MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression

Hyun, Jeongeun; Wang, Sihyung; Kim, Jieun; Rao, Kummara Madhusudana; Park, Soo Yong; Chung, Ildoo; Ha, Chang‐Sik; Kim, Sang Woo; Yun, Yang; Jung, Youngmi

doi:10.1038/ncomms10993

Cited by 205 publications

(168 citation statements)

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“…A recent study shows that miR-378a-3p, a negative regulator of TGFβ1, contributes to the suppression of cardiac fibrosis [16]. Hyun et al found that miR-378a-3p could suppress HSC activation by targeting Gli3 [17]. However, the biological role of miR-378a-3p in liver fibrosis remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Fan

Chen

et al. 2016

Cell Physiol Biochem

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Background/Aims: Wnt/β-catenin pathway is involved in liver fibrosis and microRNAs (miRNAs) are considered as key regulators of the activation of hepatic stellate cells (HSCs). A recent study showed the protective role of miR-378a-3p against cardiac fibrosis. However, whether miR-378a-3p suppresses Wnt/β-catenin pathway in liver fibrosis is largely unknown. Methods: miR-378a-3p expression was detected in carbon tetrachloride-induced liver fibrosis and activated HSCs. Effects of miR-378a-3p overexpression on HSC activation and Wnt/β-catenin pathway were analyzed. Bioinformatic analysis was employed to identify the potential targets of miR-378a-3p. Serum miR-378a-3p expression was analyzed in patients with cirrhosis. Results: Reduced miR-378a-3p expression was observed in the fibrotic liver tissues and activated HSCs. Up-regulation of miR-378a-3p inhibited HSC activation including cell proliferation, α-smooth muscle actin (α-SMA) and collagen expression. Moreover, miR-378a-3p overexpression resulted in Wnt/β-catenin pathway inactivation. Luciferase reporter assays demonstrated that Wnt10a, a member of Wnt/β-catenin pathway, was confirmed to be a target of miR-378a-3p. By contrast, miR-378a-3p inhibitor contributed to HSC activation, with an increase in cell proliferation, α-SMA and collagen expression. But all these effects were blocked down by silencing of Wnt10a. Notably, sera from patients with cirrhosis contained lower levels of miR-378a-3p than sera from healthy controls. Receiver operating characteristic curve analysis suggested that serum miR-378a-3p differentiated liver cirrhosis patients from healthy controls, with an area under the curve of ROC curve of 0.916. Conclusion: miR-378a-3p suppresses HSC activation, at least in part, via targeting of Wnt10a, supporting its potential utility as a novel therapeutic target for liver fibrosis.

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Section: Introductionmentioning

confidence: 99%

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Fan

Chen

et al. 2016

Cell Physiol Biochem

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“…4 miR-378 suppress expression of Gli3 to inhibit activation of hepatic stellate cells and liver fibrosis. 18 However, a role of miR-378 in the regulation of skeletal muscle development has not been described.…”

Section: Introductionmentioning

confidence: 99%

miR-378a-3p promotes differentiation and inhibits proliferation of myoblasts by targeting HDAC4 in skeletal muscle development

Wei

Zhang

et al. 2016

RNA Biology

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Muscle development, or myogenesis, is a highly regulated, complex process. A subset of microRNAs (miRNAs) have been identified as critical regulators of myogenesis. Recently, miR-378a was found to be involved in myogenesis, but the mechanism of how miR-378a regulates the proliferation and differentiation of myoblasts has not been determined. We found that miR-378a-3p expression in muscle was significantly higher than in other tissues, suggesting an important effect on muscle development. Overexpression of miR-378a-3p increased the expression of MyoD and MHC in C2C12 myoblasts both at the level of mRNA and protein, confirming that miR-378a-3p promoted muscle cell differentiation. The forced expression of miR-378a-3p promoted apoptosis of C2C12 cells as evidenced by CCK-8 assay and Annexin V-FITC/PI staining results. Through TargetScan, histone acetylation enzyme 4 (HDAC4) was identified as a potential target of miR-378a-3p. We confirmed targeting of HDAC4 by miR-378a-3p using a dual luciferase assay and western blotting. Our RNAi analysis results also showed that HDAC4 significantly promoted differentiation of C2C12 cells and inhibited cell survival through Bcl-2. Therefore, we conclude that miR-378a-3p regulates skeletal muscle growth and promotes the differentiation of myoblasts through the post-transcriptional down-regulation of HDAC4.

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“…Recently, miRNAs have been found to be important regulators of osteogenic signaling pathways in multiple aspects and multiple signaling pathways. MiRNAs are short non-coding RNA molecules of 17-25 nucleotides that control gene expression at the post-transcriptional level and have been shown to play critical roles in a wide variety of biological processes, including proliferation, reprogramming, differentiation, cell cycle, invasion and apoptosis [6,7,9,[42][43][44]. Each miRNA regulates numerous mRNAs and involve multiple signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…miRNAs have been shown to play critical roles in a wide variety of biological processes, including proliferation, lineage commitment, differentiation, cell cycle, invasion and apoptosis [6][7][8][9][10]. Recently, increasing evidences have indicated that bone development and homeostasis is regulated by miRNAs [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

miR-16-2* Interferes with WNT5A to Regulate Osteogenesis of Mesenchymal Stem Cells

Duan

Zhao

Xiong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoporosis is a bone metabolic disease characterized by a systemic impairment of bone mass, which results in increased propensity of fragility fractures. A reduction in the differentiation of MSCs into osteoblasts contributes to the impaired bone formation observed in osteoporosis. Mesenchymal stem cells (MSCs) are induced to differentiate into preosteoblasts, which are regulated by the signaling cascades initiated by the various signals, including miRNAs. miR-16-2* is a newly discovered miRNA that participates in diagnosis and prognosis of hepatocellular carcinoma, cervical cancer and chronic lymphocytic leukemia. However, the effect of miR-16-2* on the regulation of osteoblast differentiation and the mechanism responsible are still unclear. Here we discuss the contribution of miR-16-2* to osteoporosis, osteoblast differentiation and mineralization. Methods: The expression pattern of miR-16-2* during osteogenesis or in osteoporosis bone samples was validated by quantitative real-time PCR (qRT-PCR). The human bone marrow mesenchymal stem cells (hBMSCs) were induced to differentiate into osteoblasts by osteogenic induced medium containing dexamethasone, ascorbate-2-phosphat, beta-glycerophosphate and vitamin-D3. The target genes of miR-16-2* were predicted by TargetScan and PicTar. The mRNA and protein levels of osteogenic key markers were detected using qRT-PCR or western blot respectively. The WNT signal activity was analyzed by TOP/FOP reporter assay. Results: The expression of miR-16-2* in patient bone tissue with osteoporosis was negatively correlated with bone formation related genes. During osteoblast differentiation process, the expression of miR-16-2* was significantly decreased. Upregulation of miR-16-2* in hBMSCs impaired the osteogenic differentiation while the downregulation of miR-16-2* increased this process. Upregulation the expression of miR-16-2* could also block the WNT signal pathway by directly target WNT5A. Furthermore, knockdown of miR-16-2* could promote the activation of RUNX2, possibly by lifting the inhibitory effect of miR-16-2* on WNT pathway. Conclusion: Taken together, we report a novel biological role of miR-16-2* in osteogenesis through regulating WNT5A response for the first time. Our data support the potential utilization of miRNA-based therapies in regenerative medicine.

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MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression

Cited by 205 publications

References 68 publications

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

miR-378a-3p promotes differentiation and inhibits proliferation of myoblasts by targeting HDAC4 in skeletal muscle development

miR-16-2* Interferes with WNT5A to Regulate Osteogenesis of Mesenchymal Stem Cells

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