MicroRNA-145 Increases the Apoptosis of Activated Hepatic Stellate Cells Induced by TRAIL through NF-κB Signaling Pathway

Abstract

During the liver fibrosis recovery stage tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can effectively induce apoptosis of activated hepatic stellate cells (HSCs). Normal hepatic stellate cells are resistant to TRAIL cytotoxicity. Therefore, enhancing the sensitivity of TRAIL-induced apoptosis of HSCs may be useful to treat hepatic fibrogenesis. Here, we demonstrated that miR-145 and TRAIL were down-regulated in both liver fibrosis tissue samples and transforming growth factor-β1 induced HSCs, concomitant with increased the expression of ZEB2. In addition, we found that mimics-mediated over-expression of miR-145 led to resistance to the ZEB2 expression and up-regulation of the TRAIL-induced apoptosis after treatment of LX-2 cells with TRAIL. Furthermore, ZEB2-siRNA transfected LX-2 cells showed the increased sensitivity to TRAIL-induced apoptosis. Whereas, opposite results were obtained in miR-145-inhibitor group or ZEB2 plasmid group. Moreover, miR-145 regulated ZEB2 gene expression by specifically interacting with the 3′-UTR of ZEB2 mRNA to inhibit the expression of ZEB2. Further studies showed that the over-expression of ZEB2 could inhibit TRAIL-induced apoptosis via inhibiting nuclear factor-κB (NF-κB) signaling pathway in LX-2 cells. Collectively, our data suggest that up-regulation of miR-145 can down-regulate ZEB2 expression, consequently promoting TRAIL-induced apoptosis in LX-2 cells through NF-κB signaling pathway, which facilitates the resolution of liver fibrosis.

<p>Gut Dysbiosis and Increased Intestinal Permeability Drive microRNAs, NLRP-3 Inflammasome and Liver Fibrosis in a Nutritional Model of Non-Alcoholic Steatohepatitis in Adult Male Sprague Dawley Rats</p>

“…Corroborating with our data, Yang et al found that miR-145 was significantly down-regulated in liver fibrosis tissues by activation and proliferation of hepatic stellate cells. 43 These findings are in accordance with the cascade of events that we observed in this study, demonstrating that different hits act in parallel promoting the progression from steatosis to NASH. The expression of miR-122 and miR-145 act on the hepatic stellate cells, promoting higher deposition of collagen fibers, which were observed at the histopathological evaluation.…”

“… 42 The accumulation of fat in the liver has been associated with changes in the composition of the gut microbiota, which promotes increased intestinal permeability, activation of microRNAs, a class of small endogenous non-coding RNAs (19 to 22 nucleotides in length) that regulate gene expression at the post-transcriptional level and also the synthesis of pro-inflammatory cytokines, culminating in the influx of inflammatory cells to the liver, activating stellate cells and leading to collagen deposition events that may explain the progression of hepatic steatosis for NASH. 9 , 43 , 44 In this study, we demonstrate a clear distinction of bacterial communities between experimental groups, in addition, the intervention group showed a significant decrease in observed OTUs. Our data corroborate with experimental and clinical studies that demonstrate as a common denominator a lower bacterial diversity and dysbiosis in NASH.…”

MiR‐145 inhibits the migration and invasion of papillary thyroid carcinoma cells through NF‐κB pathway regulation

“…Mei et al suggested that miR‐145‐5p suppresses the migration and invasion process of the esophageal cancer cells through changes in the activity of the Sp1/NF‐κB signaling pathway. Yang et al certified that the upregulation of miR‐145 can promote the apoptosis of activated hepatic stellate cells through the NF‐κB signaling pathway. Those findings are consistent with our results.…”

Relevance Function of Linc-ROR in the Pathogenesis of Cancer

“…For example, circMTO1 have been demonstrated to harbor conventional miRNA binding sites and has been identified as an inhibitor of miRNA-9 in hepatocellular carcinoma (HCC) ( Han et al, 2017 ). Additionally, our previous study has demonstrated that miRNA plays a role in limiting the development of liver fibrosis by markedly blocking the activation and proliferation of hepatic stellate cells (HSCs), suggesting that miRNAs might be involved in the development and progression of several forms of cancers ( Yang J. et al, 2017 ; Yang et al, 2019 ). Of note, lncRNAs, which are mainly transcribed by RNA polymerase II, are a new kind of ncRNA that are longer than 200 nucleotides ( Ma et al, 2016 ).…”