Upregulation ofmicroRNA-126in Hepatic Stellate Cells May Affect Pathogenesis of Liver Fibrosis Through theNF-κBPathway

Abstract

Hepatic fibrosis, which results from chronic liver disease, currently lacks effective treatment. MicroRNAs, a group of small noncoding RNA molecules, have been observed to play an essential role in liver diseases, including hepatic fibrosis. In this study, we described the regulation of nuclear factor kappa B (NF-κB) inhibitor alpha (IκBα) and its possible signaling pathway by miR-126 in human hepatic stellate cell (HSC) line LX-2. The 3'-untranslated region (3'-UTR) of IκBα combined with miR-126 was analyzed by using a dual-luciferase reporter assay. Furthermore, the effects of miR-126 on IκBα mRNA and protein and NF-κB protein expression were assessed by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blot analysis in the human HSC LX-2 cell line transfected with miR-126 mimic or inhibitor. Moreover, to understand the molecular mechanism of miR-126 in promoting liver fibrosis through NF-κB signaling pathway, the NF-κB downstream signaling factors expression such as transforming growth factor (TGF)-β1 and collagen I mRNA were detected by real-time qRT-PCR. We identified that IκBα is a potential target gene of miR-126, by directly targeting its 3'-UTR. Endogenous miR-126 and exogenous miR-126 mimic inhibited IκBα expression. Moreover, overexpression of miR-126 reduced total and the cytoplasm IκBα protein expression and increased total and cytoblast NF-κB protein expression of LX-2. Conversely, knockdown of miR-126 could inhibit NF-κB activation by upregulation of IκBα protein expression. Further, miR-126 promoted TNF-a-induced TGF-β1 and collagen I mRNA expression in LX-2 cells. miR-126 may play an important role in hepatic fibrosis by downregulating the expression of IκBα partly through the NF-κB signaling pathway.

Dysregulation of miRNA Expression in Cancer Associated Fibroblasts (CAFs) and Its Consequences on the Tumor Microenvironment

“…MiR-27a/b-transfected normal fibroblast showed α-SMA expression and increased production of TGF-β as typical characteristics of CAFs [26]. In addition, miR-126 can support TNFα induced TGF-β1 expression [44]. MiR-205 has been observed as most downregulated miR in prostate cancer cells upon CAF stimulation due to direct transcriptional repression by HIF-1α, a known redox-sensitive transcription factor [45].…”

Puerarin protects against CCl4-induced liver fibrosis in mice: possible role of PARP-1 inhibition

“…HSCs subjected to stress are regarded as the major origin of myofibroblasts, the function of which are expressing some fibrosis-associated proteins, namely alpha-smooth muscle actin(α-SMA), fibronectin, and collagen type I, III, and IV [3]. Some reports uphold that HSCs could also be activated by NF-κB signaling pathway through upregulation of transforming growth factor (TGF)-β which belongs to the NF-κB downstream signaling factors [4]. Meanwhile, fibrosis response is also associated with dysfunctional mitochondria [5] and accumulated reactive oxygen species(ROS) [6].…”

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.…”

“…[25] In addition, miR-126 can support TNFα induced TGF-β1 expression. [42] MiR-205 has been observed as most downregulated miR in prostate cancer cells upon CAF stimulation due to direct transcriptional repression by HIF-1α, a known redox-sensitive transcription factor. [57] In addition, miR-127 is the best described member of a large cluster of miRs on chromosome 14 that also act as key modulators of TGF-related cellular senescence by targeting critical regulators of the senescence pathways.…”