miR-200c Accelerates Hepatic Stellate Cell-Induced Liver Fibrosis via Targeting the FOG2/PI3K Pathway

Abstract

Background Although expression of miR-200s is aberrant in liver fibrosis, its role in liver fibrogenesis still remains unknown. Here, we investigated the role of miR-200c in the activation of human hepatic stellate cells (HSCs) and induction of liver fibrosis. Methods We engineered human HSCs (LX2 cell line) to stably express miR-200c (LX2-200c) or empty vector control (LX2-nc). Results miR-200c expression upregulated α-smooth muscle actin (SMA) and vimentin, enhanced HSCs growth and migration, increased expression of collagen type I (a main component of ECM) gene and secretion of epidermal growth factor (EGF), and upregulated the phosphorylation of Akt, a downstream effector of the PI3K pathway. As a target of miR-200s and inhibitor of PI3K pathway, FOG2 protein expression was significantly suppressed in LX2-200c cells. Moreover, LY294002, a highly selective inhibitor of PI3K, blocked phosphorylation of Akt and the effects of miR-200c. Conclusions These data suggest that miR-200c activates HSCs in liver fibrosis possibly by downregulating FOG2 protein expression and upregulating PI3K/Akt signaling. Autocrine activation of EGF signaling may also be a mechanism of miR-200c-mediated HSCs activation. So miR-200c can be a potential marker for HSCs activation and liver fibrosis progression, as well as a potential target to attenuate liver fibrosis.

Effect of miR‐182 on hepatic fibrosis induced by Schistosomiasis japonica by targeting FOXO1 through PI3K/AKT signaling pathway

“…On the other hand, the over‐expression of the miR‐31/ FIH1 pathway played a positive part in TGF‐β‐induced liver fibrosis (Hu et al, ). It proved that miR‐200c upregulated α‐smooth muscle actin (α‐SMA) and Vimentin in the study of Ma et al () and so miR‐200c could be a potential target to attenuate liver fibrosis. Inspired by these previous studies, we aimed at finding the relationship between miRNAs and hepatic fibrosis progression.…”

Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-β1/Smad, nuclear factor-κB, and AKT signaling pathways in rats

“…The regulation of several cell signaling pathways is involved in this process, and the most important pathways are TGF-β1/Smad, NF-κB, and AKT. 26 – 28 TGF-β1, which is mainly synthesized by HSCs, Kupffer cells, and sinusoidal endothelial cells promotes the proliferation of HSCs, and their myofibroblastic transformation is one of the strongest pro-fibrotic factors. 26 TGF-β1 also strongly stimulates HSCs to produce collagen-I and collagen-III to produce a large amount of ECM, while inhibiting ECM degradation.…”

“…The conformation of activated Smad 2/3 changes, leading to its release from the receptor complex to reacting with Smad4 to form a Smad 2/3-Smad4 complex. 28 The transportation of this complex to the nucleus enhances the expression of α-SMA by HSCs, which further activates the HSCs. 28 NF-κB is an important transcription factor, which is involved in many physiological and pathological processes, such as inflammation, apoptosis, and liver fibrosis.…”

“… 28 The transportation of this complex to the nucleus enhances the expression of α-SMA by HSCs, which further activates the HSCs. 28 NF-κB is an important transcription factor, which is involved in many physiological and pathological processes, such as inflammation, apoptosis, and liver fibrosis. 30 NF-κB activation can contribute to hepatocyte injury and subsequent inflammation.…”

Intestinal dysbacteriosis-induced IL-25 promotes development of HCC via alternative activation of macrophages in tumor microenvironment

“…The primers used for the amplification of human genes were listed in Additional file 1: Table S3. RT-qPCR, ELISA and WB was performed as described previously [13, 21, 22].…”