MicroRNA‐708 modulates Hepatic Stellate Cells activation and enhances extracellular matrix accumulation via direct targeting TMEM88

• Published in: Journal of cellular and molecular medicine Vol. 24; no. 13; pp. 7127 - 7140
• Main Authors: Xu, Tao, Pan, Linxin, Li, Liangyun, Hu, Shuang, Zhou, Hong, Yang, Chenchen, Yang, Junfa, Li, Haodong, Liu, Yuming, Meng, Xiaoming, Li, Jun
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2020; John Wiley and Sons Inc
• Subjects: Actin; Antibodies; Apoptosis; Apoptosis - drug effects; Catenin; Cell activation; Cell culture; Cell Line; Cell proliferation; Cell Proliferation - drug effects; Collagen (type I); Dishevelled protein; Embryo cells; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Female; Fibrosis; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Humans; Liver; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; liver fibrosis; LX‐2 cells; Male; Matrix metalloproteinase; Matrix Metalloproteinases - metabolism; Membrane Proteins - metabolism; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Microscopy; Middle Aged; miRNA; miR‐708; Original; Signal transduction; Smooth muscle; Stellate cells; Tissue inhibitor of metalloproteinases; Tissue Inhibitor of Metalloproteinases - metabolism; TMEM88; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1; Tumor necrosis factor-TNF; Wnt protein; Wnt Signaling Pathway - drug effects; liver fibrosis; miR-708; TMEM88; LX-2 cells
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.15119

Transmembrane protein 88 (TMEM88) is a potential 2‐transmembrane‐type protein that interacts with the PDZ domain of Dishevelled‐1 (DVL‐1), a crucial component of Wnt signalling pathway through its C‐terminal Val‐Trp‐Val (VWV) motif in Xenopus embryo cells. Since the significant function of β‐catenin in liver fibrosis, it is urgent to study the TMEM88 mechanism in liver fibrosis. The current research was for evaluating the function of TMEM88 in the process of the liver fibrosis and clarifying the inherent mechanism. The study found that TMEM88 is decreased in human fibrotic liver tissues. Functionally, TMEM88 significantly reduced the expression levels of α‐smooth muscle actin (α‐SMA) and collagen type I (Col.I) and repressed extracellular matrix (ECM) accumulation by restoring the balance between matrix metalloproteinases (MMPs) and TIMPs (tissue inhibitor of metalloproteinases). TMEM88 inhibited HSCs proliferation and evaluated the apoptosis of activated LX‐2 cells by regulating Wnt3a, Wnt2b and β‐catenin of Wnt/β‐catenin signalling pathway. Moreover, we demonstrated that miR‐708 particularly targeted TMEM88 3′‐UTR regions and down‐regulated the expression level of TMEM88 in TGF‐β1‐stimulated LX‐2 cells. MiR‐708 promoted the generation of ECM and cell activation in activated LX‐2 cells. These results determined that miR‐708 could promote HSCs activation and enhance ECM accumulation via direct targeting TMEM88 by Wnt/β‐catenin signalling pathway. This will provide a potential target for future research in the process of liver fibrosis.