MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4

2022 ◽  
Author(s):  
Tatsuya Aonuma ◽  
Bruno Moukette ◽  
Satoshi Kawaguchi ◽  
Nipuni P. Barupala ◽  
Marisa N. Sepúlveda ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cardiac Fibroblasts ◽  
Cardiac Fibroblast ◽  
Null Mouse ◽  
Increased Risk

Background: MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction–associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive. Methods: We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis. Results: Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4 . Conclusions: Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.

Abstract 211: Long Noncoding RNA Myocardial Infarction Associated Transcript, MIAT Exacerbates Maladaptive Cardiac Remodeling by Functioning as a Competing Endogenous RNA of MicroRNA-150 During Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Tatsuya Aonuma ◽  
Bruno Moukette ◽  
Il-man Kim
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Noncoding Rna ◽  
Target Genes ◽  
Cardiac Injury ◽  
Noncoding Rnas ◽  
Nucleotide Polymorphisms ◽  
Competing Endogenous Rna ◽  
Increased Risk

Cardiac injury is accompanied by dynamic changes in the expression of noncoding RNAs such as microRNAs (miRs) and long noncoding RNAs (lncRNAs) that regulate target genes. We previously reported that β 1 -adrenergic receptor/β-arrestin1-responsive miR-150 plays a vital cardioprotective role in myocardial infarction (MI) via decreasing cardiac cell apoptosis (Fig. A). MiR-150 is regulated by MI-Associated Transcript (MIAT), a lncRNA that directly interacts with miR-150 and functions as its competing endogenous RNA in vitro . Gain-of-function single nucleotide polymorphisms in MIAT are associated with increased risk of MI in humans, and MIAT is upregulated in post-MI hearts, concurrent with downregulation of miR-150. Despite the increasing data from both human and rodent studies, the conserved functional MIAT/miR-150 axis in cardiac pathology has never been investigated in genetically modified mice. Here, we hypothesize that MIAT competitively sequesters miR-150 and blocks the inhibitory effect of miR-150 on proapoptotic genes, thereby increasing maladaptive post-MI remodeling. Using novel mouse models, we demonstrate that global genetic deletion of MIAT in mice protects hearts against MI, while genetic overexpression of MIAT worsens maladaptive cardiac remodeling. Moreover, MIAT downregulates miR-150 in the heart, while miR-150 does not repress MIAT. Importantly, we show that miR-150 overexpression prevents the detrimental post-MI effects caused by overexpression of MIAT (Fig. B). In conclusion, these findings reveal a pivotal functional interaction between MIAT and miR-150 as a novel epigenetic regulatory mechanism pertinent to ischemic cardiac injury.

scholarly journals Long noncoding RNA WEE2-AS1 plays an oncogenic role in glioblastoma by functioning as a molecular sponge for microRNA-520f-3p

2020 ◽  
Author(s):  
Hengzhou Lin ◽  
Dahui Zuo ◽  
Jiabin He ◽  
Tao Ji ◽  
Jianzhong Wang ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Tumor Diameter ◽  
Polymerase Chain ◽  
Specificity Protein

The long noncoding RNA WEE2 antisense RNA 1 (WEE2-AS1) plays anoncogenic role in hepatocellular carcinoma and triple negative breast cancerprogression. In this study, we investigated the expression and roles of WEE2-AS1 inglioblastoma (GBM). Furthermore, the molecular mechanisms behind the oncogenicactions of WEE2-AS1 in GBM cells were explored in detail. WEE2-AS1 expressionwas detected using quantitative real-time polymerase chain reaction. The roles ofWEE2-AS1 in GBM cells were evaluated by the Cell Counting Kit-8 assay, flowcytometric analysis, and Transwell cell migration and invasion assays, and tumorxenograft experiments. WEE2-AS1 expression was evidently enhanced in GBM tissuesand cell lines compared with their normal counterparts. An increased level of WEE2-AS1 was correlated with the average tumor diameter, Karnofsky Performance Scalescore, and shorter overall survival among GBM patients. Functionally, depleted WEE2-AS1 attenuated GBM cell proliferation, migration, and invasion in vitro, promoted cellapoptosis, and impaired tumor growth in vivo. Mechanistically, WEE2-AS1 functionedas a molecular sponge for microRNA-520f-3p (miR-520f-3p) and consequentlyincreased specificity protein 1 (SP1) expression in GBM cells. A series of recoveryexperiments revealed that the inhibition of miR-520f-3p and upregulation of SP1 couldpartially abrogate the influences of WEE2-AS1 downregulation on GBM cells. Inconclusion, WEE2-AS1 can adsorb miR-520f-3p to increase endogenous SP1expression, thereby facilitating the malignancy of GBM. Therefore, targeting theWEE2-AS1-miR-520f-3p-SP1 pathway might be a promising therapy for themanagement of GBM in the future.

scholarly journals Long noncoding RNA NEAT1 regulates radio-sensitivity via microRNA-27b-3p in gastric cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ying Jiang ◽  
Shan Jin ◽  
Shisheng Tan ◽  
Yingbo Xue ◽  
Xue Cao
Keyword(s):  
Gastric Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Poor Overall Survival ◽  
Survival Fraction ◽  
Radio Sensitivity

Abstract Background Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) exhibits an oncogenic role in multiple cancers, including gastric cancer (GC). But, the functions of NEAT1 in modulating radio-sensitivity of GC and its potential molecular mechanisms have not been totally elucidated. Methods qRT-PCR was performed to detect the expressions of NEAT1 and microRNA-27b-3p (miR-27b-3p). Kaplan–Meier survival curves for NEAT1 expression in GC created using KM Plotter. Colony formation assay was used to determine the survival fraction. Cell apoptosis was evaluated by flow cytometry. Luciferase reporter assay was used to verify the relationship between miR-27b-3p and NEAT1. Results NEAT1 was highly expressed while miR-27b-3p was downregulated in GC tissues and cells. NEAT1 was negatively correlated with that of miR-27b-3p and associated with poor overall survival. Moreover, NEAT1 and miR-27b-3p varied inversely after radiation in GC tissues and cells. Loss of NEAT1 or upregulation of miR-27b-3p increased the effect of radiation on cell survival fraction inhibition and apoptosis promotion. In addition, NEAT1 negatively regulated the expression of miR-27b-3p in GC cells. Interestingly, the depletion of miR-27b-3p dramatically attenuated the NEAT1 knockdown-mediated function in AGS and MKN-45 cells treated with radiation in vitro. Similarly, downregulation of NEAT1 enhanced the radiation-mediated inhibition of tumor growth, which was mitigated by decrease of miR-27b-3p. Conclusion NEAT1 depletion enhanced radio-sensitivity of GC by negatively regulating miR-27b-3p in vitro and in vivo.

scholarly journals Long Noncoding RNA AFAP1-AS1 Is a Critical Regulator of Nasopharyngeal Carcinoma Tumorigenicity

2020 ◽  
Vol 10 ◽  
Author(s):  
Min Fang ◽  
Minjun Zhang ◽  
Yiqing Wang ◽  
Fangqiang Wei ◽  
Jianhui Wu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Prognostic Indicator ◽  
Clinical Value ◽  
Interacting Protein ◽  
Mrna Stabilization

BackgroundThe long noncoding RNA actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) is a critical player in various cancers. However, the clinical value and functional mechanisms of AFAP1-AS1 during the tumorigenicity of nasopharyngeal carcinoma (NPC) remain unclear. Here, we investigated the clinical application and potential molecular mechanisms of AFAP1-AS1 in NPC tumorigenesis and progression.MethodsThe expression level of AFAP1-AS1 was determined by qRT-PCR in 10 paired fresh human NPC tissues and adjacent normal tissues. RNAscope was performed on 100 paired paraffin-embedded NPC and adjacent nontumor specimens. The biological functions of AFAP1-AS1 were assessed by in vitro and in vivo functional experiments. RNA-protein pull-down assays were performed to detect and identify the AFAP1-AS1-interacting protein KAT2B. Protein-RNA immunoprecipitation (RIP) assays were conducted to examine the interaction of AFAP1-AS1 and KAT2B. Chromatin immunoprecipitation (ChIP) and luciferase analyses were utilized to identify the binding site of transcription intermediary factor 1 alpha (TIF1α) and H3K14ac on the RBM3 promoter.ResultsAFAP1-AS1 is upregulated in NPC and is a poor prognostic indicator for survival in NPC patients. AFAP1-AS1 was required for NPC proliferation in vitro and tumorigenicity in vivo. Mechanistic investigations suggested that AFAP1-AS1 binds to KAT2B and promotes acetyltransferase activation at two residues (E570/D610). KAT2B further promotes H3K14 acetylation and protein binding to the bromo domain of TIF1α. Consequently, TIF1α acts as a nuclear transcriptional coactivator of RBM3 transcription, leading to YAP mRNA stabilization and enhanced NPC tumorigenicity.ConclusionsOur findings suggest that AFAP1-AS1 functions as an oncogenic biomarker and promotes NPC tumorigenicity through enhanced KAT2B acetyltransferase activation and YAP mRNA stabilization.

scholarly journals TRPA1 Promotes Cardiac Myofibroblast Transdifferentiation after Myocardial Infarction Injury via the Calcineurin-NFAT-DYRK1A Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Shuang Li ◽  
Xiongshan Sun ◽  
Hao Wu ◽  
Peng Yu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Cardiac Fibroblasts ◽  
Gene Transfection ◽  
Receptor Potential

Cardiac fibroblasts (CFs) are a critical cell population responsible for myocardial extracellular matrix homeostasis. After stimulation by myocardial infarction (MI), CFs transdifferentiate into cardiac myofibroblasts (CMFs) and play a fundamental role in the fibrotic healing response. Transient receptor potential ankyrin 1 (TRPA1) channels are cationic ion channels with a high fractional Ca2+ current, and they are known to influence cardiac function after MI injury; however, the molecular mechanisms regulating CMF transdifferentiation remain poorly understood. TRPA1 knockout mice, their wild-type littermates, and mice pretreated with the TRPA1 agonist cinnamaldehyde (CA) were subjected to MI injury and monitored for survival, cardiac function, and fibrotic remodeling. TRPA1 can drive myofibroblast transdifferentiation initiated 1 week after MI injury. In addition, we explored the underlying mechanisms via in vitro experiments through gene transfection alone or in combination with inhibitor treatment. TRPA1 overexpression fully activated CMF transformation, while CFs lacking TRPA1 were refractory to transforming growth factor β- (TGF-β-) induced transdifferentiation. TGF-β enhanced TRPA1 expression, which promoted the Ca2+-responsive activation of calcineurin (CaN). Moreover, dual-specificity tyrosine-regulated kinase-1a (DYRK1A) regulated CaN-mediated NFAT nuclear translocation and TRPA1-dependent transdifferentiation. These findings suggest a potential therapeutic role for TRPA1 in the regulation of CMF transdifferentiation in response to MI injury and indicate a comprehensive pathway driving CMF formation in conjunction with TGF-β, Ca2+ influx, CaN, NFATc3, and DYRK1A.

scholarly journals The long noncoding RNA LUCAT1 promotes colorectal cancer cell proliferation by antagonizing Nucleolin to regulate MYC expression

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Runliu Wu ◽  
Liang Li ◽  
Yang Bai ◽  
Bowen Yu ◽  
Canbin Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Multiple Cancer ◽  
G Quadruplex

Abstract The long noncoding RNA (lncRNA) LUCAT1 was recently reported to be upregulated and to play an essential role in multiple cancer types, especially colorectal cancer (CRC), but the molecular mechanisms of LUCAT1 in CRC are mostly unreported. Here, a systematic analysis of LUACT1 expression is performed with data from TCGA database and clinic CRC samples. LUCAT1 is identified as a putative oncogene, which is significantly upregulated in CRC and is associated with poor prognosis. Loss of LUCAT1 restricts CRC proliferative capacities in vitro and in vivo. Mechanically, NCL is identified as the protein binding partner of LUCAT1 by using chromatin isolation by RNA purification coupled with mass spectrometry (ChIRP-MS) and RNA immunoprecipitation assays. We also show that NCL directly binds to LUCAT1 via its putative G-quadruplex-forming regions from nucleotides 717 to 746. The interaction between LUCAT1 and NCL interferes NCL-mediated inhibition of MYC and promote the expression of MYC. Cells lacking LUCAT1 show a decreased MYC expression, and NCL knockdown rescue LUCAT1 depletion-induced inhibition of CRC cell proliferation and MYC expression. Our results suggest that LUCAT1 plays a critical role in CRC cell proliferation by inhibiting the function of NCL via its G-quadruplex structure and may serve as a new prognostic biomarker and effective therapeutic target for CRC.

scholarly journals Long noncoding RNA LINC00673-v4 promotes aggressiveness of lung adenocarcinoma via activating WNT/β-catenin signaling

2019 ◽  
Vol 116 (28) ◽  
pp. 14019-14028 ◽  
Author(s):  
Hongyu Guan ◽  
Ting Zhu ◽  
Shanshan Wu ◽  
Shihua Liu ◽  
Bangdong Liu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Adverse Clinical Outcome ◽  
Potential Therapeutic Target ◽  
In Vivo Experiments ◽  
Abundant Transcript

It is well recognized that metastasis can occur early in the course of lung adenocarcinoma (LAD) development, and yet the molecular mechanisms driving this capability of rapid metastasis remain incompletely understood. Here we reported that a long noncoding RNA, LINC00673, was up-regulated in LAD cells. Of note, we first found that LINC00673-v4 was the most abundant transcript of LINC00673 in LAD cells and its expression was associated with adverse clinical outcome of LAD. In vitro and in vivo experiments demonstrated that LINC00673-v4 enhanced invasiveness, migration, and metastasis of LAD cells. Mechanistically, LINC00673-v4 augmented the interaction between DDX3 and CK1ε and thus the phosphorylation of dishevelled, which subsequently activated WNT/β-catenin signaling and consequently caused aggressiveness of LAD. Antagonizing LINC00673-v4 suppressed LAD metastasis in vivo. Together, our data suggest that LINC00673-v4 is a driver molecule for metastasis via constitutively activating WNT/β-catenin signaling in LAD and may represent a potential therapeutic target against the metastasis of LAD.

scholarly journals Targeting 5-HT 2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling after Myocardial Infarction

Circulation ◽  
2021 ◽  
Author(s):  
J. Caleb Snider ◽  
Lance A. Riley ◽  
Noah T. Mallory ◽  
Matthew R. Bersi ◽  
Prachi Umbarkar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Rna Sequencing ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Cardiac Fibroblast ◽  
Scar Formation ◽  
Border Zone ◽  
Ventricular Contractility ◽  
Fibrotic Process

Background: Myocardial infarction (MI) induces an intense injury response which ultimately generates a collagen-dominated scar. While required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process post-MI. Serotonin 2B receptor (5-HT 2B ) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI. Methods: We employed two pharmacologic antagonists to explore the effect of 5-HT 2B inhibition on outcomes post-MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible, 5-HT 2B ablation driven by Tcf21 MCM and Postn MCM were used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT 2B , respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype. Results: 5-HT 2B antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT 2B antagonism resulted in collagen fiber redistribution to thinner collagen fibers which were more anisotropic, enhancing left ventricular contractility, while fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT 2B from Tcf21 -lineage resident cardiac fibroblasts and saw similar improvements to the pharmacologic approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT 2B after onset of injury in Postn -lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in Dnajb4 expression and Src phosphorylation. Conclusions: Together, our findings illustrate that 5-HT 2B expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI.

scholarly journals Inhibition of Histone Deacetylases Prevents Cardiac Remodeling After Myocardial Infarction by Restoring Autophagosome Processing in Cardiac Fibroblasts

2018 ◽  
Vol 49 (5) ◽  
pp. 1999-2011 ◽  
Author(s):  
Yaping Wang ◽  
Panpan Chen ◽  
Lihan Wang ◽  
Jing Zhao ◽  
Zhiwei Zhong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Cardiac Remodeling ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Cardiac Fibroblasts ◽  
Autophagic Flux ◽  
Simulated Hypoxia

Background/Aims: Histone deacetylases (HDACs) play a critical role in the regulation of gene transcription, cardiac development, and diseases. The aim of this study was to investigate whether the inhibition of HDACs improves cardiac remodeling and its underlying mechanisms in a mouse myocardial infarction (MI) model. Methods: The HDAC inhibitor trichostatin A (TSA, 0.1 mg/kg/day) was administered via daily intraperitoneal injections for 8 consecutive weeks after MI in C57/BL mice. Echocardiography and tissue histopathology were used to assess cardiac function. Cultured neonatal rat cardiac fibroblasts (NRCFs) were subjected to simulated hypoxia in vitro. Autophagic flux was measured using the tandem fluorescent mCherry-GFP-LC3 assay. Western blot was used to detect autophagic biomarkers. Results: After 8 weeks, the inhibition of HDACs in vivo resulted in improved cardiac remodeling and hence better ventricular function. MI was associated with increased LC3-II expression and the accumulation of autophagy adaptor protein p62, indicating impaired autophagic flux, which was reversed by TSA treatment. Cultured NRCFs exhibited increased cell death after simulated hypoxia in vitro. Increased cell death was associated with markedly increased numbers of autophagosomes but not autolysosomes, as assessed by punctate dual fluorescent mCherry-green fluorescent protein tandem-tagged light chain-3 expression, indicating that hypoxia resulted in impaired autophagic flux. Importantly, TSA treatment reversed hypoxia-induced impaired autophagic flux and led to a 40% decrease in cell death. This was accompanied by improved mitochondrial membrane potential. The beneficial effects of TSA therapy were abolished by RNAi intervention targeting LAMP2; likewise, in vivo delivery of chloroquine abolished the TSA-mediated cardioprotective effects. Conclusion: Our results provide evidence that the HDAC inhibitor TSA prevents cardiac remodeling after MI and is dependent on restoring autophagosome processing of cardiac fibroblasts.

scholarly journals Long Noncoding RNA GAS6-AS1 Inhibits Progression and Glucose Metabolism Reprogramming in Lung Adenocarcinoma Via Repressing E2F1-Mediated Transcription of GLUT1

2020 ◽  
Author(s):  
Jing Luo ◽  
Huishan Wang ◽  
Li Wang ◽  
Gaoming Wang ◽  
Yu Yao ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Lactate Production ◽  
Luciferase Reporter

Abstract BackgroundGlucose metabolism reprogramming is one of the hallmarks of cancer cells. While functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of glucose metabolism in lung adenocarcinoma (LUAD) remains incompletely understood. The aim of this study was to uncover the roles for GAS6-AS1 in the regulation of progression and glucose metabolism in LUAD.MethodsThe tumor-suppressive function of GAS6-AS1 was determined by experiments in vitro and nude mice xenograft models. The role of GAS6-AS1 in regulating cancer glucose metabolism was proved by detecting glucose uptake, lactate production, pyruvate production and extracellular acidification rate (ECAR). RNA pull-down assay, RNA immunoprecipitation (RIP) assay, luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assay were used to identify the underlying molecular mechanisms of GAS6-AS1. And the expression level of GAS6-AS1 in LUAD tissues and cells was measured by quantitative real-time PCR.ResultsOverexpression of GAS6-AS1 suppressed tumor progression of LUAD both in vitro and in vivo. Metabolic-related assays revealed that GAS6-AS1 inhibited glucose metabolism reprogramming. Mechanically, GAS6-AS1 was found to repress the expression of glucose transporter GLUT1, a key regulator of glucose metabolism. Ectopic expression of GLUT1 restored the inhibition effect of GAS6-AS1 on cancer progression and glucose metabolism reprogramming. Further investigation identified that GAS6-AS1 directly interacted with transcription factor E2F1 and suppressed E2F1-mediated transcription of GLUT1. And GAS6-AS1 was downregulated in LUAD tissues and correlated with clinicopathological characteristics and survival of patients.ConclusionsTaken together, our results identified GAS6-AS1 as a novel tumor suppressor in LUAD and unraveled its underlying molecular mechanism in reprogramming glucose metabolism. GAS6-AS1 potentially served as a prognostic marker and therapeutic target in LUAD.

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