Loss of expression of miR-335 is implicated in hepatic stellate cell migration and activation. Exp Cell Res

Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, No.415 Fengyang Road, Shanghai 200003, China.
Experimental Cell Research (Impact Factor: 3.37). 07/2011; 317(12):1714-25. DOI: 10.1016/j.yexcr.2011.05.001
Source: PubMed

ABSTRACT Activation and migration of resident stellate cells (HSCs) within the hepatic space of Disse play an important role in hepatic fibrosis, which accounts for the increased numbers of activated HSCs in areas of inflammation during hepatic fibrosis. Currently, microRNAs have been found to play essential roles in HSC differentiation, proliferation, apoptosis, fat accumulation and collagen production. However, little is known about microRNA mediated HSC activation and migration. In this study, the miRNA expression profiles of quiescent HSCs, partially activated HSCs and fully activated HSCs were compared in pairs. Gene ontology (GO) and GO-Map network analysis indicated that the activation of HSCs was regulated by microRNAs. Among them miR-335 was confirmed to be significantly reduced during HSC activation by qRT-PCR, and restoring expression of miR-335 inhibited HSC migration and reduced α-SMA and collagen type I. Previous study revealed that tenascin-C (TNC), an extracellular matrix glycoprotein involved in cell migration, might be a target of miR-335. Therefore, we further studied the TNC expression in miR-335 over-expressed HSCs. Our data showed that exogenous TNC could enhance HSC migration in vitro and miR-335 restoration resulted in a significant inhibition of TNC expression. These results demonstrated that miR-335 restoration inhibited HSC migration, at least in part, via downregulating the TNC expression.

  • Source
    • "miR-29a, -29b NAFLD, chronic HCV hepatitis, CCl4 intoxication of mice Kwiecinski et al. (2010), Ogawa et al. (2010), Roderburg et al. (2011) Kwiecinski et al. (2011), Ogawa et al. (2010), Roderburg et al. (2011) CCl4 intoxication of mice, NAFLD (HFD rat, mice), chronic HCV hepatitis miR-199a, -199a* Murakami et al. (2011) miR-200a, -200b Alisi et al. (2010), Murakami et al. (2011), Pogribny et al. (2010) p.o. miR-34a, -34b Murakami et al. (2011), Pogribny et al. (2010) p.o. miR-146b Murakami et al. (2011) miR-150, miR-194 Venugopal et al. (2010) miR-27a, -27b NAFLD (HFD rat) Alisi et al. (2010) Ji et al. (2009) miR-15b, -16 Guo et al. (2009b), Guo et al. (2009c) miR-132 Mann et al. (2010) miR-335 Chen et al. (2011) miR-19b Cholestasis (bile duct ligation) Lakner et al. (2012) Lakner et al. (2012) p.o., Personal observation; NAFLD, non-alcoholic fatty liver disease; HFD, high fat diet. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNA (miRNA) are small non-coding RNA molecules that posttranscriptionally effect mRNA stability and translation by targeting the 3'-untranslated region (3'-UTR) of various transcripts. Thus, dysregulation of miRNA affects a wide range of cellular processes such as cell proliferation and differentiation involved in organ remodeling processes. Divergent miRNA patterns were observed during chronic liver diseases of various etiologies. Chronic liver diseases result in uncontrolled scar formation ending up in liver fibrosis or even cirrhosis. Since it has been shown that miR-29 dysregulation is involved in synthesis of extracellular matrix proteins, miR-29 is of special interest. The importance of miR-29 in hepatic collagen homeostasis is underlined by in vivo data showing that experimental severe fibrosis is associated with a prominent miR-29 decrease. The loss of miR-29 is due to the response of hepatic stellate cells to exposure to the profibrogenic mediators TGF-β and PDGF-BB. Several putative binding sites for the Smad proteins and the Ap1 complex are located in the miR-29 promoter, which are suggested to mediate miR-29 decrease in fibrosis. Other miRNA are highly increased after profibrogenic stimulation, such as miR-21. miR-21 is transcriptionally upregulated in response to Smad-3 rather than Smad-2 activation after TGF-β stimulation. In addition, TGF-β promotes miR-21 expression by formation of a microprocessor complex containing Smad proteins. Elevated miR-21 may then act as a profibrogenic miRNA by its repression of the TGF-β inhibitory Smad-7 protein.
    Frontiers in Physiology 03/2012; 3(3):49. DOI:10.3389/fphys.2012.00049 · 3.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs or miRs) are small approximately 22 nucleotide RNA species that are believed to regulate diverse metabolic and physiological processes. In the recent past, several reports have surfaced that demonstrate the role of miRNAs in various biological processes and numerous disease states. For a disease as complex as diabetes, the emergence of miRNAs as key regulators leading to the disease phenotype has added a novel dimension to the area of diabetes research. On the other hand, the liver, a metabolic hub, contributes in a major way towards maintaining normal glucose levels in the body as it can both stimulate and inhibit hepatic glucose output. This equilibrium is frequently disturbed in diabetes and hence, the liver assumes special significance considering the correlation between altered hepatic physiology and diabetes. While the understanding of the mechanisms behind this altered hepatic behavior is not yet completely understood, recent reports on the status and role of miRNAs in the diabetic liver have further added to the complexities of the knowledge of hepatic pathophysiology in diabetes. Here, we bring together the various miRNAs that play a role in the altered hepatic behavior during diabetes.
    10/2011; 2(10):158-63. DOI:10.4239/wjd.v2.i10.158
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs are short noncoding, endogenous RNA species that posttranscriptionally inhibit gene expression by targeting the untranslated region (UTR) of mRNAs. Recently, it was shown that miR-29 inhibits expression of extracellular matrix proteins such as collagens, suggesting an antifibrotic function of miR-29. In the present study, we now investigated the role of miR-29 in profibrogenic growth factor expression as a further central mechanism of fibrosis. Screening of databases revealed putative miR-29 target sequences in the mRNA of platelet-derived growth factor (PDGF)-B, PDGF-B receptor, PDGF-C, vascular endothelial growth factor-A, and insulin-like growth factor (IGF)-I. To analyze miR-29 interaction with the predicted binding sites, we cloned the 3'-UTR sequences of the putative targets in fusion to the luciferase-reporter coding sequence. Functional miR-29 binding to PDGF-C and IGF-I mRNA sequences, but not to the corresponding mutants, was then proven by reporter assays. Hepatic stellate cells (HSC) that transdifferentiate into myofibroblasts, producing extracellular matrix proteins and profibrogenic growth factors, for example, the members of the PDGF family, are crucial for liver fibrosis. Myofibroblastic transition of primary HSC resulted in the loss of miR-29, but in a significant increase of PDGF-C and IGF-I. Compensation of reduced miR-29 levels by miR-29 overexpression in myofibroblastic HSC was followed by a definitive repression of IGF-I and PDGF-C synthesis. After experimental fibrosis, induced by bile-duct occlusion, miR-29 expression was shown to be reduced, but IGF-I and PDGF-C expression was upregulated, correlating inversely to the miR-29 pattern. Thus, we conclude that miR-29, downregulated during fibrosis, acts as an antifibrogenic mediator not only by targeting collagen biosynthesis, but also by interfering with profibrogenic cell communication via PDGF-C and IGF-I.
    Laboratory Investigation 05/2012; 92(7):978-87. DOI:10.1038/labinvest.2012.70 · 3.83 Impact Factor
Show more


Available from