title: MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1.
abstract: Liver fibrosis is a chronic liver disease characterized by the proliferation and activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). Research suggests that microRNAs (miRNAs) are a new type of regulator of liver fibrosis. In the present study, we investigated the role of microRNA-9 (miR-9) in the process of liver fibrosis, as well as the underlying mechanism of action. Downregulated levels of miR-9 were found in fibrotic liver tissues and activated HSCs as detected by qRT-PCR; whereas, expression of multidrug resistance‑associated protein 1 (MRP1/ABCC1) was upregulated in the fibrotic liver tissues and activated HSCs. CCK-8 and BrdU assays revealed that miR-9 reduced the proliferative ability of the HSCs. In addition, expression levels of ECM-related genes (α-SMA, Col-1 and Timp-1), which are markers of HSC activation, were downregulated by miR-9. Conversely, an miR-9 inhibitor promoted cell proliferation and HSC activation. In addition, a luciferase reporter assay indicated that miR-9 targets the 3'-untranslated region (3'-UTR) of MRP1 and causes a significant decrease in MRP1. miR-9 inhibited the activation of the Hedgehog (Hh) pathway and the expression of MRP1, while this suppression was rescued by the overexpression of MRP1. Finally, a CCl4-induced mouse model of liver fibrosis was used to investigate the effects of miR-9 on liver fibrosis in vivo. The results showed that miR-9 abrogated hepatic fibrosis by suppressing the expression of MRP1 in CCl4-induced liver fibrotic mice. In conclusion, the present study demonstrated that miR-9 suppresses the proliferation and activation of HSCs through the Hh pathway by targeting MRP1, which suggests that miR-9 has therapeutic potential for liver fibrosis.
authors.affiliation: Department of Traditional Chinese Medicine, Shandong Medical College, Linyi, Shandong 276000, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Respiration, Affiliated Hospital of Shandong Medical College, Linyi, Shandong 276000, P.R. China.
authors.forename: Huanying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Rehabilitation Medicine, Shandong Medical College, Linyi, Shandong 276000, P.R. China.
authors.forename: Liying
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Anatomy, Shandong Medical College, Linyi, Shandong 276000, P.R. China.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Respiration, Chinese Medicine Hospital of Linyi City, Linyi, Shandong 276000, P.R. China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Fu
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; C541874:MIRN92 microRNA, human; C560822:TIMP1 protein, human; C421109:multidrug resistance-associated protein 1