Lnc-Malat1 promotes slow myofiber-type transformation through sponging miR-129-5p in C2C12 myotubes.

Long non-coding metastasis-associated lung adenocarcinoma transcript (lnc-Malat1) emerges as a novel regulator in skeletal muscle development, while its function and the related mechanism is not fully revealed yet. In this study, knockdown of lnc-Malat1 by siRNA significantly inhibited the expression of myoblast marker genes (MyHC, MyoD, and MyoG) and slow muscle fiber marker genes (MyHC I), together with repressed expression of mitochondria-related genes COX5A, ACADM, CPTA1, FABP3, and NDUFA1. Overexpression of lnc-Malat1 exerted an opposite effect, promoting myoblast differentiation and slow muscle fiber formation. Dual luciferase reporter assay revealed a direct interaction between lnc-Malat1 and miR-129-5p, and overexpression of lnc-Malat1 significantly inhibited miR-129-5p expression, thereby elevating the expression of Mef2a, miR-129-5p target protein. In addition, enforced expression of lnc-Malat1 restored the inhibitory effect of miR-129-5p on myoblast differentiation and MyHC I expression. Taken together, our results suggest that lnc-Malat1 promotes myoblast differentiation, and maintains the slow muscle fiber phenotype via adsorbing miR-129-5p.

A novel mechanism regulating pyroptosis-induced fibrosis in endometriosis via lnc-MALAT1/miR-141-3p/NLRP3 pathway†.

Endometriosis is a chronic inflammatory disease distinguished by ectopic endometrium and fibrosis. NLRP3 inflammasome and pyroptosis are present in endometriosis. Aberrant increase of Long noncoding (Lnc)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a vital role in endometriosis. However, the relationship between lnc-MALAT1, pyroptosis, and fibrosis is not completely known. In the present study, we found that the pyroptosis levels in ectopic endometrium of patients with endometriosis were significantly increased, consistent with fibrosis levels. Lipopolysaccharide (LPS) + ATP could induce pyroptosis of primary endometrial stromal cells (ESCs), thereby releasing interleukin (IL)-1ß and stimulating transforming growth factor (TGF)-ß1-mediated fibrosis. NLRP3 inhibitor MCC950 had the same effect as TGF-ß1 inhibitor SB-431542 in suppressing the fibrosis-inducing effect of LPS + ATP in vivo and in vitro. The abnormal increase of lnc-MALAT1 in ectopic endometrium was connected with NLRP3-mediated pyroptosis and fibrosis. Leveraging bioinformatic prediction and luciferase assays combined with western blotting and quantitative reverse transcriptase-polymerase chain reaction, we validated that lnc-MALAT1 sponges miR-141-3p to promote NLRP3 expression. Silencing lnc-MALAT1 in HESCs ameliorated NLRP3-mediated pyroptosis and IL-1ß release, thereby relieving TGF-ß1-mediated fibrosis. Consequently, our findings suggest that lnc-MALAT1 is critical for NLRP3-induced pyroptosis and fibrosis in endometriosis through sponging miR-141-3p, which may indicate a new therapeutic target of endometriosis treatment.

A novel circulating biomarker lnc-MALAT1 for acute myocardial infarction: Its relationship with disease risk, features, cytokines, and major adverse cardiovascular events.

OBJECTIVE: Long noncoding RNA MALAT1 (lnc-MALAT1) modulates atherosclerotic progression, myocardial ischemia injury, and systematic inflammation, which may be closely involved in acute myocardial infarction (AMI) pathogenesis. Thus, the current study intended to explore the relationship of lnc-MALAT1 to disease risk, features, cytokines, and prognostication in AMI patients. METHODS: This multicenter study consecutively enrolled 160 newly diagnosed AMI patients and 50 controls (angina pectoris patients). Their peripheral blood mononuclear cells were obtained to measure lnc-MALAT1 by RT-qPCR. Serum cytokines in AMI patients were detected by ELISA. In addition, AMI patients were followed up for major adverse cardiovascular event (MACE) risk evaluation. RESULTS: Lnc-MALAT1 was higher in AMI patients than in controls (median: 2.245 vs. 0.996, p = 0.004), and it also presented a good capacity for differentiating AMI patients from controls with an area under the curve of 0.823. Lnc-MALAT1 was positively related to C-reactive protein (p = 0.005), low-density lipoprotein cholesterol (p = 0.022), cardiac troponin I (p = 0.021), and infarct size (p = 0.007), but not other biochemical indexes in AMI patients. Meanwhile, lnc-MALAT1 was positively associated with tumor necrosis factor-alpha (p = 0.001), interleukin (IL)-6 (p = 0.031), IL-17A (p = 0.042), vascular cell adhesion molecule-1 (p = 0.004), and intercellular adhesion molecule-1 (p = 0.021) among AMI patients. Importantly, after categorization, lnc-MALAT1 high (vs. low) was related to an elevated MACE accumulation rate (p = 0.035); furthermore, a higher lnc-MALAT1 quartile showed a trend to be linked with an increased MACE accumulation rate (p = 0.092). CONCLUSION: Lnc-MALAT1 may serve as a biomarker for AMI risk, infarct size, inflammation and prognosis, but further validation by large-scale studies is needed.

Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 in Extracellular Vesicles Promotes Hepatic Stellate Cell Activation, Liver Fibrosis and ß-Catenin Signaling Pathway.

Evidence shows that the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (Lnc-MALAT1) is associated with activation of hepatic stellate cells (HSCs) and liver fibrosis in animal and in vitro studies. However, its roles in human liver fibrosis and the underlying mechanism in HSC activation are not yet defined. In our current study, the expression of Lnc-MALAT1 in the fibrotic liver tissues and in the plasma extracelllar vesicles (EVs) of liver fibrosis patients was detected by FISH and qRT-PCR. The results revealed that enhanced expression of Lnc-MALAT1 was co-localized with increased expression of the fibrotic markers (collagen I and α-SMA) and the Wnt/ß-catenin signaling proteins (ß-catenin, cyclinD1 and c-myc) in the fibrotic liver tissues. The level of Lnc-MALAT1 in the plasma EVs isolated from 60 liver fibrosis patients was significantly increased compared with that of the 46 control patients, and area under receiver operating curve (AUROC) analysis showed that plasma EVs-Lnc-MALAT1 was a potential diagnostic marker for liver fibrosis, especially for high liver fibrosis. Plasma EVs with highly expressed Lnc-MALAT1 derived from high liver fibrosis patients up-regulated the expression of the fibrotic markers and enhanced the Wnt/ß-catenin signaling in human hepatic stellate cells LX-2, and the fibrogenic effects in LX-2 were inhibited by Lnc-MALAT1 knock-down. Interestingly, TGF-ß1, a potent pro-fibrotic cytokine, promoted the expression of Lnc-MALAT1 in LX-2 and its pro-fibrotic effects were also abolished by siRNA for Lnc-MALAT1, suggesting that Lnc-MALAT1 probably functions as a common mediator in the activation and fibrogenesis of HSCs. Our results indicate that enhanced expression of Lnc-MALAT1 in the fibrotic liver stimulate the activation of HSCs and thus promote their fibrogenic activity. These results also provide evidences that Lnc-MALAT1 is a potential therapeutic target and plasma EVs-Lnc-MALAT1 is a potential diagnostic biomarker for liver fibrosis.

Long noncoding RNA MALAT1 and its target microRNA-125b are potential biomarkers for Alzheimer's disease management via interactions with FOXQ1, PTGS2 and CDK5.

This study aimed to investigate the intercorrelation among long noncoding RNA MALAT1 (lnc-MALAT1), microRNA-125b (miR-125b), FOXQ1, PTGS2 and CDK5, as well as their correlations with disease risk, severity and progression of Alzheimer's disease (AD). In total, 120 AD patients, 120 Parkinson's disease (PD) patients and 120 controls were enrolled. Cerebrospinal fluid (CSF) samples were collected from 50 AD patients, 50 PD patients and 50 controls; plasma samples were obtained from all participants. Lnc-MALAT1, miR-125b, FOXQ1, PTGS2 and CDK5 were detected by RT-qPCR. CSF lnc-MALAT1/FOXQ1 and plasma lnc-MALAT1 were downregulated, while CSF miR-125b/PTGS2/CDK5 and plasma miR-125b/PTGS2 were upregulated in AD patients compared to PD patients and controls, which differentiated AD patients from PD patients and controls, as demonstrated by ROC curve analyses. In AD patients, CSF/plasma lnc-MALAT1 negatively correlated with miR-125b and PTGS2 but positively correlated with FOXQ1; CSF/plasma miR-125b negatively correlated with FOXQ1 but positively correlated with PTGS2/CDK5. In addition, CSF/plasma lnc-MALAT1 and FOXQ1 correlated with alleviated disease severity, while miR-125b, PTGS2 and CDK5 correlated with exacerbated disease severity, which were manifested by their correlations with MMSE score, Aß42, t-tau and p-tau in AD patients. However, their correlations with MMSE score, Aß42, t-tau and p-tau were weak in PD patients and controls. Notably, CSF but not plasma lnc-MALAT1 and miR-125b could predict the MMSE score decline at 1 year, 2 years and 3 years in AD patients. In conclusion, lnc-MALAT1 and its target miR-125b are potential biomarkers for AD management via their intercorrelation with FOXQ1, PTGS2 and CDK5.

Paclitaxel alleviates the sepsis-induced acute kidney injury via lnc-MALAT1/miR-370-3p/HMGB1 axis.

AIMS: To investigate the effects of paclitaxel on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and its related mechanisms. MAIN METHODS: The sepsis-associated AKI was induced by LPS using HK-2 cells. Then the mRNA and protein expression levels of relevant genes in the serum of sepsis patients and HK-2 cells with LPS-induced AKI were detected by qRT-PCR and western blot analyses before and after paclitaxel treatment, respectively. Subsequently, the cell counting kit-8 (CCK-8) and flow cytometry assays were performed to estimate the effects of paclitaxel, lnc-MALAT1, miR-370-3p and HMGB1 on the proliferation and apoptosis of HK-2 cells injured by LPS. KEY FINDINGS: Lnc-MALAT1 was increased both in the serum of sepsis patients and cells injured by LPS, which could inhibit the cell proliferation, promote the cell apoptosis and increase the expression of TNF-α, IL-6 and IL-1ß caused by paclitaxel. Moreover, lnc-MALAT1 was sponged with miR-370-3p which had the inverse effects with lnc-MALAT1 in LPS induced HK-2 cells. What's more, miR-370-3p targeted HMGB1 which was induced in serum and cells of sepsis. Knockdown of miR-370-3p inhibited the expression of HMGB1 and suppressed the proliferation but promoted the apoptosis of HK-2 cells injured by LPS as well as the expression of TNF-α, IL-6 and IL-1ß. Besides, paclitaxel restrained the expression of HMGB1 via regulating lnc-MALAT1/miR-370-3p axis. SIGNIFICANCE: Paclitaxel could protect against LPS-induced AKI via the regulation of lnc-MALAT1/miR-370-3p/HMGB1 axis and the expression of TNF-α, IL-6 and IL-1ß, revealing that paclitaxel might act as a therapy drug in reducing sepsis-associated AKI.

Long Non-coding RNA MALAT1 Inhibits Neuron Apoptosis and Neuroinflammation While Stimulates Neurite Outgrowth and Its Correlation With MiR-125b Mediates PTGS2, CDK5 and FOXQ1 in Alzheimer's Disease.

BACKGROUND: This study aimed to investigate the effect of long noncoding ribonucleic acids (RNAs) metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1) on regulating neuron apoptosis, neurite outgrowth and inflammation, and further explore its molecule mechanism in Alzheimer's disease (AD). METHODS: Control overexpression, lnc-MALAT1 overexpression, control shRNA, and lnc-MALAT1 shRNA were transfected into NGF-stimulated PC12 cellular AD model and cellular AD model from primary cerebral cortex neurons of rat embryo, which were established by Aß1-42 insult. Rescue experiments were performed by transferring lnc-MALAT1 overexpression and lnc-MALAT1 overexpression & miR-125b overexpression plasmids. Neuron apoptosis, neurite outgrowth and inflammation were detected by Hoechst-PI/apoptosis marker expressions, and observations were made using microscope and RT-qPCR/Western blot assays. PTGS2, CDK5 and FOXQ1 expressions in rescue experiments were also determined. RESULTS: In two AD models, lnc-MALAT1 overexpression inhibited neuron apoptosis, promoted neurite outgrowth, reduced IL-6 and TNF-α levels, and increased IL-10 level compared to control overexpression, while lnc-MALAT1 knockdown promoted neuron apoptosis, repressed neurite outgrowth, elevated IL-6 and TNF-α levels, but reduced IL-10 level compared to control shRNA. Additionally, lnc- MALAT1 reversely regulated miR-125b expression, while miR-125b did not influence the lnc- MALAT1 expression. Subsequently, rescue experiments revealed that miR-125b induced neuron apoptosis, inhibited neurite outgrowth and promoted inflammation, also increased PTGS2 and CDK5 expressions but decreased FOXQ1 expression in lnc-MALAT1 overexpression treated AD models. CONCLUSION: Lnc-MALAT1 might interact with miR-125b to inhibit neuron apoptosis and inflammation while promote neurite outgrowth in AD.

The MALAT1 gene polymorphism and its relationship with the onset of congenital heart disease in Chinese.

Many long non-coding RNAs (lncRNAs), including lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), are involved in various cardiac diseases. We evaluated the effects of tag single nucleotide polymorphisms (tag-SNPs) on MALAT1 gene in a Chinese population of children with congenital heart disease (CHD). In the present study, 713 CHD patients and 730 gender- and age-matched children without CHD were genotyped for MALAT1 tag-SNPs rs11227209, rs619586, and rs3200401. Further investigation of SNP's function was performed by luciferase assay. Statistical analyses, including uni- and multivariate logistic regression were performed to quantitate the association between these tag SNPs and CHD. We discovered that MALAT1 rs619586 GG allele was significantly associated with lower risk of CHD (odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.59-0.92, P=0.014) in additive model. Functional investigation indicated that G allele of rs619586 could trigger higher expression of MALAT1. We demonstrated that the functional MALAT1 polymorphism rs619586 A>G was significantly associated with CHD susceptibility in Chinese population, potentially via regulating MALAT1 expression.