Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783335931241037824 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6023793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT youkai microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT lisongyang microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT gongjiao microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT fangjianhong microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT zhangchong microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT zhangmin microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT yuanyunfei microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT yangjine microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling AT zhuangshimei microrna125bpromoteshepaticstellatecellactivationandliverfibrosisbyactivatingrhoasignaling |