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MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling

miR-125b is frequently dysregulated in different diseases. Activation of hepatic stellate cells (HSCs) is a critical event during liver fibrogenesis. However, the function and its underlying mechanism of miR-125b in HSC activation and liver fibrosis are still unknown. Here, we showed that miR-125b w...

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Autores principales: You, Kai, Li, Song-Yang, Gong, Jiao, Fang, Jian-Hong, Zhang, Chong, Zhang, Min, Yuan, Yunfei, Yang, Jine, Zhuang, Shi-Mei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023793/
https://www.ncbi.nlm.nih.gov/pubmed/30195793
http://dx.doi.org/10.1016/j.omtn.2018.04.016
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author You, Kai
Li, Song-Yang
Gong, Jiao
Fang, Jian-Hong
Zhang, Chong
Zhang, Min
Yuan, Yunfei
Yang, Jine
Zhuang, Shi-Mei
author_facet You, Kai
Li, Song-Yang
Gong, Jiao
Fang, Jian-Hong
Zhang, Chong
Zhang, Min
Yuan, Yunfei
Yang, Jine
Zhuang, Shi-Mei
author_sort You, Kai
collection PubMed
description miR-125b is frequently dysregulated in different diseases. Activation of hepatic stellate cells (HSCs) is a critical event during liver fibrogenesis. However, the function and its underlying mechanism of miR-125b in HSC activation and liver fibrosis are still unknown. Here, we showed that miR-125b was upregulated in HSCs, but not in hepatocytes, during hepatic fibrogenesis in vivo and upon culture activation in vitro. Inhibition of miR-125b suppressed the expression of profibrogenic genes in culture-activated primary HSCs and reduced the basal and transforming growth factor β (TGF-β)-induced alpha-smooth muscle actin (α-SMA) expression and cell contraction of the immortalized HSC cell line. In contrast, ectopic expression of miR-125b promoted α-SMA expression and HSC contraction. Moreover, antagonizing miR-125b in vivo significantly alleviated liver fibrosis in CCl(4)-treated mice. Mechanistically, overexpression of miR-125b in HSCs enhanced RhoA activity by directly targeting StAR-related lipid transfer (START) domain containing 13 (Stard13), a RhoA-specific GTPase-activating protein, whereas knockdown of miR-125b abrogated RhoA activation. Furthermore, inhibition of RhoA or its downstream molecules, Mrtf-A and Srf, attenuated the miR-125b-induced α-SMA expression and HSC contraction. Therefore, our findings identify a miR-125b-Stard13-RhoA-α-SMA signaling cascade in HSCs and highlight its importance in hepatic fibrosis.
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spelling pubmed-60237932018-06-29 MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling You, Kai Li, Song-Yang Gong, Jiao Fang, Jian-Hong Zhang, Chong Zhang, Min Yuan, Yunfei Yang, Jine Zhuang, Shi-Mei Mol Ther Nucleic Acids Article miR-125b is frequently dysregulated in different diseases. Activation of hepatic stellate cells (HSCs) is a critical event during liver fibrogenesis. However, the function and its underlying mechanism of miR-125b in HSC activation and liver fibrosis are still unknown. Here, we showed that miR-125b was upregulated in HSCs, but not in hepatocytes, during hepatic fibrogenesis in vivo and upon culture activation in vitro. Inhibition of miR-125b suppressed the expression of profibrogenic genes in culture-activated primary HSCs and reduced the basal and transforming growth factor β (TGF-β)-induced alpha-smooth muscle actin (α-SMA) expression and cell contraction of the immortalized HSC cell line. In contrast, ectopic expression of miR-125b promoted α-SMA expression and HSC contraction. Moreover, antagonizing miR-125b in vivo significantly alleviated liver fibrosis in CCl(4)-treated mice. Mechanistically, overexpression of miR-125b in HSCs enhanced RhoA activity by directly targeting StAR-related lipid transfer (START) domain containing 13 (Stard13), a RhoA-specific GTPase-activating protein, whereas knockdown of miR-125b abrogated RhoA activation. Furthermore, inhibition of RhoA or its downstream molecules, Mrtf-A and Srf, attenuated the miR-125b-induced α-SMA expression and HSC contraction. Therefore, our findings identify a miR-125b-Stard13-RhoA-α-SMA signaling cascade in HSCs and highlight its importance in hepatic fibrosis. American Society of Gene & Cell Therapy 2018-05-03 /pmc/articles/PMC6023793/ /pubmed/30195793 http://dx.doi.org/10.1016/j.omtn.2018.04.016 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
You, Kai
Li, Song-Yang
Gong, Jiao
Fang, Jian-Hong
Zhang, Chong
Zhang, Min
Yuan, Yunfei
Yang, Jine
Zhuang, Shi-Mei
MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling
title MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling
title_full MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling
title_fullStr MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling
title_full_unstemmed MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling
title_short MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling
title_sort microrna-125b promotes hepatic stellate cell activation and liver fibrosis by activating rhoa signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023793/
https://www.ncbi.nlm.nih.gov/pubmed/30195793
http://dx.doi.org/10.1016/j.omtn.2018.04.016
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