MicroRNA 27b promotes cardiac fibrosis by targeting the FBW7/Snail pathway

Fu, Qiang; Lü, Zhihong; Fu, Xiao; Ma, Shengming; Lu, Xiaochun

doi:10.18632/aging.102465

Cited by 22 publications

(20 citation statements)

References 32 publications

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“…Primary CFs were isolated from neonatal mice (1–2-day-old) using a previously described method. 24 Briefly, neonatal mice were quickly rinsed in 75% ethanol and decapitated. The heart was removed, atrium was excised, and the ventricles were minced and washed with PBS at 4°C to remove excess blood.…”

Section: Methodsmentioning

confidence: 99%

<p>MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation</p>

Li¹,

Mao²,

Zhou³

et al. 2020

JIR

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Post myocardial infarction (MI) fibrosis has been identified as an important factor in the progression of heart failure. Previous studies have revealed that microRNA-21 (miR-21) plays an important role in the pathogenesis of fibrosis. The purpose of this study was to explore the role of miR-21 in post-MI cardiac fibrosis. Material and Methods: MI was established in wild-type (WT) and miR-21 knockout (KO) mice. Primary mice cardiac fibroblasts (CFs) were isolated from WT and miR-21 KO mice and were treated with angiotensin II (Ang II) or Sprouty1 (Spry1) siRNA. Histological analysis and echocardiography were used to determine the extent of fibrosis and cardiac function. Results: Compared with WT mice, miR-21 KO mice displayed smaller fibrotic areas and decreased expression of fibrotic markers and inflammatory cytokines. In parallel, Ang IIinduced myofibroblasts transformation was partially inhibited upon miR-21 KO in primary CFs. Mechanistically, we found that the expression of Spry1, a previously reported target of miR-21, was markedly increased in miR-21 KO mice post MI, further inhibiting ERK1/2 activation. In vitro studies showed that Ang II activated ERK1/2/TGF-β/Smad2/3 pathway. Phosphorylated Smad2/3 further enhanced the expression of α-SMA and FAP and may promote the maturation of miR-21, thereby downregulating Spry1. Additionally, these effects of miR-21 KO on fibrosis were reversed by siRNA-mediated knockdown of Spry1. Conclusion: Our findings suggest that miR-21 promotes post-MI fibrosis by targeting Spry1. Furthermore, it mediates a positive feedback on Ang II, thereby inducing the ERK/ TGF-β/Smad pathway. Therefore, targeting the miR-21-Spry1 axis may be a promising therapeutic option for ameliorating post-MI cardiac fibrosis.

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Section: Methodsmentioning

confidence: 99%

<p>MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation</p>

Li¹,

Mao²,

Zhou³

et al. 2020

JIR

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“…siRNA mediated inhibition of MMP-9 significantly reduces expression of Snail, and conversely, knockdown of Snail, a transcription factor of MMP-9, suppresses expression of MMP-9 (39). FBW7 abrogation of Snail protein also inhibits MMP-9 expression (40). Interestingly, MCV sT induced Snail expression in our initial transcriptional analysis (Fig.…”

Section: St Activates Expression Of Emt Regulator Snailmentioning

confidence: 67%

“…In this report, we show that MCV sT LSD inhibition of FBW7 promotes the upregulation of MMP-9 and contributes to MCV sT-mediated cell migration and invasion. The mechanism by which FBW7 regulates MMP-9 expression is currently unclear, although many studies have shown MMP-9 expression is directly and indirectly regulated by FBW7 substrates such as XBP1, Notch1, and Snail (12,40,51). Snail is known to be a substrate of both FBW7 (40) and -TrCP (52), another major SCF E3 ligase that MCV sT targets through the LSD (7).…”

Section: Discussionmentioning

confidence: 99%

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

Nwogu

Ortiz

Whitehouse

et al. 2020

J Virol

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Merkel cell polyomavirus (MCV) small T antigen (sT) is the main oncoprotein for the development of Merkel cell carcinoma (MCC). MCC is a rare, clinically aggressive neuroendocrine tumor of the skin with a high propensity for local, regional, and distant spread. The dysregulation of matrix metalloproteinase-9 (MMP-9) has been implicated in multiple essential roles in the development of various malignant tumor cell invasion and metastasis. Previously, MCV sT was shown to induce the migratory and invasive phenotype of MCC cells through the transcriptional activation of the sheddase molecule, ADAM 10 (A disintegrin and metalloprotease domain-containing protein 10). In this study, we show that MCV sT protein stimulates differential expression of epithelial–mesenchymal transition (EMT)-associated genes, including MMP-9 and Snail. This effect is dependent on the presence of the large T stabilization domain (LSD), which is known to be responsible for cell transformation through targeting of promiscuous E3 ligases, including FBW7, a known MMP-9 and Snail regulator. Chemical treatments of MMP-9 markedly inhibited MCV sT-induced cell migration and invasion. These results suggest that MCV sT contributes to the activation of MMP-9 as a result of FBW7 targeting, and increases the invasive potential of cells, which can be used for targeted therapeutic intervention. IMPORTANCE Merkel cell carcinoma (MCC) is the most aggressive cutaneous tumor without clearly defined treatment. Although MCC has a high propensity for metastasis, little is known about the underlying mechanisms that drive MCC invasion and metastatic progression. MMP-9 has shown to play a detrimental role in many metastatic human cancers, including melanoma and other non-melanoma skin cancers. Our study shows that MCV sT-mediated MMP-9 activation is driven through the LSD, a known E3 ligase targeting domain, in MCC. MMP-9 may serve as the biochemical culprit to target and develop a novel approach for the treatment of metastatic MCC.

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“…The sections were stained according to the HE staining procedure. After sealing with a neutral resin (Solarbiolife sciences, G8590), the slices were photographed using an optical microscope (Leica Microsystems, DMILLED) [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Catechins from oolong tea improve uterine defects by inhibiting STAT3 signaling in polycystic ovary syndrome mice

Hong

et al. 2020

Chin Med

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Background It is showed that inflammation is causative factor for PCOS, leading to a decline in ovarian fertility. Previous studies have reported that tea consumption can reduce the incidence of ovarian cancer. We speculate that catechins from oolong tea (Camellia sinensis (L.) O. Kuntze) may have a potential therapeutic effect on PCOS. This study aims to investigate the effects of oolong tea catechins on the uterus of polycystic ovary syndrome (PCOS) mice induced by insulin combined with human chorionic gonadotropin (hCG). Methods Sixty female mice were divided into 6 groups (n = 10): model, model + Metformin 200 mg/kg, model + catechins 25 mg/kg, model + catechins 50 mg/kg, and model + catechins 100 mg/kg. Another forty female mice were divided into 4 groups (n = 10): control, control + catechins 100 mg/kg, model, and model + catechins 100 mg/kg. Ovarian and uterine weight coefficients, sex hormone levels, glucose metabolism and insulin resistance, and ovarian and uterine pathology were examined. Changes in NF-κB-mediated inflammation, MMP2 and MMP9 expressions, and STAT3 signaling were evaluated in the uterus of mice. Results Catechins could effectively reduce the ovarian and uterine organ coefficients, reduce the levels of E2, FSH and LH in the blood and the ratio of LH/FSH, and improve glucose metabolism and insulin resistance in PCOS mice induced by insulin combined with hCG. In addition, catechins could significantly down-regulated the expression of p-NF-κB p65 in the uterus and the protein expressions of the pro-inflammatory factors (IL-1β, IL-6, and TNF-α). The expressions of mmp2 and mmp9 associated with matrix degradation in uterine tissue were also significantly down-regulated by catechins. Further, catechins significantly reduced the expression of p-STAT3 and increased the expression of p-IRS1 and p-PI3K in the uterus of PCOS mice. Conclusion Catechins from oolong tea can alleviate ovarian dysfunction and insulin resistance in PCOS mice by inhibiting uterine inflammation and matrix degradation via inhibiting p-STAT3 signaling.

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MicroRNA 27b promotes cardiac fibrosis by targeting the FBW7/Snail pathway

Cited by 22 publications

References 32 publications

<p>MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation</p>

<p>MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation</p>

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

Catechins from oolong tea improve uterine defects by inhibiting STAT3 signaling in polycystic ovary syndrome mice

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