The Epigenetically-Regulated microRNA-378a Targets TGF-β2 in TGF-β1-Treated Hepatic Stellate Cells
Autor: | Jianhuan Yang, Kate Huang, Fujun Yu, Jianjian Zheng, Xiaodong Pan, Peihong Dong, Bicheng Chen |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Liver Cirrhosis Male Physiology Cardiac fibrosis Down-Regulation Apoptosis MicroRNA-378a Collagen Type I lcsh:Physiology Epigenesis Genetic Rats Sprague-Dawley Transforming Growth Factor beta1 lcsh:Biochemistry 03 medical and health sciences Transforming Growth Factor beta2 0302 clinical medicine TGF-β2 microRNA medicine Hepatic Stellate Cells Animals Humans lcsh:QD415-436 DNA (Cytosine-5-)-Methyltransferases Promoter Regions Genetic 3' Untranslated Regions Hepatic stellate cell Cell Proliferation DNA methylation Base Sequence lcsh:QP1-981 Cell growth Chemistry Cell Cycle Methylation Cell cycle medicine.disease MicroRNAs 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Azacitidine Transforming growth factor |
Zdroj: | Cellular Physiology and Biochemistry, Vol 40, Iss 1-2, Pp 183-194 (2016) |
ISSN: | 1421-9778 1015-8987 |
Popis: | Background/Aims: In liver fibrosis, the activation of hepatic stellate cells (HSCs) is considered as a pivotal event. It is well known that transforming growth factor-β1 (TGF-β1) is the main stimuli factor responsible for HSC activation. microRNAs (miRNAs), regulating various biological processes, have recently been shown to be involved in HSC activation. A recent study reported that deficiency of miR-378a contributes to cardiac fibrosis via TGF-β1-dependent paracrine mechanism. However, the involvement of miR-378a and its roles in TGF-β1-induced HSC activation remains largely unknown. Methods: miR-378a expression was detected in TGF-β1-treated cells and patients with cirrhosis. Then, effects of miR-378a overexpression on cell proliferation and HSC activation were analyzed. We also analyzed the binding of miR-378a to the 3′-untranslated region of TGF-β2. Results: In response to TGF-β1, miR-378a expression was down-regulated in a dose-dependent manner. miR-378a overexpression suppressed both cell proliferation and cell cycle in TGF-β1-treated LX-2 cells. Moreover, miR-378a overexpression inhibited TGF-β1-induced HSC activation including the reduction of α-smooth muscle actin (α-SMA) and type I collagen. Similarly, miR-378a resulted in a reduction in cell proliferation, and the expressions of α-SMA and Col1A1 in TGF-β1-treated primary HSCs. Notably, TGF-β2 was confirmed as a target of miR-378a by luciferase reporter assays. Interestingly, miR-378a promoter methylation may be responsible for miR-378a down-regulation in TGF-β1-treated LX-2 cells and TGF-β1-treated primary HSCs. Further studies confirmed that reduced miR-378a was associated with promoter methylation in patients with cirrhosis compared with healthy controls. Conclusion: Our results demonstrate that miR-378a expression is associated with its methylation status in TGF-β1-treated cells, and epigenetically-regulated miR-378a inhibits TGF-β1-induced HSC activation, at least in part, via TGF-β2. |
Databáze: | OpenAIRE |
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