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: 3.25). 07/2011; 317(12):1714-25. DOI: 10.1016/j.yexcr.2011.05.001
Source: PubMed


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.

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    • "MicroRNAs (miRNAs) are endogenous, small and noncoding RNAs, which have the ability to regulate gene expression in a mature form by binding to the 3′-untranslated region (3′-UTR) of target mRNAs and repressing translation or inducing mRNA cleavage [6,7]. Previous studies have revealed that miRNAs play indispensable roles in the progress of liver fibrosis by being involved in the differentiation, fat metabolism and ECM production of HSCs [8,9] and the proliferation and apoptosis of HSCs [10-12]. Over-expression of miR-146a can suppress TGF-β1-induced HSC proliferation and induce HSC apoptosis [11]. "
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    ABSTRACT: In the process of hepatic fibrosis, hepatic stellate cells (HSCs) can be activated by many inflammatory cytokines. The transforming growth factor-beta1 (TGF-beta1) is one of the main profibrogenic mediators. Recently, some studies have also shown that microRNAs (miRNAs) play essential roles in the progress of liver fibrosis by being involved in the differentiation, fat metabolism and ECM production of HSCs. The expression of miR-454 in LX-2 cells treated with TGF-beta1 and in the fibrotic livers with Schistosoma japonicum infection was detected by qRT-PCR. The role of miR-454 on LX-2 cells was then analyzed by Western blot, flow cytometry and luciferase assay. The results showed that the expression of miR-454 was down-regulated in the TGF-beta1-treated LX-2 cells and miR-454 could inhibit the activation of HSCs by directly targeting Smad4. However, we found that miR-454 had no effect on cell cycle and cell proliferation in TGF-beta1-treated LX-2. Besides these, miR-454 was found to be regulated in the process of Schistosoma japonicum infection. All the results suggested that miR-454 could provide a novel therapeutic approach for treating liver fibrosis, especially the liver fibrosis induced by Schistosoma japonicum.
    Parasites & Vectors 03/2014; 7(1):148. DOI:10.1186/1756-3305-7-148 · 3.43 Impact Factor
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    • "Indeed, Dickkopf-related protein 1 (DKK1) and breast cancer 1, early onset (BRCA1) are known targets of miR-335 (Heyn et al. 2011; Zhang et al. 2011). Because a recent study has suggested that miR-335 regulates cell migration (Chen et al. 2011), which, in turn, is regulated by actin (Rottner and Stradal 2011), we evaluated regulation of the cytoskeleton by miR-335-5p in the present study. "
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    ABSTRACT: MicroRNA is a short RNA molecule expressed in eukaryotic cells that is involved in multiple processes, including translational repression, target degradation and gene silencing. However, its specific role(s) in these processes remains largely unknown, especially in terms of germ cell development. The present study identified a microRNA, namely miR-335-5p, that is involved in mouse oocyte meiosis. MiR-335-5p was highly expressed in oocytes, but levels decreased markedly shortly after fertilisation. Microinjection of miR-335-5p or its inhibitor into oocytes resulted in a higher proportion of 2-cell-like MII oocytes and oocytes at the germinal vesicle breakdown and/or MI stage, indicating failure of asymmetric oocyte division. This may be due to regulation of actin because perturbation of miR-335-5p resulted in reduced expression of actin nucleator Daam1, a member of the Formin family. Moreover, injection of miR-335-5p or its inhibitor resulted in aberrant spindle morphology, namely an elongated spindle and multiple poles spindle. After injection of oocytes, levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) decreased, suggesting that miR-335-5p may regulate spindle formation via the mitogen-activated protein kinase pathway. Overexpression and inhibition of miR-335-5p had no effect on embryo development. Together, the results of the present study indicate that miR-335-5p is a novel regulator expressed in oocytes that is involved in cytoskeleton dynamics.
    Reproduction Fertility and Development 07/2012; 25(4). DOI:10.1071/RD12138 · 2.40 Impact Factor
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    • "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. "
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    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 · 3.53 Impact Factor
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