The mechanism of lncRNA MALAT1 targeting the miR-124-3p/IGF2BP1 axis to regulate osteogenic differentiation of periodontal ligament stem cells.

OBJECTIVES: This study aimed to investigate the regulatory roles of lncRNA MALAT1, miR-124-3p, and IGF2BP1 in osteogenic differentiation of periodontal ligament stem cells (PDLSCs). MATERIALS AND METHODS: We characterized PDLSCs by employing quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses to evaluate the expression of key osteogenic markers including ALPL, SPP1, and RUNX2. Manipulation of lncRNA MALAT1 and miR-124-3p expression levels was achieved through transfection techniques. In addition, early osteogenic differentiation was assessed via Alkaline phosphatase (ALP) staining, and mineral deposition was quantified using Alizarin Red S (ARS) staining. Cellular localization of lncRNA MALAT1 was determined through Fluorescence In Situ Hybridization (FISH). To elucidate the intricate regulatory network, we conducted dual-luciferase reporter assays to decipher the binding interactions between lncRNA MALAT1 and miR-124-3P as well as between miR-124-3P and IGF2BP1. RESULTS: Overexpression of lncRNA MALAT1 robustly promoted osteogenesis in PDLSCs, while its knockdown significantly inhibited the process. We confirmed the direct interaction between miR-124-3p and lncRNA MALAT1, underscoring its role in impeding osteogenic differentiation. Notably, IGF2BP1 was identified as a direct binding partner of lncRNA MALAT1, highlighting its pivotal role within this intricate network. Moreover, we determined the optimal IGF2BP1 concentration (50 ng/ml) as a potent enhancer of osteogenesis, effectively countering the inhibition induced by si-MALAT1. Furthermore, in vivo experiments utilizing rat calvarial defects provided compelling evidence, solidifying lncRNA MALAT1's crucial role in bone formation. CONCLUSIONS: Our study reveals the regulatory network involving lncRNA MALAT1, miR-124-3p, and IGF2BP1 in PDLSCs' osteogenic differentiation. CLINICAL RELEVANCE: These findings enhance our understanding of lncRNA-mediated osteogenesis, offering potential therapeutic implications for periodontal tissue regeneration and the treatment of bone defects.

Long non-coding RNA MALAT1 promotes the proliferation and migration of Schwann cells by elevating BDNF through sponging miR-129-5p.

The proliferation and migration of Schwann cells contribute to nerve regeneration after peripheral nerve injury (PNI). In recent years, roles of long non-coding RNAs (lncRNAs) in PNI have been gradually uncovered. However, a highly conserved nuclear lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in peripheral nerve regeneration remains enigmatic. MALAT1 expression in injured sciatic nerve of mice with PNI was measured by real-time PCR. The proliferative and migrative abilities of Schwann cells were determined after upregulating or downregulating Malat1. The relationship among MALAT1, miR-129-5p, and BDNF was measured. In this study, we found elevated MALAT1 expression in injured sciatic nerve. MALAT1 upregulation in Schwann cells promoted cell proliferation and migration. However, downregulation of MALAT1 caused the suppression of Schwann cell proliferation and migration. Mechanistically, we discovered MALAT1 negatively regulated miR-129-5p through directly binding. Brain-derived neurotrophic factor (BDNF) was a target of miR-129-5p. MALAT1 positively modulated BDNF expression and secretion via decreasing miR-129-5p. Downregulation of BDNF rescued the influences of MALAT1 overexpression on Schwann cell proliferation and migration. In conclusion, MALAT1 was enhanced after PNI and it promoted the proliferation and migration of Schwann cells through sponging miR-129-5p to increase BDNF expression and secretion. This study proved that MALAT1 may be a vital regulator in peripheral nerve regeneration.

Long non-coding RNA MALAT1 and its target microRNA-125b associate with disease risk, severity, and major adverse cardiovascular event of coronary heart disease.

BACKGROUND: This study aimed to explore the correlation of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) with microRNA (miR)-125b and further investigated their associations with disease risk, severity, and prognosis of coronary heart disease (CHD). METHODS: Totally, 230 patients who underwent diagnostic coronary angiography were recruited; meanwhile, 140 of them were diagnosed as CHD and the remaining 90 non-CHD patients served as controls. Plasma sample was collected from each participant for lncRNA MALAT1 and miR-125b mRNA expression detection by reverse transcription-quantitative polymerase chain reaction. The extent of coronary stenosis was evaluated by the Gensini score, and major adverse cardiovascular event (MACE) occurrence during the follow-up was documented in CHD patients. RESULTS: Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 relative expression was increased, but miR-125b relative expression was decreased in CHD patients compared with controls. ROC curve exhibited that lncRNA MALAT1 and miR-125b were of good value in differentiating CHD patients from controls, and further logistic regression analysis verified their independent correlation with CHD risk. Furthermore, lncRNA MALAT1 presented a closely negative correlation with miR-125b in CHD patients, while it presented a weakly negative association with miR-125b in controls. In CHD patients, lncRNA MALAT1 was positively correlated with Gensini score, total cholesterol, low-density lipoprotein cholesterol, C-reactive protein, tumor necrosis factor α, interleukin (IL)-1ß, IL-6, IL-17, and accumulating MACE occurrence; reversely, miR-125b presented a opposite trend. CONCLUSION: Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 might be associated with increased CHD risk, severity, and accumulating MACE incidence via negative interaction with miR-125b, suggesting their possible clinical application as biomarkers in the CHD screening and surveillance.

LncRNA MALAT1 regulates diabetic cardiac fibroblasts through the Hippo-YAP signaling pathway.

Diabetic cardiomyopathy (DCM) is a major diabetes-related microvascular disease. LncRNA MALAT1 is widely expressed in cardiomyocytes responding to hypoxia and high levels of glucose (high glucose). In this study, cardiac fibroblasts (CFs) were transfected with si-MALAT1 and exposed to high glucose. CFs in the high glucose groups were treated with 30 mmol/L glucose, and the control CFs were treated with 5.5 mmol/L glucose. The expression of MALAT1 in the nucleus and cytoplasm of CFs was detected. The biological behavior of CFs, as well as collagen production, activity of the Hippo-YAP pathway, and nuclear localization of YAP were measured. Mouse models of DCM were established to observe the pathological changes to myocardium and determine the levels of collagen I, Bax, and Bcl-2. The interaction between MALAT1 and YAP was analyzed, and CREB expression in the high-glucose treated CFs was detected. MALAT1 was upregulated in high-glucose CFs and located in the nucleus. High-glucose increased collagen production, inflammation, cell proliferation, cell invasiveness, and phosphorylation of MST1 and LATS1, and also promoted nuclear translocation of YAP. These trends in high-glucose treated CFs and the DCM mice were reversed by transfection with si-MALAT1. MALAT1 positively regulated the nuclear translocation of YAP by binding to CREB. CREB levels were increased in the high-glucose CFs, but decreased after silencing MALAT1. These results indicate that si-MALAT1 reduces inflammation and collagen accumulation in high-glucose CFs and DCM mice via the Hippo-YAP pathway and CREB.

Long non-coding RNA MALAT1 promotes odontogenic differentiation of human dental pulp stem cells by impairing microRNA-140-5p-dependent downregulation of GIT2.

Accumulating research continues to highlight the notable role of microRNAs (miRs) and long non-coding RNAs (lncRNAs) as important regulators in the process of human dental pulp stem cell (hDPSCs) differentiation. The current study aimed to investigate the novel regulatory circuitry of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/miR-140-5p/G protein-coupled receptor (GPCR)-kinase 2 interacting protein 2 (GIT2) on the odontogenic differentiation of hDPSCs. In hDPSCs, miR-140-5p was downregulated during the odontogenic differentiation, which was verified to directly target GIT2. RNA crosstalk determined by dual-luciferase reporter and RNA pull-down assays revealed that MALAT1 could bind to miR-140-5p to upregulate the expression of GIT2. After that, the levels of MALAT1, miR-140-5p, and GIT2 in hDPSCs were up- or downregulated by exogenous transfection or lentivirus infection in order to investigate their effects on the differentiation of hDPSCs. It was observed that elevation of miR-140-5p or knockdown of GIT2 resulted in inhibited alkaline phosphatase (ALP) activity, expression of dentin sialophosphoprotein (DSPP), dentin matrix-protein-1 (DMP-1), and distal-less homeobox 3 (DLX3) as well as positive expression of desmoplakin (DSP) protein. The promotive effects of MALAT1 on odontogenic differentiation were diminished by restoration of miR-140-5p or inhibition of GIT2. Taken together, this study provides valuable evidence suggesting MALAT1 as a potential contributor to the odontogenic differentiation of hDPSCs.

Long non-coding RNA MALAT1/microRNA 125a axis presents excellent value in discriminating sepsis patients and exhibits positive association with general disease severity, organ injury, inflammation level, and mortality in sepsis patients.

OBJECTIVE: The present study aimed to investigate the potential value of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1)/microRNA (miR)-125a axis in disease management and prognosis surveillance of sepsis. METHODS: Totally, 196 sepsis patients and 196 healthy controls were enrolled. Blood samples were collected within 24 hours after admission in sepsis patients and were collected at enrollment in healthy controls. The relative expression of lnc-MALAT1 and miR-125a in all participants was detected by reverse transcription quantitative polymerase chain reaction, and the inflammatory cytokines in plasma of sepsis patients were measured by enzyme-linked immunosorbent assay. RESULTS: Lnc-MALAT1/miR-125a axis was increased in sepsis patients compared with healthy controls (P < .001) and was of excellent value in distinguishing septic patients from healthy controls with the area under the curve (AUC) of 0.931 (95% CI: 0.908-0.954). In sepsis patients, lnc-MALAT1 was negatively associated with miR-125a, and lnc-MALAT1/miR-125a axis was positively correlated with acute pathologic and chronic health evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, serum creatinine, C-reactive protein, tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-8, while negatively associated with albumin. Furthermore, lnc-MALAT1/miR-125a axis was of value in predicting increased 28-day mortality risk to some extent (AUC: 0.678, 95% CI: 0.603-0.754). CONCLUSION: Lnc-MALAT1/miR-125a axis presents excellent value in differentiating sepsis patients from healthy controls and also exhibits positive association with general disease severity, organ injury, inflammation level, and mortality in sepsis patients.

Long Non-Coding RNA-MALAT1 Mediates Retinal Ganglion Cell Apoptosis Through the PI3K/Akt Signaling Pathway in Rats with Glaucoma.

BACKGROUND/AIMS: The aim of the present study is to investigate the effect of long non-coding RNA-MALAT1 (LncRNA-MALAT1) on retinal ganglion cell (RGC) apoptosis mediated by the PI3K/Akt signaling pathway in rats with glaucoma. METHODS: RGCs were isolated and cultured, and monoclonal antibodies (anti-rat Thy-1, Brn3a and RBPMS) were examined by immunocytochemistry. An overexpression vector MALAT1-RNA activation (RNAa), gene knockout vector MALAT1-RNA interference (RNAi), and control vector MALAT1-negative control (NC) were constructed. A chronic high intraocular pressure (IOP) rat model of glaucoma was established by episcleral vein cauterization. The RGCs were divided into the RGC control, RGC pressure, RGC pressure + MALAT1-NC, RGC pressure + MALAT1-RNAi and RGC pressure + MALAT1-RNAa groups. Sixty Sprague-Dawley (SD) rats were randomly divided into the normal, high IOP, high IOP + MALAT1-NC, high IOP + MALAT1-RNAa and high IOP + MALAT1-RNAi groups. qRT-PCR and western blotting were used to detect the expression levels of LncRNA-MALAT1 and PI3K/Akt. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and flow cytometry were used to detect RGC apoptosis. RESULTS: Immunocytochemistry revealed that the cultured RGCs reached 90% purity. Compared with the RGC pressure + MALAT1-NC group, the RGC pressure + MALAT1-RNAa group exhibited elevated expression levels of MALAT1, lower total protein levels of PI3K and Akt and decreased RGC apoptosis, while these expression levels were reversed in the RGC pressure + MALAT1-RNAi group. RGC numbers and PI3K/Akt expression levels in the high IOP model groups were lower than those in the normal group. In the high IOP + MALAT1-RNAa group, the mRNA and protein expression levels of PI3K/Akt were reduced but higher than those in the other three high IOP model groups. Additionally, RGC numbers in the high IOP + MALAT1-RNAa group were lower than those in the normal group but higher than those in the other three high IOP model groups. CONCLUSION: Our study provides evidence that LncRNA-MALAT1 could inhibit RGC apoptosis in glaucoma through activation of the PI3K/Akt signaling pathway.

[JAG1 affects monocytes-macrophages to reshape the pre-metastatic niche of triple-negative breast cancer through LncRNA MALAT1 in exosomes].

OBJECTIVE: To investigate the effect of JAG1 on the activities of monocytes-macrophages in pre-metastatic niche (PMN) of triple-negative breast cancer (TNBC) and explore the possible regulatory mechanism. METHODS: JAG1 expression in human TNBC MDA-MB-231 and MDA-MB-231B cells was detected using quantitative real-time PCR (qRT-PCR).Ten female nude mice were inoculated with MDA-MB-231 cells (n=5) or MDA-MB-231B cells (n=5) in the mammary fat pad, and 6 weeks later, the tumor tissues were collected for immunohistochemistry.Human monocytes THP-1 cells were treated with rhJAG1 or conditioned media (CM) of TNBC MDA-MB-231 and MDA-MB-231B cells to assess the direct effect of JAG1 on monocytes and its effect on monocytes in the PMN using monocyte-endothelial adhesion, Transwell assay, qRT-PCR and Western blotting.Transmission electron microscopy and nanoparticle tracking analyses were used to identify the effect of JAG1 on exosome release from the TNBC cells.MiRNAs interacting with lncRNA MALAT1 were identified by bioinformatics and validated using qRT-PCR. RESULTS: Compared with MDA-MB-231 cells, the invasive strain MDA-MB-231B cells showed significantly higher JAG1 expression and greater liver metastasis potential (P<0.01).Both direct treatment with rhJAG1 and treatment with the conditioned media promoted adhesion and migration and affected differentiation of the monocytes (P<0.05).Transmission electron microscopy and nanoparticle tracking analysis showed that JAG1 strongly enhanced exosome secretion from MDAMB-231 cells (P<0.01) and increased MALAT1 content in the exosomes (P<0.0001).Five candidate miRNAs related to MALAT1 and JAG1 were identified by bioinformatics analysis, and miR-26a-5p was identified as a potential target of MALAT1 in monocytes-macrophages in TMN (P<0.0001). CONCLUSION: JAG1 can promote exocrine secretion of TNBC and increase the expression of MALAT1 to cause targeted downregulation of miR-26a-5p in monocytes-macrophages in the PMN, which in turn increases JAG1 expression in monocytes-macrophages to affect their adhesion, migration and osteoclast differentiation in the PMN.

MALAT1 knockdown alleviates myocardial injury in mice with severe acute pancreatitis via the miR-374a/Sp1/Wnt/ß-catenin pathway.

BACKGROUND: Severe acute pancreatitis (SAP) contributes to high mortality (as high as 30%) and multiple organ injuries. In this study, we established a mouse model with SAP to detect biomolecules implicated in myocardial injury and to expound the signal transduction pathway involved. METHODS: A SAP mouse model was established to assess inflammation- and myocardial injury-related markers. Also, pancreatic and myocardial injuries and cardiomyocyte apoptosis were evaluated. Microarray analysis was implemented to filter differentially expressed long non-coding RNAs (lncRNAs) in myocardial tissues of normal and SAP mice. Then, miRNA-based microarray analysis and bioinformatics prediction were performed to probe the downstream molecules of MALAT1, followed by rescue experiments. RESULTS: SAP mice showed pancreatic and myocardial injuries and increased apoptosis of cardiomyocytes. MALAT1 was expressed highly in SAP mice, and inhibition of MALAT1 reduced myocardial injury and cardiomyocyte apoptosis in SAP mice. MALAT1 was found to localize to the cytoplasm of cardiomyocytes and bind to miR-374a. Inhibition of miR-374a inhibited the alleviating effects of MALAT1 knockdown on the myocardial injury. miR-374a targeted Sp1, and Sp1 silencing reversed the promoting effects of miR-374a inhibitor on myocardial injury. Sp1 regulated myocardial injury in SAP via the Wnt/ß-catenin pathway. CONCLUSION: MALAT1 promotes myocardial injury complicated by SAP via the miR-374a/Sp1/Wnt/ß-catenin pathway.

Long non-coding RNA MALAT1 promotes cell proliferation, migration and invasion by targeting miR-590-3p in osteosarcoma.

Osteosarcoma (OS) is a common malignant bone cancer and commonly occurs in adolescents and children. Long non-coding RNAs (lncRNAs) play major roles in cancer cell proliferation and metastasis. The present study aimed to investigate the potential molecular mechanism of lncRNA MALAT1 in OS. The levels of lncRNA MALAT1 and microRNA-590-3p were detected by reverse transcription-quantitative PCR in OS tissues and cells. Cell Counting Kit-8 and flow cytometry assays were conducted to assess cell proliferation and apoptosis. Cell migration and invasion were examined by Transwell assay. The levels of E-cadherin, N-Cadherin, Vimentin and Snail were measured by western blotting. The target of MALAT1 was predicted using online software and confirmed by luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. The results indicated that MALAT1 was highly expressed in OS tissues and cell lines. MALAT1 knockdown promoted apoptosis and suppressed proliferation, migration, invasion and epithelial- mesenchymal transition (EMT) of OS cells. Overexpression of miR-590-3p increased cell apoptosis and hampered cell proliferation, migration, invasion and EMT in OS cells. In addition, MALAT1 knockdown upregulated the expression of miR-590-3p in OS cells. In conclusion, MALAT1 was demonstrated to suppress cell apoptosis and induce cell proliferation, migration, invasion and EMT by inhibiting miR-590-3p in OS, which indicated that MALAT1 has potential value in the diagnosis and treatment of OS.

Long non-coding RNA MALAT1 promotes Th2 differentiation by regulating microRNA-135b-5p/GATA-3 axis in children with allergic rhinitis.

Allergic rhinitis (AR) threatens patient survival. CD4+ T cells play key roles in AR progression. Long non-coding RNAs (lncRNAs) are key regulators of cell differentiation. Therefore, we investigated the molecular mechanism of the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in AR. Expression levels of MALAT1, microRNA (miR)-135b-5p, interleukin-4 (IL-4), and GATA-binding protein 3 (GATA-3) in the nasal mucosa of AR patients were quantified. CD4+ T cells were isolated from the peripheral blood of healthy volunteers and treated with ovalbumin (OVA) and Th2 inducers. After MALAT1 and miR-135b-5p levels changed in CD4+ T cells, the proportion of IL-4-expressing cells and the levels of IL-4 and GATA-3 in OVA-induced CD4+ T cells were determined. Binding relationships among MALAT1, miR-135b-5p, and GATA-3 were predicted and verified. Rescue experiments were performed to confirm the role of the MALAT1/miR-135b-5p/GATA-3 axis in Th2 differentiation of CD4+ T cells. MALAT1, IL-4, and GATA-3 expression was upregulated, whereas miR-135b-5p expression was downregulated, in patients with AR. MALAT1 knockdown or miR-135b-5p overexpression in CD4+ T cells notably decreased the proportion of IL-4-expressing cells and downregulated GATA-3 and IL-4 expression in OVA-induced CD4+ T cells. MALAT1 and GATA-3 exhibited competitive binding toward miR-135b-5p. MALAT1 facilitated CD4+ T cell Th2 differentiation via the miR-135b-5p/GATA-3 axis. MALAT1 facilitated AR development by facilitating CD4+ T cell Th2 differentiation via the miR-135b-5p/GATA-3 axis. This study may provide guidance for clinical treatment of AR.

Mechanism of long non­coding RNA metastasis­associated lung adenocarcinoma transcript 1 in lipid metabolism and inflammation in heart failure.

Heart failure (HF) is a serious threat to human health. Long noncoding RNAs (lncRNAs) are critical regulators of HF. The aim of the study was to investigate the molecular mechanism of MALAT1 in HF rats. MALAT1 expression was detected in serum of normal volunteers and HF patients, HF rats and isoproterenol (ISO)­induced H9C2 cells, and its diagnostic value was evaluated in HF patients. Indexes related to cardiac functions and hemodynamics, myocardial injury, lipid metabolism, lipid oxidation, and inflammation were detected. Moreover, the downstream mechanism of MALAT1 was predicted and verified and in vivo experiments were further performed in ISO­induced H9C2 cells to verify the effects of MALAT1 in HF. MALAT1 was highly expressed in serum of HF patients, HF rats and ISO­induced H9C2 cells and was valuable in predicting HF. Inhibition of MALAT1 increased cardiac function and anti­inflammation and alleviated myocardial injury, lipid metabolism, lipid oxidation and apoptosis rates. Inhibition of MALAT1 reduced H9C2 cell injury. MALAT1 competitively bound to microRNA (miR)­532­3p to upregulate LDLR protein. Inhibition of miR­532­3p weakened the protective effect of downregulated MALAT1 against H9C2 cell injury. We concluded that MALAT1 upregulated LDLR expression by competitively binding to miR­532­3p, thereby increasing pathological injury in HF.

Targeting long non-coding RNA MALAT1 alleviates retinal neurodegeneration in diabetic mice.

AIM: To observe the effect of inhibiting long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on diabetic neurodegeneration. METHODS: Thirty-six 8-week-old C57BL/6 mice were randomly divided into normal control, diabetic control, diabetic scrambled small interfering RNAs (siRNAs) and diabetic MALAT1-siRNA groups. After diabetic induction with streptozocin intraperitoneally-injection, the diabetic MALAT1-siRNA group was intravitreally injected with 1 µL 20 µmol/L MALAT1 siRNA, and the diabetic scrambled siRNA group was injected with the same amount of scrambled siRNA. Electroretinography was performed to examine photoreceptor functions 16wk after diabetes induction. MALAT1 expression was detected via real time polymerase chain reaction. Cone morphological changes were examined using immunofluorescence. Rod morphological changes were examined by determining outer nuclear layer (ONL) thickness. RESULTS: The upregulation of retinal MALAT1 expression was detected in the diabetic control mice, while MALAT1 expression in the diabetic MALAT1-siRNA mice was decreased by 91.48% compared to diabetic control mice. The diabetic MALAT1-siRNA and diabetic control mice showed lower a-wave and b-wave amplitudes than did the normal control mice in scotopic and photopic electroretinogram, while the diabetic MALAT1-siRNA mice showed higher amplitudes than diabetic control mice. Morphological examination revealed that ONL thickness in the diabetic MALAT1-siRNA and diabetic control mice was lower than normal control mice. However, ONL thickness was greater in the diabetic MALAT1-siRNA mice than diabetic control mice. Moreover, the diabetic control mice performed a sparser cone cell arrangement and shorter outer segment morphology than diabetic MALAT1-siRNA mice. CONCLUSION: Inhibiting retinal MALAT1 results in mitigative effects on the retinal photoreceptors, thus alleviating diabetic neurodegeneration.

lncRNA MALAT1 Accelerates Skeletal Muscle Cell Apoptosis and Inflammatory Response in Sepsis by Decreasing BRCA1 Expression by Recruiting EZH2.

Sepsis is a serious and elusive syndrome caused by infection, which is accompanied by a high mortality worldwide. Recent evidence has documented the regulatory role of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) during the inflammatory process, the effects of which in the development of sepsis have become the focus of the current study. An in vivo mouse model and in vitro cell model of sepsis induced by lipopolysaccharide (LPS) were developed. High expression of lncRNA MALAT1 along with low expression of breast cancer susceptibility gene 1 (BRCA1) were identified in septic mice and human skeletal muscle cells of sepsis. Then, lncRNA MALAT1 expression was altered in vivo and in vitro to examine serum levels of inflammatory factors, as well as skeletal muscle cell apoptosis. lncRNA MALAT1 was noted to regulate the expression and export from the nucleus of BRCA1 by recruiting zeste homolog 2 (EZH2) in skeletal muscle cells of sepsis. Silencing lncRNA MALAT1 resulted in reduced serum levels of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), neutrophil migration, skeletal muscle cell apoptosis, and AKT-1 phosphorylation. Taken together, lncRNA MALAT1 interacting with EZH2 stimulated AKT-1 phosphorylation and decreased BRCA1 expression, consequently aggravating the progression of sepsis, highlighting a promising therapeutic option for sepsis.

Long noncoding RNA MALAT1 promotes cardiomyocyte apoptosis after myocardial infarction via targeting miR-144-3p.

Our study aims to excavate the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in myocardial infarction (MI), especially in an ischemia/reperfusion injury model and the underlying mechanism involving the MALAT1-miR144 axis. Our results demonstrated that the expression of MALAT1 has a higher level, while miR-144 expression significantly reduced in myocardial tissue after MI and also in left anterior descending (LAD)-ligation mice. This result was confirmed in vitro studies in HL-1 cardiomyocytes followed with hypoxia/reoxygenation. In addition, overexpression of MALAT1 by MALAT1-pcDNA injection into the mice with LAD increased myocardial apoptosis in vivo, while this effect was attenuated by miR-144 mimic. Bioinformatics analysis exhibits that 3'-UTR of MALAT1 is targeted to the miR-144-3p. Up-regulation miR-144 blunted the hypoxia- or MALAT1-induced cell apoptosis. In conclusion, the expression of MALAT1 was increased, whereas miR-144 expression was down-regulated in the myocardium after AMI. MALAT1 up-regulation plays a critical role in promoting cardiomyocytes apoptosis via targeting miR-144.

Long non-coding RNA MALAT1 promotes cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD.

Hypertension is the leading preventable cause of premature deaths worldwide. Although long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been identified to play important roles in the development of cardiovascular diseases, the regulatory function of lncRNA MALAT1 in hypertension remains poorly understood. This study aimed to explore the role of lncRNA MALAT1 in spontaneously hypertensive rats (SHRs). LncRNA MALAT1 was determined to be elevated and MyoD to be reduced in myocardial tissues and thoracic aortic vascular tissues of SHRs. Over-expression of lncRNA MALAT1 caused severe myocardial fibrosis in SHRs. In addition, lncRNA MALAT1 over-expression in vitro enhanced arterial smooth muscle cells (ASMCs) activity and fibrosis of SHRs, which, was rescued by over-expressed MyoD. Furthermore, lncRNA MALAT1 transcripts were found to be highly enriched in the nucleus, and lncRNA MALAT1 suppressed the transactivation of MyoD. Moreover, lncRNA MALAT1 was found to recruit Suv39h1 to MyoD-binding loci, leading to H3K9me3 trimethylation and down-regulation of the target gene. Taken conjointly, this study revealed an important role of lncRNA MALAT1 in promoting cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD. These results highlight the value of lncRNA MALAT1 as a therapeutic target for the management of hypertension.

Long non-coding RNA MALAT1 sponges microRNA-429 to regulate apoptosis of hippocampal neurons in hypoxic-ischemic brain damage by regulating WNT1.

Hypoxic-ischemic brain damage (HIBD) is a common neurological disorder. Emerging reports reveal that long non-coding RNAs and microRNAs (miRs) are implicated in the progress of HIBD. In this study we tried to ascertain whether lncRNA MALAT1, with the involvement of miR-429 and WNT1, affects HIBD. Initially, a HIBD mouse model was established. Then, we treated HIBD mice with dexmedetomidine (DEX) and then up- or down-regulated the expression of MALAT1, miR-429 and WNT1 in HIBD mice and neurons. Meanwhile, brain injury and hippocampal neuronal apoptosis were evaluated. Moreover, the interaction among MALAT1, miR-429 and WNT1 in HIBD was investigated. MALAT1 and WNT1 were high-expressed in brain tissues of HIBD mice while miR-429 was low-expressed in brain tissues from HIBD mice. Interestingly, MALAT1 silencing was observed to enhance the cerebral protection of DEX against HIBD. In addition, it was confirmed that MALAT1 sponged miR-429 downregulating expression of miR-429, thereby promoting apoptosis of hippocampal neurons. This effect was achieved through up-regulating the level of WNT1. Taken together, this study demonstrates that silencing of MALAT1 enhances the cerebral protection of DEX against HIBD by suppressing WNT1 expression through miR-429.

lncRNA MALAT1 Accelerates Wound Healing of Diabetic Mice Transfused with Modified Autologous Blood via the HIF-1α Signaling Pathway.

Impaired wound healing is a debilitating complication of diabetes. The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been recognized to be differentially expressed in various diseases. However, its underlying mechanism in diabetes has not been fully understood. Notably, we aim to examine the expression of MALAT1 in diabetic mice and its role in wound healing involving the hypoxia-inducible factor-1α (HIF-1α) signaling pathway with a modified autologous blood preservative solution reported. A mouse model of diabetes was established. MALAT1 was identified to promote the activation of the HIF-1α signaling pathway and to be enriched in autologous blood through modified preservation, which might facilitate the improvement of physiological function of blood cells. Through gain- or loss-of-function approaches, viability of fibroblasts cultured in high glucose, wound healing of mice, and collagen expression in wound areas were enhanced by MALAT1 and HIF-1α. Taken together, the present study demonstrated that the physiological status of mouse blood was effectively improved by modified autologous blood preservation, which exhibited upregulated MALAT1, thereby accelerating the fibroblast activation and wound healing in diabetic mice via the activation of the HIF-1α signaling pathway. The upregulation of MALAT1 activating the HIF-1α signaling pathway provides a novel insight into drug targets against diabetes.

IL-21R functions as an oncogenic factor and is regulated by the lncRNA MALAT1/miR-125a-3p axis in gastric cancer.

Interleukin-21 receptor (IL-21R) is involved in the immunological regulation of immune cells and tumor progression in multiple malignancies. However, the potential molecular mechanisms through which non-coding RNAs (ncRNAs) modulate IL-21R signaling in gastric cancer (GC) remain elusive. In this study, the expression of IL-21R was detected by RT-qPCR and western blot analysis in GC cell lines. The association between IL-21R expression and clinicopathological characteristics and the prognosis of patients with GC was analyzed by immunohistochemistry and Kaplan-Meier plotter analysis. The biological functions of IL-21R were analyzed by a series of in vitro and in vivo experiments, and its regulation by ncRNAs was predicted by bioinformatics analysis and confirmed by luciferase assays and rescue experiments. As a result, the expression of IL-21R was found to be significantly increased in GC cell lines and tissues as compared with normal tissues, and was associated with tumor size and lymphatic metastasis, acting as an independent prognostic factor of poor survival and recurrence in patients with GC. The knockdown of IL-21R markedly suppressed GC cell proliferation and invasion, and IL-21R expression was further validated to be negatively regulated by miR-125a-3p (miR-125a). The overexpression of IL-21R reversed the tumor suppressive effects of miR-125a in vitro and in vivo. Moreover, lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a sponge of miR-125a to modulate the IL-21R signaling pathway in GC cells and represented a risk factor for survival and recurrence in patients with GC. Taken together, the findings of this study reveal an oncogenic role for IL-21R in gastric tumorigenesis and verify that its activation is partly due to the dysregulation of the lncRNA MALAT1/miR-125a axis. These findings may provide a potential prognostic marker for patients with GC.

The effects of the long non-coding RNA MALAT-1 regulated autophagy-related signaling pathway on chemotherapy resistance in diffuse large B-cell lymphoma.

OBJECTIVE: Our study aimed to investigate the effects of the long non-coding RNA MALAT-1 (lncRNA MALAT-1) regulated autophagy-related signaling pathway on chemotherapy resistance in diffuse large B-cell lymphoma (DLBCL). METHODS: Human normal B lymphocytes (IM-9I) and DLBCL cell lines (Farage, Pfeiffer, Raji, Daud, Ly1, Ly3, Ly8 and Ly10) were chosen for our experiment. qRT-PCR was applied to detect the expression of lncRNA MALAT-1 in each DLBCL cell line. Farage and Daud cells were induced to be drug-resistant using 0.05µg/ml Adriamycin. LncRNA MALAT-1 interfering stable transfected cell lines were constructed and cells were transfected with lentivirus. The cells were divided into the blank, siNC, and siRNA-MALAT-1 groups. CCK-8 assay, flow cytometry, and Transwell assay were performed to detect cell survival rate, cycle, apoptosis, and invasion, respectively. The autophagosome formation in each group was observed under a transmission electron microscope. Western blotting was used to detect the expressions of the autophagy-related proteins and genes. The in vivo drug sensitivity of the tumor was observed using a subcutaneous tumor xenograft model in nude mice. RESULTS: The expression of lncRNA MALAT-1 in each DLBCL cell line was higher than in the IM-9 cells, with the Farage cells ranking highest (all P<0.05). When compared with the blank and the siNC groups, the siRNA-MALAT-1 group showed a decreased cell survival rate, an increased percentage of cells in G0/G1 phase, a decreased proportion of cells in S and G2/M phases, and a reduced number of migratory cell at each time point (all P<0.05). When compared with the blank and the siNC groups, the formation of autophagosomes, increased LC3-II/LC3-I expression, decreased p62 expression, and increased expression of the autophagy gene ATG5 were observed in the siRNA-MALAT-1 group at each time point (all P<0.05). Also, the siRNA-MALAT-1 group had a decreased tumor volume and weight in the subcutaneous tumor xenograft model in nude mice, and increased LC3-II/LC3-I expression but decreased p62 expression in tumor tissues when compared with the blank group and the siNC group (all P<0.05). CONCLUSION: Our study provides evidence that inhibiting lncRNA MALAT-1 can improve the chemotherapy sensitivity of DLBCL by enhancing autophagy-related proteins.