Cytoplasmic NEAT1 Suppresses AML Stem Cell Self‐Renewal and Leukemogenesis through Inactivation of Wnt Signaling

Yan, Huiwen; Wang, Zhi; Sun, Yan; Hu, Liangding; Bu, Pengcheng

doi:10.1002/advs.202100914

Cited by 29 publications

(26 citation statements)

References 34 publications

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“…It has been reported that Lnc NEAT1 mediated by exosomes can facilitate endometrial cancer progression [ 18 ]. Recent evidence indicates that Lnc NEAT1 regulates stem cell function [ 19 , 20 ]. Nevertheless, the roles of Lnc NEAT1 in EPC function and skin flap survival remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

et al. 2022

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Background Flap transplantation is commonly used in reconstructive surgery. A prerequisite for skin flap survival is sufficient blood supply. However, such approaches remain unclear. This study aimed to explore the underlying mechanisms of exosomes derived from human umbilical vascular endothelial cells (HUVECs) exposed to oxidative stress on endothelial progenitor cells (EPCs) and their subsequent influence on the survival of skin flaps. Methods HUVECs were treated with various concentrations of H2O2 to establish an oxidative stress model. To investigate the effects of H2O2-HUVEC-Exos and HUVEC-Exos, Cell Counting Kit-8, tube formation, invasion assays, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed in EPCs. Microarray analysis was used to reveal the differentially expressed long non-coding RNAs (lncRNAs) in the H2O2-HUVEC-Exos and HUVEC-Exos. In addition, gene silencing and western blotting were employed to determine the mechanism behind lncRNA nuclear enrichment enriched transcript 1 (Lnc NEAT1) in EPCs. Further, a rat skin flap model was used to determine the role of the exosomes in skin flap survival in vivo. Results HUVECs were stimulated with 100 μmol/L H2O2 for 12 h to establish an oxidative stress model. H2O2-HUVEC-Exos promoted the proliferation, tube formation, and invasion of EPCs and remarkably increased skin flap survival compared to the HUVEC-Exos and control groups. Sequencing of exosome RNAs revealed that the Lnc NEAT1 level was dramatically increased in the H2O2-HUVEC-Exos, leading to activation of the Wnt/β-catenin signaling pathway. Comparatively, knockdown of Lnc NEAT1 in HUVEC-Exos and H2O2-HUVEC-Exos significantly inhibits the angiogenic capacity of EPCs, reduced the survival area of skin flap and downregulated the expression levels of Wnt/β-catenin signaling pathway proteins, whereas Wnt agonist partly reversed the negative effect of NEAT1 downregulation on EPCs through the Wnt/β-catenin signaling pathway. Conclusions Exosomes derived from HUVECs stimulated by oxidative stress significantly promoted the pro-angiogenic ability of EPCs through the Wnt/β-catenin signaling pathway mediated by Lnc NEAT1 and hence enhanced random flap survival in vivo. Therefore, the application of H2O2-HUVEC-Exos may serve as an alternative therapy for improving random skin flap survival.

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Section: Introductionmentioning

confidence: 99%

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

et al. 2022

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“…Is the role of Neat1 exclusively nuclear in the paraspeckle, or is it exported to the cytoplasm with the IRESome complex? Several observations argue for the presence of Neat1 in the cytoplasm: our FISH experiments clearly identify the Neat1-2 isoform in the cytoplasm (Fig.1, figure supplement 2), while a recent report shows that Neat1-1 isoform is released from nucleus to cytoplasm where it suppresses the Wnt signaling in leukemia stem cells and acts as a tumor suppressor in acute myeloid leukemia (Yan et al, 2021). Neat1-2 isoform has been detected in the cytoplasm of hematopoietic cells by other authors.…”

Section: Discussionmentioning

confidence: 57%

Long non-coding RNA Neat1 and paraspeckle components are translational regulators in hypoxia

Godet

David

Roussel

et al. 2021

Preprint

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Internal ribosome entry sites (IRESs) drive translation initiation during stress. In response to hypoxia, (lymph)angiogenic factors responsible for tissue revascularization in ischemic diseases are induced by the IRES-dependent mechanism. Here we searched for IRES trans-acting factors (ITAFs) active in early hypoxia in mouse cardiomyocytes. Using knock-down and proteomics approaches, we show a link between a stressed-induced nuclear body, the paraspeckle, and IRES-dependent translation. Our data reveal that the long non-coding RNA Neat1, an essential paraspeckle component, is a key translational regulator, active on IRESs of (lymph)angiogenic and cardioprotective factor mRNAs. In addition, paraspeckle proteins p54nrb and PSPC1 as well as nucleolin and Rps2, two p54nrb-interacting proteins identified by mass spectrometry, are ITAFs for IRES subgroups. Paraspeckle thus appears as the site of IRESome assembly in the nucleus. Polysome PCR array shows that the Neat1_2 isoform widely affects translation of mRNAs containing IRESs, involved in stress response, angiogenesis or cardioprotection.

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“…The Wnt/ β-catenin pathway is one of the significant signaling pathways involved in stem cell self-renewal. The positive effect of the Wnt/β-catenin pathway on CSC self-renewal has been reported in various cancers [ 90 , 91 ], such as liver cancer [ 90 ], breast cancer [ 92 ], colorectal cancer [ 93 ], and acute myelogenous leukemia [ 94 , 95 ]. Wnt ligands can combine with their receptors Frizzled receptors (Fz) and co-receptors low-density lipoprotein receptor-related protein 5 (LRP5)/6, phosphorylating the cytoplasmic domain of LRP and then recruiting the scaffolding protein Disheveled (Dvl) to disassemble the destruction complex.…”

Section: Csc Self-renewal and Lipid Raftmentioning

confidence: 99%

The lipid rafts in cancer stem cell: a target to eradicate cancer

Zhang

Zhu

et al. 2022

Stem Cell Res Ther

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Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem cell properties that sustain cancers, which may be responsible for cancer metastasis or recurrence. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in the plasma membrane that mediate various intracellular signaling. The occurrence and progression of cancer are closely related to lipid rafts. Emerging evidence indicates that lipid raft levels are significantly enriched in CSCs compared to cancer cells and that most CSC markers such as CD24, CD44, and CD133 are located in lipid rafts. Furthermore, lipid rafts play an essential role in CSCs, specifically in CSC self-renewal, epithelial-mesenchymal transition, drug resistance, and CSC niche. Therefore, lipid rafts are critical regulatory platforms for CSCs and promising therapeutic targets for cancer therapy.

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Cytoplasmic NEAT1 Suppresses AML Stem Cell Self‐Renewal and Leukemogenesis through Inactivation of Wnt Signaling

Cited by 29 publications

References 34 publications

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

Long non-coding RNA Neat1 and paraspeckle components are translational regulators in hypoxia

The lipid rafts in cancer stem cell: a target to eradicate cancer

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