MicroRNA-137 regulates hypoxia-induced retinal ganglion cell apoptosis through Notch1

Li, Haiyan; Zhu, Zhongqiao; Liu, Jianrong; Wang, Jianzhou; Qu, Chaoyi

doi:10.3892/ijmm.2017.3319

Cited by 12 publications

(17 citation statements)

References 52 publications

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“…The results of the present study suggested that the activation of the Notch signaling pathway serves a pivotal role in HG-mediated HRECs injury. In retinal ganglion cells, hypoxia-induced Notch1 expression and signaling activation, and inhibition of Notch signaling significantly aggravated hypoxia-induced cell apoptosis (40). In a co-culture system of ligand-dependent Notch activation using primary cultured retinal pericytes and a mesenchymal cell line derived from an inducible mouse model expressing δ-like 1 Notch ligand, ligand-mediated Notch activity was observed to protect retinal pericytes from light-induced cell death (41).…”

Section: Discussionmentioning

confidence: 99%

Activation of the Notch‑Nox4‑reactive oxygen species signaling pathway induces cell death in high glucose‑treated human retinal endothelial cells

Jiao

et al. 2018

Mol Med Report

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Diabetic retinopathy (DR) occurs in almost all patients with diabetes and remains as one of the major causes of vision loss worldwide. Nevertheless, the molecular mechanisms underlying the pathogenesis of DR remain elusive. The present study aimed to investigate the role and association of Notch signaling and NADPH oxidase 4 (Nox4)-mediated oxidative stress in high glucose (HG)-treated retinal cells. Human retinal endothelial cells were cultured for various durations in RPMI-1640 medium containing 30 mM glucose (HG) or 30 mM mannitol (MN) as an osmotic control; apoptotic cell death and reactive oxygen species (ROS) levels were assessed, respectively. Alterations in the expression profiles of Nox and Notch proteins were evaluated using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Knockdown of Nox4 and recombination signal-binding protein J (RBPj) was generated by transfection with specific small interfering (siRNA). Persistent activation of Notch signaling was induced via the overexpression of Notch intracellular domain (NICD). In the present study, time-dependent increases in ROS production and cell death were detected in HG-treated cells. Depletion of ROS by diphenyleneiodonium decreased HG-induced cell death, and suppressed increases in caspase 3 activity and B-cell lymphoma 2-associated X protein levels. In HG-treated cells, Nox4 expression was upregulated at the mRNA and protein levels, and inhibition of Nox4 by GKT137831 or knockdown of expression by siRNA Nox4 significantly reduced ROS levels and cell death. In the presence of HG, Notch1 expression levels were elevated, and increased NICD abundance was detected in whole cell lysates and nuclear fractions. Additionally, HG-induced cell death was decreased by treatment with γ-secretase inhibitor (GSI), but increased via the overexpression of NICD. The application of GSI or knockdown of RBPj by siRNA RBPj prevented increases in Nox4 expression within HG-treated cells. The findings of the present study demonstrated that Nox4-mediated ROS serves an important role in HG-induced retinal cell damage, in which the activation of Notch signaling may be responsible for Nox4 upregulation. Therefore, inhibition of Notch signaling or Nox4 expression may be considered as potential therapeutic targets in patients with DR.

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Section: Discussionmentioning

confidence: 99%

Activation of the Notch‑Nox4‑reactive oxygen species signaling pathway induces cell death in high glucose‑treated human retinal endothelial cells

Jiao

et al. 2018

Mol Med Report

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“…Previous studies have reported that miR-137 could directly target on Notch1 and participate in diabetic kidney disease [35], ischemic stroke [36], and hypoxia-induced retinal ganglion cell apoptosis [37]. Our finding indicated that silence of DSCAM-AS1 and miR-137 mimics could suppress Notch-1 signaling, which is a novel pathway regulating cell proliferation and EMT.…”

Section: Discussionmentioning

confidence: 50%

Long Noncoding RNA DSCAM-AS1 Facilitates Colorectal Cancer Cell Proliferation and Migration via miR-137/Notch1 Axis

Xu¹,

Wu²,

Zhao³

et al. 2020

J. Cancer

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Growing evidences demonstrate that long noncoding RNAs (lncRNAs) participate in various cancers including colorectal cancer (CRC). In the current study, we found that the expression of DSCAM-AS1 in CRC tissues and cell lines was significantly upregulated, and was positively correlated with metastasis status and advanced stage of CRC. In addition, Kaplan-Meier assays also indicated that the expression of DSCAM-AS1 was correlated with poor prognosis in patients with CRC. Silence of DSCAM-AS1 inhibited proliferation and migration of CRC cells. Subcellular fractionation and FISH analyses suggested that DSCAM-AS1 was majorly distributed in cytoplasm of HT29 and LOVO cells. Thus, DSCAM-AS1 might act as a competing endogenous RNA (ceRNA). Subsequently, RT-qPCR results displayed that the expression of miR-137 in CRC tissues was relatively lower than that in the neighboring normal tissues. The interaction between miR-137 and DSCAM-AS1 was demonstrated by luciferase reporter assay. Functionally, miR-137 reversed the pro-proliferation and-metastasis effect of DSCAM-AS1 on CRC cells. Collectively, DSCAM-AS1 promotes CRC progression via sponging miR-137. MiR-137 can suppress the expression of Notch-1, a novel signaling regulating cell proliferation and EMT, by working on the 3'UTR of Notch-1. At last, Notch-1 overexpression or miR-137 inhibition could restore the DSCAM-AS1 silencing-mediated repressive function on cell proliferation and migration. The above data suggested that, DSCAM-AS1 may contribute to CRC cell proliferation and migration by targeting miR-137/Notch-1 axis.

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“…Though it is still debatable whether NOTCH signal plays a positive or negative role in osteogenesis [55], our data displayed impaired osteogenic capacity of hASCs after knocking down NOTCH1. More strikingly, NOTCH1 was validated as a direct target gene of miR-137 in hASCs, the same as in other cell lines [40][41][42][43][44]. HES1 is known as a potential downstream target of NOTCH1 in many studies, but it is not affected in NOTCH1 knockout mice while the expression of HES5, HES-related repressor protein (HERP)1, -2, and − 3 are greatly diminished [56][57][58].…”

Section: Discussionmentioning

confidence: 92%

“…HES1 inactivation not only increases the femoral length and trabecular number in the limb bud of transgenic mice, but also enhances mineral apposition rate and suppresses bone resorption in osteoblasts [39]. NOTCH1 has emerged as a target of miR-137 in human renal mesangial cells [40], retinal ganglion cells [41], neurons [42], non-small cell lung cancer cells [43] and breast cancer cells [44], but whether it is directly inhibited by miR-137 has not yet been identi ed in hASCs. In small cell lung cancer cells, NOTCH1 pathway is activated by LSD1 inhibitor and suppressed due to the binding of LSD1 [45].…”

mentioning

confidence: 99%

A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

Fan

Wang

et al. 2020

Preprint

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Background: MicroRNAs have been recognized as critical regulators for the osteoblastic lineage differentiation of human adipose-derived stem cells (hASCs). Previously, we have displayed that silencing of miR-137 enhances the osteoblastic differentiation potential of hASCs partly through the coordination of lysine-specific histone demethylase 1 (LSD1), bone morphogenetic protein 2 (BMP2), and mothers against decapentaplegic homolog 4 (SMAD4). However, still numerous molecules involved in the osteogenic regulation of miR-137 remain unknown. This study aimed to further elucidate the epigenetic mechanisms of miR-137 on the osteogenic differentiation of hASCs.Methods: hASCs transfected with miR-137 overexpression or knockdown lentiviruses were used to assess the osteogenic capacity by testing the alkaline phosphatase activity, matrix mineralization degree, relative expression level of osteogenesis-associated genes and ectopic osteogenesis in nude mice. Dual-luciferase reporter assay was performed to examine the targeting of the 3' untranslated region (3' UTR) of NOTCH1 by miR-137. Interrelationships of signaling pathways of NOTCH1-hairy and enhancer of split 1 (HES1), LSD1, and BMP2-SMAD4 were thoroughly investigated by separate knockdown of NOTCH1, LSD1, and BMP2.Results: We confirmed that miR-137 directly targeted the 3' UTR of NOTCH1 while positively regulated HES1. After knocking down NOTCH1 or BMP2 individually, we found that these two signals formed a positive feedback loop and activated LSD1. In addition, LSD1 knockdown induced the expression of NOTCH1 while suppressed HES1.Conclusions: Collectively, we proposed a NOTCH1/LSD1/BMP2 co-regulatory signaling network to elucidate the modulation of miR-137 on the osteoblastic differentiation of hASCs, thus providing mechanism-based rationale for miRNA-targeted therapy of bone defect.

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MicroRNA-137 regulates hypoxia-induced retinal ganglion cell apoptosis through Notch1

Cited by 12 publications

References 52 publications

Activation of the Notch‑Nox4‑reactive oxygen species signaling pathway induces cell death in high glucose‑treated human retinal endothelial cells

Activation of the Notch‑Nox4‑reactive oxygen species signaling pathway induces cell death in high glucose‑treated human retinal endothelial cells

Long Noncoding RNA DSCAM-AS1 Facilitates Colorectal Cancer Cell Proliferation and Migration via miR-137/Notch1 Axis

A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

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