling and fibrosis. Cardiac miR-21 was upregulated in infarcted hearts due to TGF-β1 activation whereas its target gene (TGF receptor III) was downregulated. However, low TGF receptor III expression could reinforce TGF-β1 activation.[10] miR-24 was protective against cardiac fibrosis in response to myocardial infarction depending on the suppressive effect on its target gene FURIN, through which the TGF-β signaling pathway was inhibited.[13] Upregulation of miR-29b due to TGF/Smad3 inactivation resulted in the downregulation of COL1A1, COL3A1, and alpha smooth muscle actin (α-SMA) and contributed to the cardioprotective effect of carvedilol against acute myocardial infarction-induced myocardial fibrosis.[16] Another study confirmed that the targets of miR-29b (insulin-like growth factor 1 and leukemia inhibitory factor) were involved in regulating cardiac fibroblast activation and ECM proliferation.[25] miR-101 was downregulated in infarcted heart in rats and in angiotensin-cultured cardiac fibroblasts. Interestingly, overexpression of miR-101 suppressed proliferation and COL production by suppressing its target c-Fos and the downstream protein TGF-β1.[31] The same protective effect ofmiR-122 for myocardial fibrosis in human aortic stenosis was revealed and was dependent on the targeting and inhibition of TGF-β1.[33] Studies showed that overexpression of miR-133a inhibited cardiac fibrosis in both diabetes and angiotensin II-dependent hypertension although the effector proteins differed for diabetes (fibronectin and COL4A1) and angiotensin II-dependent hypertension (COL1A1).[3452]

MicroRNA-related mitogen-activated protein kinase pathway in cardiac fibrosis

miR-378 blocked activation of Ras signaling in cardiac hypertrophy by targeting of the cardiac hypertrophy modulator growth factor receptor-bound protein 2, leading to the alleviation of cardiac remodeling.[56] However, miR-250 was sufficient to induce cardiac hypertrophy through the suppression of p38 and JNK protein synthesis by targeting MAPK11/14 and MAPK8/9 in rats with transverse aortic constriction.[55] These miRNAs (miR-378 and miR-250) played important roles countering one another in the regulation of the cardiac MAPK signal, and both were predicted to be targets for the prevention of cardiac fibrosis.

Lung

MicroRNA-related transforming growth factor-beta and integrin pathways in pulmonary fibrosis

miR-144 played an important role in fibroproliferation, leading to bronchiolitis obliterans syndrome after human lung transplantation.[35] Overexpression of miR-144 led to a reduction in TGF-β-induced factor homeobox 1 and an increase in profibrotic factors whereas knockdown of miR-144 diminished fibrogenesis.[35] miR-199a-5p overexpression in TGF-β-induced lung fibroblasts could promote pulmonary fibrosis by targeting caveolin-1, through which pulmonary fibroblasts proliferate, migrate, and differentiate into myofibroblasts.[70]

An interesting study revealed that the miR-29 expression level was inversely related to the expression of the profibrotic target genes laminin and integrin α as well as the severity of pulmonary fibrosis.[14] Moreover, miR-29 could be suppressed by TGF-β activation, supporting the hypothesis that both the TGF-β and integrin pathways were involved in pulmonary fibrosis mediated by miR-29, which could be an important potential target for medical practice. Finally, the study proved thatmiR-29 prevented bleomycin-induced fibrosis in the lungs; this finding was also supported by other research.[17] miR-29c, which targeted both matrix metalloproteinase 2 and integrin β1, could inhibit ECM proliferation and lung cancer cell adhesion to the ECM.[63]

Liver

MicroRNA-related transforming growth factor-beta pathway in liver fibrosis

miR-21 upregulated activation protein 1 by targeting programmed cell death protein 4 (PDCD4) in hepatic stellate cells (HSCs), thereby enhancing ECM production; however, the elevated activation protein 1 activity upregulated miR-21 expression to form an autofeedback loop and promoted the progression of liver fibrosis.[11] Unlike miR-21, miR-29 appeared to be a suppressor of hepatic fibrosis by downregulating COL1 and COL4 induced by TGF-β activation in HSCs.[18] The same antifibrotic effect was found with miR-30, whose target was Krüppel-like factor 11 (KFL11), which was an inhibitor of Smad7 in the TGF-β pathway.[28] miR-30 was able to deactivate HSCs by inhibiting TGF-β activation through the target and substrate mentioned previously. Interestingly, miR-122 was found to be an antifibrotic miRNA by downregulating prolyl 4-hydroxylase subunit alpha 1, thereby decreasing COL maturation and ECM production.[32] Another miRNA (miR-146a) also suppressed TGF-β-induced HSC activation and hepatic fibrosis development by targeting Smad4.[37]

MicroRNA-related mitogen-activated protein kinase pathway in liver fibrosis

In addition to PDCD4, Phosphatase and Tensin Homologue Deleted on Chromosome 10 was confirmed as another target of miR-21 that served as a mediator for AKT pathway regulation and HSC activation.[49] Insulin-like growth factor 1, platelet-derived growth factor c, phosphoinositide-3-kinase regulatory subunit 1, and protein kinase B were all thought to be involved in the antifibrotic effect of miR-29by deactivating HSCs, indicating an important role for MAPK in inducing fibrosis and the multiple antifibrotic effects of miR-29.[5051]

Kidney

MicroRNA-related transforming growth factor-beta pathway in kidney fibrosis

Fibrosis, which was one of the features of diabetic nephropathy (DN), could be reversed by miR-29b and the downregulation of its target genes specificity protein 1 (an effector for the TGF-β-Smad3-induced fibrotic response) and tbx21 (a transcription factor that enhances the Th1 immune response).[24] Moreover, miR-29 downregulation and the consequent upregulation of the target gene COL1A1 contributed to Ochratoxin A-induced COL formation and the development of kidney fibrosis.[19] In addition to miR-29b, miR-29c was shown to target specificity protein 1, thereby abolishing TGF-β1-induced COL1 production in kidney tubular epithelial cells (TECs).[47] miR-29c was upregulated by hypoxia-inducible factor α activation to inhibit the direct targets COL2A 1 and tropomyosin 1 and attenuate renal tubulointerstitial fibrosis.[26] Two other targets of miR-29 (A disintegrin and metalloprotease [ADAM] 12 and ADAM19) were reported to be effectors that antagonized TGF-β signaling-induced renal fibrosis.[15] miR-302, whose target was TGF-β receptor II, was reportedly upregulated in both unilateral ureteral obstruction-induced kidney fibrosis and mesangial cells treated with CTGF.[44] The study further showed that miR-302 was a mediator of the regulation of TGF-β by CTGF, thereby supporting an important role for miRNAs in preventing TGF-β-induced renal fibrosis.[44] Recent evidence showed that miR-346 could bind the 3’-UTR of Smad3/4, downregulate Smad3/4 expression, and block TGF-β signal activation, resulting in the amelioration of kidney fibrosis in DN.[45]

Other miRNAs were also thought to be involved in the regulation of TGF-β-related renal fibrosis. For example, miR-30e inhibited TGF-β1-induced ECM production in TECs by targeting mitochondrial uncoupling protein 2,[29] whereas miR-34a promoted kidney fibrosis by targeting Notch 1 and Jagged 1 in hypoxia-induced renal TECs.[30]

MicroRNA-related mitogen-activated protein kinases pathway in kidney fibrosis

miR-451 negatively regulated the expression of its target gene Ywhaz, which was required for the activation of p38 MAPK signaling, and inhibited glomerular mesangial cell proliferation in early DN, thus preventing mesangial hypertrophy.[58]

The roles and mechanisms of other miRNAs that regulate renal fibrosis could be found elsewhere.[5]

Skin

MicroRNA-related transforming growth factor-beta pathway in skin fibrosis

Smad7, which was one of the substrates that negatively regulate TGF-β signal-induced excessive fibrosis in systemic sclerosis (SSc), has been shown to be the target of miR-21, which was upregulated by bleomycin and downregulated by bortezomib.[9] The study suggested that miR-21 could be a new target for alimenting the fibrotic process of SSc. However, miR-29b acted as a protective regulator by targeting COL1A1 and COL1A2, leading to the deactivation of ECM production.[20] Unlike miR-21, miR-146a targeted Smad4 in TGF-β-stimulated HSCs, deactivating both HSCs and human dermal fibroblasts.[3738] In addition to Smad7 and Smad4, Smad3 was also a fibrotic miRNA target. A study showed that miR-145 inhibited the inflammatory response in cystic fibrosis by downregulating the Smad3 expression levels.[36]

MicroRNA-related integrin pathway in skin fibrosis

miR-378a inhibited fibroblast migration and differentiation by decreasing its targets integrin β3 and vimentin in vitro and suppressed wound healing of the skin in vivo, suggesting its pivotal role in regulating skin recovery.[67] miR-150 also targeted integrin β3, leading to decreased ECM production in SSc fibroblasts.[65]

Another report suggested that miR-152 reduced cellular adhesion and ECM remodeling in human dermal fibroblasts partially through integrin α5 downregulation.[66]

Other tissues

MicroRNA-related transforming growth factor-beta pathway

miR-21 was involved in TGF-β1 signal activation in the cancer stroma by targeting PDCD4 and promoting myofibroblast differentiation when miR-21 was downregulated, thereby inhibiting differentiation when upregulated.[12] miR-29 suppressed the transdifferentiation of myoblasts into myofibroblasts through the downregulation of the ECM genes.[21] The study further demonstrated that miR-29 was under negative regulation by TGF-β-Smad3 signaling by the dual mechanisms of MyoD binding inhibition and Yin Yang 1-recruited Polycomb association enhancement. Moreover, the study confirmed the final effector molecules under negative regulation by miR-29 were COL1A1, COL1A2, and COL3A1. Using similar targets, miR-29 inhibited profibrotic gene expression in periodontal ligament cells.[22] One additional study showed that miR-29bcould alleviate peritoneal dialysis-associated fibrosis by targeting specificity protein 1 and consequently inhibiting TGF-β1-Smad2/3 signaling.[23] It was obvious that the effects of miR-29were induced by multiple targets. Another miRNA (miR-200c) showed the same multi-target characteristic. This miRNA inhibited ECM remodeling in leiomyomas by targeting zinc finger e-box-binding homeobox, vascular endothelial growth factor a, tissue inhibitor of metalloproteinase 2, and FBLN 5.[41] By targeting TGF-β1, miR-744 was involved in many different pathophysiological processes, including fibrosis.[46] A recent study showed that miR-188-5pindirectly regulated COL1A1 and COL12A1 in the ECM of synovial fibroblasts in rheumatoid arthritis, suggesting a potential antifibrotic therapeutic effect.[39]

MicroRNA-related mitogen-activated protein kinase pathway

miR-146 inhibited interleukin (IL)-1β, IL-6, and tumor necrosis factor-α secretion through IL-1 receptor-associated kinase 1 in human gingival fibroblasts, indicating that miR-146 was a negative regulator of periodontal inflammation.[53] miR-155 (another MAPK-related miRNA) activated the PI3K/AKT signaling pathway through the promotion of the IL-8-dependent inflammatory response in cystic fibrosis lung epithelial cells by lowering SHIP1 expression.[54]

CONCLUSIONS

Fibrosis is mediated by different signaling pathways composed of cellular constituents, including inflammatory cells, epithelial cells, and fibrogenic effector cells, and is a general condition leading to organ injury and failure.[3] Although the cellular and molecular processes underlying fibrosis have been illustrated, the strategies and targets for the treatment of fibrosis are still unsatisfactory.[3] Epigenetic modification, including miRNA posttranscriptional modification, is capable of controlling the fibrotic process by regulating fibroblast activity, thereby providing a novel therapeutic target for the treatment of fibrosis.[371]

Based on the studies mentioned above and others, we conclude that special miRNAs are involved in fibroblast activation, ECM production, and other fibrotic processes and that moderating miRNA expression might be a novel therapy for fibrotic diseases.[17727374] A single fibrotic miRNA and related signaling pathway might show similar activity in different organs. For example, miR-199a-5p shows an elevated expression level in three types of organ fibrosis (unilateral ureteral obstruction model of the kidney, carbon tetrachloride-damaged liver, and bleomycin-treated lungs); the underlying mechanisms share a common regulatory mechanism involving the TGF-β signaling pathway.[70] Moreover, the miRNA-induced therapeutic effects of drugs such as bortezomib and carvedilol have been confirmed.[913] Thus, it is encouraging that blocking or reversing the fibrotic process can be achieved by targeting special miRNAs and their signaling pathways, thereby protecting the structures and functions of different organs.

Financial support and sponsorship

This study was supported by the grant from the Science Foundation for the Excellent Youth of Beijing (No. 2014000057592G296).

Conflicts of interest

There are no conflicts of interest.

REFERENCES

1. Yates LA, Norbury CJ, Gilbert RJ. The long and short of microRNA Cell. 2013;153:516–9 doi: 10.1016/j.cell.2013.04.003
2. Ha M, Kim VN. Regulation of microRNA biogenesis Nat Rev Mol Cell Biol. 2014;15:509–24 doi: 10.1038/nrm3838
3. Rockey DC, Bell PD, Hill JA. Fibrosis – A common pathway to organ injury and failure N Engl J Med. 2015;372:1138–49 doi: 10.1056/NEJMra1300575
4. Tijsen AJ, Pinto YM, Creemers EE. Non-cardiomyocyte microRNAs in heart failure Cardiovasc Res. 2012;93:573–82 doi: 10.1093/cvr/cvr344
5. Wang B, Ricardo S. Role of microRNA machinery in kidney fibrosis Clin Exp Pharmacol Physiol. 2014;41:543–50 doi: 10.1111/1440-1681.12249
6. Weigel C, Schmezer P, Plass C, Popanda O. Epigenetics in radiation-induced fibrosis Oncogene. 2015;34:2145–55 doi: 10.1038/onc.2014.145
7. MacDonald EM, Cohn RD. TGFß signaling: Its role in fibrosis formation and myopathies Curr Opin Rheumatol. 2012;24:628–34 doi: 10.1097/BOR.0b013e328358df34
8. Lan HY, Chung AC. TGF-ß/Smad signaling in kidney disease Semin Nephrol. 2012;32:236–43 doi: 10.1016/j.semnephrol.2012.04.002
9. Zhu H, Luo H, Li Y, Zhou Y, Jiang Y, Chai J, et al MicroRNA-21 in scleroderma fibrosis and its function in TGF-ß-regulated fibrosis-related genes expression J Clin Immunol. 2013;33:1100–9 doi: 10.1007/s10875-013-9896-z
10. Liang H, Zhang C, Ban T, Liu Y, Mei L, Piao X, et al A novel reciprocal loop between microRNA-21 and TGFß RIII is involved in cardiac fibrosis Int J Biochem Cell Biol. 2012;44:2152–60 doi: 10.1016/j.biocel.2012.08.019
11. Zhang Z, Zha Y, Hu W, Huang Z, Gao Z, Zang Y, et al The autoregulatory feedback loop of microRNA-21/programmed cell death protein 4/activation protein-1 (MiR-21/PDCD4/AP-1) as a driving force for hepatic fibrosis development J Biol Chem. 2013;288:37082–93 doi: 10.1074/jbc.M113.517953
12. Yao Q, Cao S, Li C, Mengesha A, Kong B, Wei M. Micro-RNA-21 regulates TGF-ß-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction Int J Cancer. 2011;128:1783–92 doi: 10.1002/ijc.25506
13. Wang J, Huang W, Xu R, Nie Y, Cao X, Meng J, et al MicroRNA-24 regulates cardiac fibrosis after myocardial infarction J Cell Mol Med. 2012;16:2150–60 doi: 10.1111/j.1582-4934.2012.01523.x
14. Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, et al miR-29 is a major regulator of genes associated with pulmonary fibrosis Am J Respir Cell Mol Biol. 2011;45:287–94 doi: 10.1165/rcmb.2010-0323OC
15. Ramdas V, McBride M, Denby L, Baker AH. Canonical transforming growth factor-ß signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29 Am J Pathol. 2013;183:1885–96 doi: 10.1016/j.ajpath.2013.08.027
16. Zhu JN, Chen R, Fu YH, Lin QX, Huang S, Guo LL, et al Smad3 inactivation and MiR-29b upregulation mediate the effect of carvedilol on attenuating the acute myocardium infarction-induced myocardial fibrosis in rat PLoS One. 2013;8:e75557 doi: 10.1371/journal.pone.0075557
17. Montgomery RL, Yu G, Latimer PA, Stack C, Robinson K, Dalby CM, et al MicroRNA mimicry blocks pulmonary fibrosis EMBO Mol Med. 2014;6:1347–56 doi: 10.15252/emmm.201303604
18. Kwiecinski M, Noetel A, Elfimova N, Trebicka J, Schievenbusch S, Strack I, et al Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction PLoS One. 2011;6:e24568 doi: 10.1371/journal.pone.0024568
19. Hennemeier I, Humpf HU, Gekle M, Schwerdt G. Role of microRNA-29b in the ochratoxin A-induced enhanced collagen formation in human kidney cells Toxicology. 2014;324:116–22 doi: 10.1016/j.tox.2014.07.012
20. Cheng J, Wang Y, Wang D, Wu Y. Identification of collagen 1 as a post-transcriptional target of miR-29b in skin fibroblasts: Therapeutic implication for scar reduction Am J Med Sci. 2013;346:98–103 doi: 10.1097/MAJ.0b013e318267680d
21. Zhou L, Wang L, Lu L, Jiang P, Sun H, Wang H. Inhibition of miR-29 by TGF-beta-Smad3 signaling through dual mechanisms promotes transdifferentiation of mouse myoblasts into myofibroblasts PLoS One. 2012;7:e33766 doi: 10.1371/journal.pone.0033766
22. Chen Y, Mohammed A, Oubaidin M, Evans CA, Zhou X, Luan X, et al Cyclic stretch and compression forces alter microRNA-29 expression of human periodontal ligament cells Gene. 2015;566:13–7 doi: 10.1016/j.gene.2015.03.055
23. Yu JW, Duan WJ, Huang XR, Meng XM, Yu XQ, Lan HY. MicroRNA-29b inhibits peritoneal fibrosis in a mouse model of peritoneal dialysis Lab Invest. 2014;94:978–90 doi: 10.1038/labinvest.2014.91
24. Chen HY, Zhong X, Huang XR, Meng XM, You Y, Chung AC, et al MicroRNA-29b inhibits diabetic nephropathy in db/db mice Mol Ther. 2014;22:842–53 doi: 10.1038/mt.2013.235
25. Abonnenc M, Nabeebaccus AA, Mayr U, Barallobre-Barreiro J, Dong X, Cuello F, et al Extracellular matrix secretion by cardiac fibroblasts: Role of microRNA-29b and microRNA-30c Circ Res. 2013;113:1138–47 doi: 10.1161/CIRCRESAHA.113.302400
26. Fang Y, Yu X, Liu Y, Kriegel AJ, Heng Y, Xu X, et al miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-a activation Am J Physiol Renal Physiol. 2013;304:F1274–82 doi: 10.1152/ajprenal.00287.2012
27. Nishikawa R, Goto Y, Kojima S, Enokida H, Chiyomaru T, Kinoshita T, et al Tumor-suppressive microRNA-29s inhibit cancer cell migration and invasion via targeting LAMC1 in prostate cancer Int J Oncol. 2014;45:401–10 doi: 10.3892/ijo.2014.2437
28. Tu X, Zheng X, Li H, Cao Z, Chang H, Luan S, et al MicroRNA-30 protects against carbon tetrachloride-induced liver fibrosis by attenuating transforming growth factor beta signaling in hepatic stellate cells Toxicol Sci. 2015;146:157–69 doi: 10.1093/toxsci/kfv081
29. Jiang L, Qiu W, Zhou Y, Wen P, Fang L, Cao H, et al A microRNA-30e/mitochondrial uncoupling protein 2 axis mediates TGF-ß 1-induced tubular epithelial cell extracellular matrix production and kidney fibrosis Kidney Int. 2013;84:285–96 doi: 10.1038/ki.2013.80
30. Du R, Sun W, Xia L, Zhao A, Yu Y, Zhao L, et al Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells PLoS One. 2012;7:e30771 doi: 10.1371/journal.pone.0030771
31. Pan Z, Sun X, Shan H, Wang N, Wang J, Ren J, et al MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-ß 1 pathway Circulation. 2012;126:840–50 doi: 10.1161/CIRCULATIONAHA.112.094524
32. Li J, Ghazwani M, Zhang Y, Lu J, Li J, Fan J, et al miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression J Hepatol. 2013;58:522–8 doi: 10.1016/j.jhep.2012.11.011
33. Beaumont J, López B, Hermida N, Schroen B, San José G, Heymans S, et al microRNA-122 down-regulation may play a role in severe myocardial fibrosis in human aortic stenosis through TGF-ß 1 up-regulation Clin Sci (Lond). 2014;126:497–506 doi: 10.1042/CS20130538
34. Chen S, Puthanveetil P, Feng B, Matkovich SJ, Dorn GW 2nd, Chakrabarti S. Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes J Cell Mol Med. 2014;18:415–21 doi: 10.1111/jcmm.12218
35. Xu Z, Ramachandran S, Gunasekaran M, Zhou F, Trulock E, Kreisel D, et al MicroRNA-144 dysregulates the transforming growth factor-ß signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation J Heart Lung Transplant. 2015;34:1154–62 doi: 10.1016/j.healun.2015.03.021
36. Megiorni F, Cialfi S, Cimino G, De Biase RV, Dominici C, Quattrucci S, et al Elevated levels of miR-145 correlate with SMAD3 down-regulation in cystic fibrosis patients J Cyst Fibros. 2013;12:797–802 doi: 10.1016/j.jcf.2013.03.007
37. He Y, Huang C, Sun X, Long XR, Lv XW, Li J. MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4 Cell Signal. 2012;24:1923–30 doi: 10.1016/j.cellsig.2012.06.003
38. Liu Z, Lu CL, Cui LP, Hu YL, Yu Q, Jiang Y, et al MicroRNA-146a modulates TGF-ß 1-induced phenotypic differentiation in human dermal fibroblasts by targeting SMAD4 Arch Dermatol Res. 2012;304:195–202 doi: 10.1007/s00403-011-1178-0
39. Ruedel A, Dietrich P, Schubert T, Hofmeister S, Hellerbrand C, Bosserhoff AK. Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts Int J Clin Exp Pathol. 2015;8:4953–62
40. Mungunsukh O, Day RM. Transforming growth factor-ß 1 selectively inhibits hepatocyte growth factor expression via a micro-RNA-199-dependent posttranscriptional mechanism Mol Biol Cell. 2013;24:2088–97 doi: 10.1091/mbc.E13-01-0017
41. Chuang TD, Panda H, Luo X, Chegini N. miR-200c is aberrantly expressed in leiomyomas in an ethnic-dependent manner and targets ZEBs, VEGFA, TIMP2, and FBLN5 Endocr Relat Cancer. 2012;19:541–56 doi: 10.1530/erc-12-0007
42. Xiong M, Jiang L, Zhou Y, Qiu W, Fang L, Tan R, et al The miR-200 family regulates TGF-ß 1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression Am J Physiol Renal Physiol. 2012;302:F369–79 doi: 10.1152/ajprenal.00268.2011
43. Wang B, Koh P, Winbanks C, Coughlan MT, McClelland A, Watson A, et al miR-200a Prevents renal fibrogenesis through repression of TGF-ß 2 expression Diabetes. 2011;60:280–7 doi: 10.2337/db10-0892
44. Faherty N, Curran SP, O’Donovan H, Martin F, Godson C, Brazil DP, et al CCN2/CTGF increases expression of miR-302 microRNAs, which target the TGFß type II receptor with implications for nephropathic cell phenotypes J Cell Sci. 2012;125(Pt 23):5621–9 doi: 10.1242/jcs.105528
45. Zhang Y, Xiao HQ, Wang Y, Yang ZS, Dai LJ, Xu YC. Differential expression and therapeutic efficacy of microRNA-346 in diabetic nephropathy mice Exp Ther Med. 2015;10:106–112 doi: 10.3892/etm.2015.2468
46. Martin J, Jenkins RH, Bennagi R, Krupa A, Phillips AO, Bowen T, et al Post-transcriptional regulation of transforming growth factor beta-1 by microRNA-744 PLoS One. 2011;6:e25044 doi: 10.1371/journal.pone.0025044
47. Jiang L, Zhou Y, Xiong M, Fang L, Wen P, Cao H, et al Sp1 mediates microRNA-29c-regulated type I collagen production in renal tubular epithelial cells Exp Cell Res. 2013;319:2254–65 doi: 10.1016/j.yexcr.2013.06.007
48. Kim EK, Choi EJ. Compromised MAPK signaling in human diseases: An update Arch Toxicol. 2015;89:867–82 doi: 10.1007/s00204-015-1472-2
49. Wei J, Feng L, Li Z, Xu G, Fan X. MicroRNA-21 activates hepatic stellate cells via PTEN/Akt signaling Biomed Pharmacother. 2013;67:387–92 doi: 10.1016/j.biopha.2013.03.014
50. Kwiecinski M, Elfimova N, Noetel A, Töx U, Steffen HM, Hacker U, et al 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;92:978–87 doi: 10.1038/labinvest.2012.70
51. Wang J, Chu ESH, Chen H-Y, Man K, Go MYY, Huang XR, et al microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway Oncotarget. 2015;6:7325–38 doi: 10.18632/oncotarget.2621
52. Castoldi G, Di Gioia CR, Bombardi C, Catalucci D, Corradi B, Gualazzi MG, et al MiR-133a regulates collagen 1A1: Potential role of miR-133a in myocardial fibrosis in angiotensin II-dependent hypertension J Cell Physiol. 2012;227:850–6 doi: 10.1002/jcp.22939
53. Xie YF, Shu R, Jiang SY, Liu DL, Ni J, Zhang XL. MicroRNA-146 inhibits pro-inflammatory cytokine secretion through IL-1 receptor-associated kinase 1 in human gingival fibroblasts J Inflamm (Lond). 2013;10:20 doi: 10.1186/1476-9255-10-20
54. Bhattacharyya S, Balakathiresan NS, Dalgard C, Gutti U, Armistead D, Jozwik C, et al Elevated miR-155 promotes inflammation in cystic fibrosis by driving hyperexpression of interleukin-8 J Biol Chem. 2011;286:11604–15 doi: 10.1074/jbc.M110.198390
55. Ge Y, Pan S, Guan D, Yin H, Fan Y, Liu J, et al MicroRNA-350 induces pathological heart hypertrophy by repressing both p38 and JNK pathways Biochim Biophys Acta. 2013;1832:1–10 doi: 10.1016/j.bbadis.2012.09.004
56. Nagalingam RS, Sundaresan NR, Gupta MP, Geenen DL, Solaro RJ, Gupta M. A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling J Biol Chem. 2013;288:11216–32 doi: 10.1074/jbc.M112.442384
57. Knezevic I, Patel A, Sundaresan NR, Gupta MP, Solaro RJ, Nagalingam RS, et al A novel cardiomyocyte-enriched microRNA, miR-378, targets insulin-like growth factor 1 receptor: Implications in postnatal cardiac remodeling and cell survival J Biol Chem. 2012;287:12913–26 doi: 10.1074/jbc.M111.331751
58. Zhang Z, Luo X, Ding S, Chen J, Chen T, Chen X, et al MicroRNA-451 regulates p38 MAPK signaling by targeting of Ywhaz and suppresses the mesangial hypertrophy in early diabetic nephropathy FEBS Lett. 2012;586:20–6 doi: 10.1016/j.febslet.2011.07.042
59. Ginsberg MH. Integrin activation BMB Rep. 2014;47:655–9 doi: 10.5483/BMBRep.2014.47.12.241
60. De Franceschi N, Hamidi H, Alanko J, Sahgal P, Ivaska J. Integrin traffic –The update J Cell Sci. 2015;128:839–52 doi: 10.1242/jcs.161653
61. Henderson NC, Sheppard D. Integrin-mediated regulation of TGFß in fibrosis Biochim Biophys Acta. 2013;1832:891–6 doi: 10.1016/j.bbadis.2012.10.005
62. Chen W, Harbeck MC, Zhang W, Jacobson JR. MicroRNA regulation of integrins Transl Res. 2013;162:133–43 doi: 10.1016/j.trsl.2013.06.008
63. Wang H, Zhu Y, Zhao M, Wu C, Zhang P, Tang L, et al miRNA-29c suppresses lung cancer cell adhesion to extracellular matrix and metastasis by targeting integrin ß 1 and matrix metalloproteinas. e2 (MMP2) PLoS One. 2013;8:e70192 doi: 10.1371/journal.pone.0070192
64. Liu Y, Taylor NE, Lu L, Usa K, Cowley AW Jr, Ferreri NR, et al Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes Hypertension. 2010;55:974–82 doi: 10.1161/hypertensionaha.109.144428
65. Honda N, Jinnin M, Kira-Etoh T, Makino K, Kajihara I, Makino T, et al miR-150 down-regulation contributes to the constitutive type I collagen overexpression in scleroderma dermal fibroblasts via the induction of integrin ß 3 Am J Pathol. 2013;182:206–16 doi: 10.1016/j.ajpath.2012.09.023
66. Mancini M, Saintigny G, Mahe C, Annicchiarico-Petruzzelli M, Melino G, Candi E. MicroRNA-152 and-181a participate in human dermal fibroblasts senescence acting on cell adhesion and remodeling of the extracellular matrix Aging US. 2012;4:843–53 doi: 10.18632/aging.100508
67. Li H, Chang L, Du WW, Gupta S, Khorshidi A, Sefton M, et al Anti-microRNA-378a enhances wound healing process by upregulating integrin beta-3 and vimentin Mol Ther. 2014;22:1839–50 doi: 10.1038/mt.2014.115
68. Thum T. Noncoding RNAs and myocardial fibrosis Nat Rev Cardiol. 2014;11:655–63 doi: 10.1038/nrcardio.2014.125
69. van Almen GC, Verhesen W, van Leeuwen RE, van de Vrie M, Eurlings C, Schellings MW, et al MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure Aging Cell. 2011;10:769–79 doi: 10.1111/j1474-9726.2011.00714.x
70. Lino Cardenas CL, Henaoui IS, Courcot E, Roderburg C, Cauffiez C, Aubert S, et al miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1 PLoS Genet. 2013;9:e1003291 doi: 10.1371/journal.pgen.1003291
71. Yao HW, Li J. Epigenetic modifications in fibrotic diseases: Implications for pathogenesis and pharmacological targets J Pharmacol Exp Ther. 2015;352:2–13 doi: 10.1124/jpet.114.219816
72. Luo Y, Dong HY, Zhang B, Feng Z, Liu Y, Gao YQ, et al miR-29a-3p attenuates hypoxic pulmonary hypertension by inhibiting pulmonary adventitial fibroblast activation Hypertension. 2015;65:414–20 doi: 10.1161/HYPERTENSIONAHA.114.04600
73. Thum T, Condorelli G. Long noncoding RNAs and microRNAs in cardiovascular pathophysiology Circ Res. 2015;116:751–62 doi: 10.1161/CIRCRESAHA.116.303549
74. Monaghan M, Browne S, Schenke-Layland K, Pandit A. A collagen-based scaffold delivering exogenous microrna-29B to modulate extracellular matrix remodeling Mol Ther. 2014;22:786–96 doi: 10.1038/mt.2013.288

Edited by: Peng Lyu

Keywords:

Fibrosis; Integrins; MicroRNAs; Mitogen-activated Protein Kinases; Signal Transduction Pathway; Transforming Growth Factor-beta

© 2016 Chinese Medical Association