Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells

Genz, Berit; Coleman, Miranda A.; Irvine, Katharine M.; Kutasovic, Jamie R.; Miranda, Mariska; Gratte, Francis D.; Tirnitz–Parker, Janina E.E.; Olynyk, John K.; Calvopina, Diego A.; Weis, Anna; Cloonan, Nicole; Robinson, Harley; Hill, Michelle M.; Al-Ejeh, Fares; Ramm, Grant A.

doi:10.1038/s41598-019-44865-1

Cited by 24 publications

(18 citation statements)

References 74 publications

(84 reference statements)

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“…The dose-related fold increase over that of the control was exceptional. The large increase in miRNA levels after transfection was consistent with recent literature 19 , 20 . When transfecting the inhibitors, the target miRNAs were detected to be near zero, indicating the successful inhibition of the miRNAs of interest using their inhibitors.…”

Section: Resultssupporting

confidence: 92%

microRNA-25 as a novel modulator of circadian Period2 gene oscillation

Park

Kim

et al. 2020

Exp Mol Med

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Circadian clock controls an organism’s biological rhythm and regulates its physiological processes in response to external time cues. Most living organisms have their own time-keeping mechanism that is maintained by transcriptional–translational autoregulatory feedback loops involving several core clock genes, such as Period. Recent studies have found the relevance between the modulation of circadian oscillation and posttranscriptional modifications by microRNAs (miRNAs). However, there are limited studies on candidate miRNAs that regulate circadian oscillation. Here, we characterize the functions of novel miRNA-25 regulating circadian Period2 (Per2) expression. Using several in silico algorithms, we identified novel miR-25-3p that, together with miR-24-3p, targets the Per2 gene. Luciferase reporter assays validated that miR-25-3p and miR-24-3p repressed Per2 expression and confirmed their predicted binding sites in the 3′-untranslated region (UTR) of Per2 mRNA. Real-time bioluminescence analyses using Per2::Luc mouse embryonic fibroblasts confirmed that PER2 protein oscillation patterns were responsive to miR-25-3p and miR-24-3. The overexpression of miR-25-3p or miR-24-3p resulted in the dampening and period shortening of the PER2::LUC oscillation, while inhibition of either miRNA increased the relative amplitude of the PER2::LUC oscillation. Notably, endogenous miR-25-3p expression in the suprachiasmatic nucleus (SCN) showed no circadian rhythmicity, but the expression levels differed in various brain regions and peripheral tissues. These results suggest that the posttranscriptional regulation of miR-25-3p and miR-24-3p may differ according to Per2 gene expression in different tissue regions. In summary, we found that novel miR-25-3p was involved in fine-tuning circadian rhythmicity by regulating Per2 oscillation at the posttranscriptional level and that it functioned synergistically with miR-24-3p to affect Per2 oscillation.

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Section: Resultssupporting

confidence: 92%

microRNA-25 as a novel modulator of circadian Period2 gene oscillation

Park

Kim

et al. 2020

Exp Mol Med

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“…In a very recent study, we could demonstrate that profibrogenic effects of miR-942 are mediated through targeting BAMBI, a TGF-β decoy receptor, leading to enhanced fibrogenic TGF-β signaling [176]. Further, Genz et al showed an antifibrotic role for miR-25-3p, mediated by its ability to inhibit TGF-β induced SMAD2 phosphorylation and collagen deposition in LX-2 cells [186].…”

Section: Tgf-β Signaling and Epigenetics In Liver Fibrosismentioning

confidence: 99%

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Dewidar

Meyer

Dooley

et al. 2019

Cells

514

363

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Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

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“…miRNAs are involved in almost all physiological and pathological events, including the fine regulation of the Notch pathway. Indeed, an ever-growing number of miRNAs have been reported as modulators of the Notch pathway [ 40 – 43 ]. A list of miRNAs experimentally-validated by gene reporter assay as negative regulators of Notch receptors and ligands is available as Supplementary Information [see Additional file 1 : Table S1].…”

Section: Notch Activation Processing and Regulationmentioning

confidence: 99%

Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway

et al. 2021

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Fibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibrogenic process, often in a context-dependent manner. However, the pathogenetic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibroproliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-β1, and therapeutic strategies under development.

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Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells

Cited by 24 publications

References 74 publications

microRNA-25 as a novel modulator of circadian Period2 gene oscillation

microRNA-25 as a novel modulator of circadian Period2 gene oscillation

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway

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