Role Of Metastasis-associated Lung Adenocarcinoma Transcript 1 Research Articles

The Role of MALAT1 in Regulating the Proangiogenic Functions, Invasion, and Migration of Trophoblasts in Selective Fetal Growth Restriction.

Epigenetic regulation is an important entry point to study the pathogenesis of selective fetal growth restriction (sFGR), and an understanding of the role of long noncoding RNAs (lncRNAs) in sFGR is lacking. Our study aimed to investigate the potential role of a lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), in sFGR using molecular biology experiments and gain- or loss-of-function assays. We found that the levels of MALAT1, ERRγ, and HSD17B1 were downregulated and that of miR-424 was upregulated in the placental shares of the smaller twins. Moreover, angiogenesis was impaired in the placental share of the smaller fetus and MALAT1 could regulate the paracrine effects of trophoblasts on endothelium angiogenesis and proliferation by regulating miR-424. In trophoblasts, MALAT1 could competitively bind to miR-424 to regulate the expression of ERRγ and HSD17B1, thus regulating trophoblast invasion and migration. MALAT1 overexpression could decrease apoptosis and promote proliferation, alleviating cell damage induced by hypoxia. Taken together, the downregulation of MALAT1 can reduce the expression of ERRγ and HSD17B1 by competitively binding to miR-424, impairing the proangiogenic effect of trophoblasts, trophoblast invasion and migration, and the ability of trophoblasts to compensate for hypoxia, which may be involved in the pathogenesis of sFGR through various aspects.

Mechanistic actions of long non-coding RNA MALAT1 within the ovary and at the feto-maternal interface.

Long non-coding RNAs (LncRNAs) are being unveiled as crucial regulators of several biological processes and pathways. Among the lncRNAs is metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which is also known as nuclear enriched abundant transcript 2 (NEAT2). MALAT1 is highly conserved in mammals, and controls cellular processes such as proliferation, migration, invasion, angiogenesis, and apoptosis in both physiological and pathological conditions. Roles of MALAT1 in the female reproductive system are gradually getting explored. Within the ovarian micro-environment, the physiological expression of MALAT1 potentially modulates folliculogenesis while its upregulation promotes the metastasis of epithelial ovarian cancers. Interestingly, women with polycystic ovary syndrome have been shown to exhibit aberrant ovarian expression of MALAT1 and this is believed to contribute to the development of the disease. At the feto-maternal interface, MALAT1 potentially promotes trophoblast development. While its placental downregulation is linked to the pathogenesis of preeclampsia, its placental upregulation is associated with placenta increta and placenta percreta. Hence, abnormal expression of MALAT1 is a candidate molecular biomarker and therapeutic target for the treatment of these obstetric and gynecologic anomalies. To enhance a quick uncovering and detailed characterization of the mechanistic actions of MALAT1 in the female reproductive system, we have highlighted some knowledge deficits and have recommended ideal experimental models to be employed in prospective investigations.

Role of LncMALAT1-miR-141-3p/200a-3p-NRXN1 Axis in the Impairment of Learning and Memory Capacity in ADHD.

As a prevalent neurodevelopmental disease, attention-deficit hyperactivity disorder (ADHD) impairs the learning and memory capacity, and so far, there has been no available treatment option for long-term efficacy. Alterations in gene regulation and synapse-related proteins influence learning and memory capacity; nevertheless, the regulatory mechanism of synapse-related protein synthesis is still unclear in ADHD. LncRNAs have been found participating in regulating genes in multiple disorders. For instance, lncRNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) has an essential regulatory function in numerous psychiatric diseases. However, how MALAT1 influences synapse-related protein synthesis in ADHD remains largely unknown. Here, our study found that MALAT1 decreased in the hippocampus tissue of spontaneously hypertensive rats (SHRs) compared to the standard controls, Wistar Kyoto (WKY) rats. Subsequent experiments revealed that MALAT1 enhanced the expression of neurexin 1 (NRXN1), which promoted the synapse-related genes (SYN1, PSD95, and GAP43) expression. Then, the bioinformatic analyses predicted that miR-141-3p and miR-200a-3p, microRNAs belonging to miR-200 family and sharing same seed sequence, could interact with MALAT1 and NRXN1 mRNA, which were further confirmed by luciferase report assays. Finally, rescue experiments indicated that MALAT1 influenced the expression of NRXN1 by sponging miR-141-3p/200a-3p. All data verified our hypothesis that MALAT1 regulated synapse-related proteins (SYN1, PSD95, and GAP43) through the MALAT1-miR-141-3p/200a-3p-NRXN1 axis in ADHD. Our research underscored a novel role of MALAT1 in the pathogenesis of impaired learning and memory capacity in ADHD and may shed more light on developing diagnostic biomarkers and more effective therapeutic interventions for individuals with ADHD.

Potential roles of lncRNA MALAT1-miRNA interactions in ocular diseases.

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts that are longer than 200 nucleotides in length. LncRNAs are implicated in gene expression at the transcriptional, translational, and epigenetic levels, and thereby impact different cellular processes including cell proliferation, migration, apoptosis, angiogenesis, and immune response. In recent years, numerous studies have demonstrated the significant contribution of lncRNAs to the pathogenesis and progression of various diseases, such as stroke, heart disease, and cancer. Further investigations have shown that lncRNAs have altered expression patterns in ocular tissues and cell lines during pathological conditions. The pathogenesis of various ocular diseases, including glaucoma, cataract, corneal diseases, proliferative vitreoretinopathy, diabetic retinopathy, and retinoblastoma, is influenced by the involvement of specific lncRNAs which play a critical role in the development and progression of these diseases. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a well-researched lncRNA in the context of ocular diseases, which has been shown to exert its biological effects through several signaling pathways and downstream targets. The present review provides a comprehensive summary of the molecular mechanisms underlying the biological functions and roles of MALAT1 in ocular diseases.

MALAT-1 regulates the AML progression by promoting the m6A modification of ZEB1.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) is abnormally upregulated in various human cancers. However, the role of MALAT-1 in acute myeloid leukemia (AML) remains unclear. This study investigated the expression and function of MALAT-1 in AML. MTT assay was used to determine cell viability, qRT-PCR was applied to determine the RNA levels. Western blot was performed to detect the protein expression. Flow cytometry was conducted to measure cell apoptosis. RNA pull-down assay was carried out to detect the interaction between MALAT-1 and METTL14. RNA FISH assay was performed to determine the localization of MALAT-1 and METTL14 in AML cells. Our results have revealed the key role of MEEL14 and m6A modification in AML. Besides, MALAT-1 was significantly up-regulated in AML patients. MALAT-1 knockdown inhibited the proliferation, migration and invasion of AML cells, and induced cell apoptosis; additionally, MALAT-1 binding to METTL14 promoted the m6A modification of ZEB1. Besides, ZEB1 overexpression partially reversed the effect of MALAT-1 knockdown on the cellular functions of AML cells. Taken together, MALAT-1 promoted the aggressiveness of AML through regulating m6A modification of ZEB1.

Long non-coding RNA MALAT1 modulate cell migration, proliferation and apoptosis by sponging microRNA-146a to regulate CXCR4 expression in acute myeloid leukemia

ABSTRACT Objectives To investigate the role of Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in acute myeloid leukemia (AML) and analyze the potential regulatory network of MALAT1/miR-146a/ CXCR4. Methods The expressions of MALAT1, miR-146a and CXCR4 were performed by qRT-PCR and Western Blot. We conducted trans-well assay, CCK-8 assay and flow cytometry to evaluate the migration, proliferation and apoptosis of AML cells. Also by using luciferase reporter assay, we investigated the interaction between miR-146a and MALAT1 or CXCR4. Results Firstly, MALAT1 and CXCR4 were upregulated while miR-146a was downregulated in AML patients compared with healthy controls. We observed a negative correlation between miR-146a and MALAT1 or CXCR4, but a positive correlation between MALAT1 and CXCR4 in AML patients. MALAT1 knockdown inhibited migration and proliferation but induced apoptosis of HL-60 cells. MALAT1 restrained miR-146a expression by acting as a ceRNA. miR-146a regulated HL-60 cells migration, proliferation and apoptosis by directly targeting CXCR4 expression. Finally, we found that CXCR4 expression was downregulated by MALAT1 knockdown and partially restored by miR-146a abrogation. Conclusions Our results showed that MALAT1 regulates migration, proliferation and apoptosis by sponging miR-146a to regulate CXCR4 expression in AML cells, providing novel insights into the role of MALAT1 as a therapeutic target in AML.

LncRNA MALAT1 Aggravates the Progression of Non-Small Cell Lung Cancer by Stimulating the Expression of COMMD8 via Targeting miR-613.

BackgroundNon-small cell lung cancer (NSCLC) is a common malignant tumor in humans. Long non-coding RNA (lncRNA) involved in cancer progression has been reported frequently. The objective of this study was to investigate the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and explore a novel mechanism in NSCLC development.Materials and MethodsThe expression of MALAT1, copper metabolism MURR1 domain-containing 8 (COMMD8) and microRNA-613 (miR-613) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of COMMD8, Cyclin D1, Ki67, B cell lymphoma/leukemia-2 (Bcl-2), Bcl-2 associated X protein (Bax), lactate dehydrogenase A (LDHA), CD63 and CD81 were determined by Western blot. Cell proliferation, the number of colonies and cell apoptosis were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation and flow cytometry assays, respectively. Glycolysis was distinguished based on glucose consumption, lactate production and LDHA activity. The role of MALAT1 in vivo was verified by animal experiments. The relationship between miR-613 and MALAT1 or COMMD8 was predicted by the bioinformatics tool starbase and verified by dual-luciferase reporter assay. The exosomes were isolated using the corresponding kit and identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA).ResultsMALAT1 and COMMD8 were aberrantly upregulated in NSCLC tissues and cells. MALAT1 or COMMD8 knockdown blocked cell proliferation, colony formation and glycolysis but accelerated cell apoptosis in vitro. Besides, MALAT1 knockdown reduced tumor growth in vivo. We found that miR-613 was a target of MALAT1, and miR-613 could bind to the 3ʹ untranslated region (3ʹUTR) of COMMD8. MALAT1 regulated the expression of COMMD8 by absorbing miR-613. Moreover, the extracellular MALAT1 was transmitted by wrapping into exosomes.ConclusionMALAT1 promoted malignant activities of NSCLC cells through targeting miR-613/COMMD8 axis, and exosome-mediated transfer of NSCLC might be a novel approach for NSCLC treatment.

Long non-coding RNA MALAT1 suppresses the proliferation and migration of endothelial progenitor cells in deep vein thrombosis by regulating the Wnt/β-catenin pathway.

Deep vein thrombosis (DVT) is one of the most common circulating vascular diseases with an incidence of ~0.1% worldwide. Although anticoagulant medication remains to be the main therapeutic approach for patients with DVT, existing thrombus and pulmonary embolisms still pose as a threat to patient life. Therefore, effective targeted therapies need to be developed and studies are required to improve understanding of this condition. Endothelial progenitor cells (EPCs) originate from the bone marrow, are located in the peripheral blood and are involved in thrombus resolution. Long non-coding RNAs (lncRNAs) are non-coding RNAs that are >200 nucleotides in length. LncRNAs are associated with the development of numerous vascular diseases. Among these lncRNAs, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is downregulated in human atherosclerotic plaques. Furthermore, MALAT1 polymorphism resulted in vascular disease in Chinese populations. In the present study, the expression profile and potential functions of MALAT1 in DVT were investigated. The results revealed that MALAT1 was upregulated in DVT tissues. Furthermore, MALAT1 was able to regulate the biological behaviors of EPCs, including proliferation, migration, cell cycle arrest and apoptosis. In addition, the Wnt/β-catenin signaling pathway is a promising downstream target of MALAT1 in DVT. The changes in biological behaviors in EPCs caused by silenced MALAT1 were reversed by inhibition of the Wnt/β-catenin signaling pathway. In summary, the data indicated the roles of MALAT1 in the pathogenesis of DVT, and the MALAT1/Wnt/β-catenin axis could be a novel therapeutic target for the treatment of DVT.

Long noncoding RNA MALAT1 sponges miR-129-5p to regulate the development of bronchopulmonary dysplasia by increasing the expression of HMGB1.

ObjectiveTo explore the function and mechanism of long noncoding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in bronchopulmonary dysplasia.MethodsAlveolar epithelial cell line BEAS-2B was used as the cell model. The role of MALAT1 and microRNA miR-129-5p in regulating cellular viability and migration were examined by using the CCK-8 and Transwell assays, respectively, in vitro. The luciferase reporter assay and real-time (RT)-PCR were performed to confirm that miR-129-5p was a target of MALAT1. ELISA was conducted to validate MALAT1 and show that miR-129-5p regulated the gene encoding high-mobility group protein 1 (HMGB1).ResultsOverexpression of MALAT1 significantly promoted cellular viability, whereas miR-129-5p had the opposite effect. miR-129-5p was shown to be a target of MALAT1, and HMGB1 could be upregulated by MALAT1 overexpression or miR-129-5p inhibition.ConclusionMALAT1 reduced the expression of miR-129-5p, promoting the viability of cells and blocking the development of bronchopulmonary dysplasia. In addition, MALAT1 increased the expression of HMGB1, which contributed to inflammation as the disease progressed.

Increased Level of Long Non-Coding RNA MALAT1 is a Common Feature of Amoeboid Invasion.

The ability of cancer cells to adopt various migration modes (the plasticity of cancer cell invasiveness) is a substantive obstacle in the treatment of metastasis, yet still an incompletely understood process. We performed a comparison of publicly available transcriptomic datasets from various cell types undergoing a switch between the mesenchymal and amoeboid migration modes. Strikingly, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was one of three genes that were found upregulated in all amoeboid cells analyzed. Accordingly, downregulation of MALAT1 in predominantly amoeboid cell lines A375m2 and A2058 resulted in decrease of active RhoA (Ras homolog family member A) and was accompanied by the amoeboid-mesenchymal transition in A375m2 cells. Moreover, MALAT1 downregulation in amoeboid cells led to increased cell proliferation. Our work is the first to address the role of MALAT1 in MAT/AMT (mesenchymal to amoeboid transition/amoeboid to mesenchymal transition) and suggests that increased MALAT1 expression is a common feature of amoeboid cells.

MALAT1 affects hypoxia-induced vascular endothelial cell injury and autophagy by regulating miR-19b-3p/HIF-1α axis.

Cardiovascular disease has become the leading cause of death in the world. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in cardiovascular disease, such as stroke. However, the role of MALAT1 in hypoxia (HYP)-induced vascular endothelial cells (VECs) remains unclear. In the present study, HYP-treated human umbilical vein endothelial cells (HUVECs) were utilized to simulate HYP-induced VEC injury. It was found that after HYP treatment, the levels of MALAT1 and hypoxia-induced factor-1 (HIF-1α) in HUVECs were upregulated, while the level of miR-19b-3p was downregulated. Knockdown of MALAT1 with siRNA significantly reduced the HIF-1α level induced by HYP. In addition, MALAT1 knockdown inhibited HYP-induced HUVECs apoptosis, autophagy and inflammation. The overexpression of HIF-1α overcame the effect of MALAT1 knockdown. Mechanism analysis showed that MALAT1-targeted miR-19b-3p and then regulated downstream HIF-1α. MALAT1 knockdown increased the level of miR-19b-3p in cells, and increased miR-19b-3p further inhibited the expression of HIF-1α, thereby reducing the HYP-induced HUVECs apoptosis, autophagy and inflammation. Taken together, these results suggest that MALAT1 may be a potential target for mitigating HYP-induced endothelial cell injury.

MALAT1: a therapeutic candidate for a broad spectrum of vascular and cardiorenal complications.

Cardiovascular and renal complications cover a wide array of diseases. The most commonly known overlapping complications include cardiac and renal fibrosis, cardiomyopathy, cardiac hypertrophy, hypertension, and cardiorenal failure. The known or reported causes for the abovementioned complications include injury, ischemia, infection, and metabolic stress. To date, various targets have been reported and investigated in detail that are considered to be the cause of these complications. In the past 5 years, the role of noncoding RNAs has emerged in the area of cardiovascular and renal research, especially in relation to metabolic stress. The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) has shown immense promise among the long noncoding RNA targets for treating cardiorenal complications. In this review, we shed light on the role of MALAT1 as a primary and novel target in treating cardiovascular and renal diseases as a whole.

Overexpression of MALAT1 Relates to Lung Injury through Sponging miR-425 and Promoting Cell Apoptosis during ARDS.

Background Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury during which severe inflammatory responses induce cell apoptosis, necrosis, and fibrosis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a multiple function long noncoding RNA that was found overexpressed during acute lung injury. However, the roles of MALAT1 in ARDS patients are still unknown. Methods Total RNA was extracted from the plasma, plasma exosome, and peripheral blood mononuclear cells (PBMCs) from 65 ARDS patients and 36 healthy controls. The MALAT1 and six candidate miRNAs levels were detected by qRT-PCR. The interaction between MALAT1 and miR-425 was predicted using a bioinformatics tool and verified by dual luciferase assay. Exosomes from ARDS patients were cultured with A549 and HFL-1 cells to confirm the delivery of miR-425 by exosomes. Cell apoptosis and viability were determined by flow cytometry and MTT assay. Results We found MALAT1 was significantly increased in the ARDS patients' plasma and PBMCs. The MALAT1 level in PBMCs was negatively correlated with exosomal miR-425 level. MALAT1 interacted with miR-425 and protected phosphatase and tensin homolog (PTEN) expression in A549 and HFL-1 cells. Exosomes from ARDS patients delivered less miR-425 into A549 and HFL-1 cells and induced cell apoptosis via upregulating PTEN. Conclusion This study identified increased MALAT1 and decreased miR-425 in ARDS patients and unveiled their roles during the pathogenesis of ARDS.

Metastasis Associated Lung Adenocarcinoma Transcript 1: An update on expression pattern and functions in carcinogenesis

The Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is among long non-coding RNAs (lncRNAs) which has disapproved the old term of "junk DNA" which was used for majority of human genome which are not transcribed to proteins. An extensive portion of literature points to the fundamental role of this lncRNA in tumorigenesis process of diverse cancers ranging from solid tumors to leukemia. Being firstly identified in lung cancer, it has prognostic and diagnostic values in several cancer types. Consistent with the proposed oncogenic roles for this lncRNA, most of studies have shown up-regulation of MALAT1 in malignant tissues compared with non-malignant/normal tissues of the same source. However, few studies have shown down-regulation of MALAT1 in breast cancer, endometrial cancer, colorectal cancer and glioma. In the current study, we have conducted a comprehensive literature search and provided an up-date on the role of MALAT1 in cancer biology. Our investigation underscores a potential role as a diagnostic/prognostic marker and a putative therapeutic target for MALAT1.

Secondary Structural Model of Human MALAT1 Reveals Multiple Structure-Function Relationships.

Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an abundant nuclear-localized long noncoding RNA (lncRNA) that has significant roles in cancer. While the interacting partners and evolutionary sequence conservation of MALAT1 have been examined, much of the structure of MALAT1 is unknown. Here, we propose a hypothetical secondary structural model for 8425 nucleotides of human MALAT1 using three experimental datasets that probed RNA structures in vitro and in various human cell lines. Our model indicates that approximately half of human MALAT1 is structured, forming 194 helices, 13 pseudoknots, five structured tetraloops, nine structured internal loops, and 13 intramolecular long-range interactions that give rise to several multiway junctions. Evolutionary conservation and covariation analyses support 153 of 194 helices in 51 mammalian MALAT1 homologs and 42 of 194 helices in 53 vertebrate MALAT1 homologs, thereby identifying an evolutionarily conserved core that likely has important functional roles in mammals and vertebrates. Data mining revealed that RNA modifications, somatic cancer-associated mutations, and single-nucleotide polymorphisms may induce structural rearrangements that sequester or expose binding sites for several cancer-associated microRNAs. Our findings reveal new mechanistic leads into the roles of MALAT1 by identifying several intriguing structure–function relationships in which the dynamic structure of MALAT1 underlies its biological functions.

MALAT1 is involved in the pathophysiological process of PCOS by modulating TGFβ signaling in granulosa cells

Polycystic ovary syndrome (PCOS) is an endocrine disorder, the etiology of which is complex and unclear. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a conserved long non-coding RNA which has been found to play a role in the pathophysiological process of reproductive system diseases, such as endometriosis and pregnancy loss. However, the role of MALAT1 in PCOS is still unknown. In this study, reduced MALAT1 expression was found in granulosa cells (GCs) from 68 patients with PCOS and 30 healthy controls, which relates to upregulated cell proliferation and downregulated apoptosis. Using phosphorylation pathway profiling array, MALAT1 reduction was identified to contribute to the repression of transforming growth factor beta (TGFβ) signaling in GCs. Subsequently, MALAT1 was confirmed to function as a competing endogenous RNA (ceRNA), interacting with miR-125b and miR-203a. Meanwhile, miR-125b and miR-203a was identified as two novel TGFβ signaling negative regulators by targeting TGFBR1 and TGFBR2. Finally, MALAT1 knockdown was found to induce the upregulation of miR-125b and miR-203a, which further repressed TGFβ signaling, changed some downstream gene expression, and resulted in a disordered cell cycle. In conclusion, MALAT1 reduction was identified in GCs, which may contribute to the pathophysiological processes of PCOS by regulating TGFβ signaling through sponging miR-125b and miR-203a.

MALAT1 promotes gastric adenocarcinoma through the MALAT1/miR-181a-5p/AKT3 axis.

Gastric adenocarcinoma, which originates from the gastric mucosal epithelium, has the highest incidence among various malignant tumours in China. As a crucial long non-coding RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been suggested to play an important role in many tumours. Here, we aimed to investigate the role and underlying mechanism of MALAT1 in gastric adenocarcinoma. Quantitative reverse transcription polymerase chain reaction was applied to determine the expression levels of MALAT1 in serum and cell lines. A CCK-8 assay and a clonogenic survival assay were used to examine cell proliferation and apoptosis. The protein level of RAC-γ serine/threonine-specific protein kinase (AKT3) was determined by western blot. Our results showed that MALAT1 was highly expressed in the serum of patients with gastric adenocarcinoma and in cell lines. Downregulating MALAT1 inhibited proliferation and promoted apoptosis of MGC-803 cells. In addition, MALAT1 directly targeted and decreased the expression of miR-181a-5p, which in turn upregulated the expression of AKT3. Further, overexpressing miR-181a-5p or directly inhibiting the AKT pathway with the inhibitor ipatasertib exhibited similar effects to MALAT1 knockdown. Our research proposes a novel mechanism where the role of MALAT1 is dependent on the MALAT1/miR-181a-5p/AKT3 axis. MALAT1 competes with AKT3 for miR-181a-5p binding, thereby upregulating the AKT3 protein level and ultimately promoting the growth of gastric adenocarcinoma.

Long non‑coding RNA MALAT1 sponges miR‑124‑3p.1/KLF5 to promote pulmonary vascular remodeling and cell cycle progression of pulmonary artery hypertension.

Previous studies have demonstrated that long non-coding RNA (lncRNA) is involved in vascular remodeling. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA is associated with the proliferation and migration of vascular smooth muscle and endothelial cells; however, its biological role in pulmonary artery hypertension (PAH) is currently unclear. The aim of the present study was to investigate the post-transcriptional regulation of MALAT1 in human pulmonary artery smooth muscle cells (HPASMCs). The results revealed that MALAT1 expression levels were significantly upregulated in the pulmonary arteries (PAs) and HPASMCs obtained from patients with PAH compared with adjacent normal PA tissues and HPASMCs. Knockdown of MALAT1 suppressed the viability and proliferation of HPASMCs and prevented cells entering the G0/G1 cell cycle phase. MALAT1 overexpression exerted the opposite effects. Bioinformatics analysis predicted complementary binding of hsa-microRNA (miR)-124-3p.1 with the 3′-untranslated region of MALAT1. Luciferase reporter assays and RNA immunoprecipitation experiments demonstrated molecular binding between MALAT1 and hsa-miR-124-3p.1. This resulted in the formation of an RNA-induced silencing complex. In addition, Kruppel-like factor 5 (KLF5) was confirmed to be a target gene of MALAT1/hsa-miR-124-3p.1. MALAT1 silencing did not inhibit the proliferation and migration of HPASMCs following knockdown of hsa-miR-124-3p.1. In addition, MALAT1 knockdown was demonstrated to attenuate the expression of KLF5. Following MALAT1 knockdown, the expression level of KLF5 was rescued by inhibition of hsa-miR-124-3p.1 expression. The results of the current study indicate that the MALAT1/hsa-miR-124-3p.1/KLF5 axis may serve a key role in HPASMCs. In addition, the results contribute to what is known regarding the role of MALAT1 in PAH development and provide a novel theoretical basis for the development of new therapeutic interventions for patients with PAH.

Long Non-Coding RNA MALAT1 Accelerates Skeletal Muscle Cell Apoptosis and Inflammatory Response in Sepsis Through Decreasing BRCA1 Expression by Recruiting EZH2

Background: Sepsis is a serious and elusive syndrome caused by infection, which is accompanied by a high rate of mortality worldwide. Studies have speculated the role of long non-coding RNAs (lncRNAs) in sepsis. However, the potential role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in sepsis is largely unknown. Thus, the present study intended to investigate the possible role of MALAT1 in relation to the development of sepsis and to explore the underlying mechanism. Methods: In vivo mouse model and in vitro cell model of sepsis induced by lipopolysaccharide (LPS) were constructed. Then in order to evaluate the effect of MALAT1 on the progression of sepsis, the expression of MALAT1 was silenced in sepsis mice, followed by the measurement of number of neutrophils in peripheral blood, serum levels of inflammatory factors, as well as skeletal muscle cell apoptosis. Furthermore, interactions among MALAT1, EZH2 and BRCA1 and the regulatory role of MALAT1/EZH2 on sepsis were determined in skeletal muscles cells of sepsis. Results: High expression of MALAT1 along with low expression of BRCA1 was detected in sepsis. MALAT1 was observed to regulate the expression and nucleation of BRCA1. Silencing MALAT1 resulted in reduced serum levels of IL-6, IL-8 and TNF-α, neutrophil migration, skeletal muscle cell apoptosis, number of EZH2 positive cells, extent of AKT-1 phosphorylation along with stimulated BRCA1 expression. Furthermore, MALAT1 regulated the expression and localization of BRCA1 by recruiting EZH2. Conclusion: Taken together, the key observations of the study provide evidence that 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. Funding Statement: This study was supported by the National Natural Science Foundation of China (No. 81772128). Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: All animal experiment protocols were approved by the Animal Care Committee of The First Affiliated Hospital of Southwest Medical University and were in compliance with the guidelines established by the Guide for the Care and Use of Laboratory Animals.

LncRNA MALAT1 modulates ox-LDL induced EndMT through the Wnt/\u03b2-catenin signaling pathway

BackgroundEndothelial-to-mesenchymal transition (EndMT) plays significant roles in atherosclerosis, but the regulatory mechanisms involving lncRNAs remain to be elucidated. Here we sort to identify the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in ox-LDL-induced EndMT.MethodsThe atherosclerosis model was established by feeding ApoE−/− mice with high-fat diet, and the levels of lncRNA MALAT1 in mouse arterial tissue were detected by RT-qPCR. Cell model was established by treating human umbilical vein endothelial cells (HUVECs) with ox-LDL, and the levels of EndMT markers, such as CD31, vWF, α-SMA and Vimentin and lncRNA MALAT1 levels were detected and their correlations were analyzed. The role of MALAT1 in EndMT and its dependence on Wnt/β-catenin signaling pathway was further detected by knocking down or overexpressing MALAT1.ResultsMALAT1 was upregulated in high-fat food fed ApoE−/− mice. HUVECs treated with ox-LDL showed a significant decrease in expression of CD31 and vWF, a significant increase in expression of α-SMA and vimentin, and upregulated MALAT1. An increased MALAT1 level facilitated the nuclear translocation of β-catenin induced by ox-LDL. Inhibition of MALAT1 expression reversed nuclear translocation of β-catenin and EndMT. Moreover, overexpression of MALAT1 enhanced the effects of ox-LDL on HUVEC EndMT and Wnt/β-catenin signaling activation.ConclusionsOur study revealed that the pathological EndMT required the activation of the MALAT1-dependent Wnt/β-catenin signaling pathway, which may be important for the onset of atherosclerosis.Trial registrationNot applicable.