miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression

Abstract

Background & Aims MicroRNAs (miRNAs) have been shown to be involved in many biological processes by affecting their target gene expression. miR-122 has been extensively studied in hepatocarcinogenesis. However, the role of miR-122 in liver fibrosis remains unknown. Methods The mRNA expression levels of miR-122, prolyl 4-hydroxylase subunit alpha-1 (P4HA1), and CCAAT/enhancer binding protein alpha (C/EBPα) were assessed by real-time PCR. The protein expression levels of P4HA1, C/EBPα and collagen, type I, alpha 1 (COL1A1) were analyzed by Western blot and immunofluorescence. MTT assay was used to assess cell proliferation. Chromatin immunoprecipitation (ChIP) assay was used to examine the binding activity of C/EBPα to miR-122 promoter. Results miR-122 expression was significantly reduced in transactivated HSCs and in the livers of mice treated with CCl4. Overexpression of miR-122 inhibited the proliferation of LX2 cells. We also demonstrated that P4HA1 was a target gene of miR-122. The mRNA expression level of PAHA1 inversely correlated with that of miR-122 in HSCs and in the mouse liver. Overexpression of miR-122 markedly attenuated the expression of P4HA1 via targeting a binding site located at 3′-UTR of P4HA1 mRNA. We further showed that miR-122 overexpression led to decreased collagen maturation and ECM production. Finally, the binding activity of C/EBPα to miR-122 promoter was significantly decreased in activated HSCs. Conclusions Our study suggests that miR-122 may play an important role in negatively regulating collagen production in HSCs and that targeted expression of miR-122 in HSCs may represent a new strategy for the treatment of liver fibrosis.

The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation

“…In detail, mir-122 and mir-133 appear related to functions ascribed to secretomes of MSCs and Muse cells, such as remodeling of extracellular matrix, metabolic processes and stemness control. [64][65][66] Globally speaking, the upstream regulators identified by IPA analysis lend further credit to the putative identified functions of MSC and Muse cells secretomes. Indeed, literature data evidenced that the pinpointed factors do act in controlling cellular process identified by GO and canonical pathway analyses.…”

Reduction of MicroRNA 122 Expression in IFNL3 CT/TT Carriers and during Progression of Fibrosis in Patients with Chronic Hepatitis C

“…Although the IFNL3 polymorphisms seem not to be associated with fibrosis (28,29), the IFNL3 CC genotype was associated with a state of enhanced immunity that can promote necroinflammation (30). Moreover, reports suggested a role of miR-122 in liver fibrosis (31,32). Since miR-122 regulates HCV replication, it is particularly interesting to investigate its role during fibrosis.…”

MicroRNAs in the Communication between Cancer Associated Fibroblasts (CAF) and Cancer Cells

“…MiR-122 overexpression also led to decreased collagen maturation and ECM production [46] whereas miR-126 [42] and miR-17-92 cluster members [37] induced type 1 collagen expression. Reduced expression of miR-335 during HSC activation promotes their cell migration via targeting tenascin-C and enhanced expression of α-SMA and type 1 collagen.…”

“…Binding activity of CCAAT/enhancer binding protein alpha (C/EBPα) to the miR-122 promoter region was reduced in these cells. [46] Furthermore, one member of the miR-33 family (miR-33a), which is located in intronic regions within protein-coding genes for Sterol regulatory element-binding proteins (SREBP-2 and SREBP-1), is highly expressed during TGF-β1 induced activation of the PI3K/Akt pathway in HSCs. This appears to result in expression of type 1 collagen (Col1A1) and α-SMA due to direct targeting of peroxisome proliferator activated receptor-alpha (PPARα).…”