Noncoding RNA Metastasis-associated Lung Adenocarcinoma Transcript 1 Research Articles

The Long Non-Coding RNA MALAT1 Modulates NR4A1 Expression through a Downstream Regulatory Element in Specific Cancer Cell Types.

Long non-coding RNAs (lncRNAs) have been shown to modulate gene expression and are involved in the initiation and progression of various cancer types. Despite the wealth of studies describing transcriptome changes upon lncRNA knockdown, there is limited information describing lncRNA-mediated effects on regulatory elements (REs) modulating gene expression. In this study, we investigated how the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA regulates primary target genes using time-resolved MALAT1 knockdown followed by parallel RNA-seq and ATAC-seq assays. The results revealed that MALAT1 primarily regulates specific protein-coding genes and a substantial decrease in the accessibility downstream of the NR4A1 gene that was associated with a decreased NR4A1 expression. Moreover, the presence of an NR4A1-downstream RE was demonstrated by CRISPR-i assays to define a functional MALAT1/NR4A1 axis. By analyzing TCGA data, we identified a positive correlation between NR4A1 expression and NR4A1-downstream RE accessibility in breast cancer but not in pancreatic cancer. Accordingly, this regulatory mechanism was experimentally validated in breast cancer cells (MCF7) but not in pancreatic duct epithelial carcinoma (PANC1) cells. Therefore, our results demonstrated that MALAT1 is involved in a molecular mechanism that fine-tunes NR4A1 expression by modulating the accessibility of a downstream RE in a cell type-specific manner.

Long non-coding RNA MALAT1 in hematological malignancies and its clinical applications.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a well-established oncogenic long non-coding RNA, the higher expression of which is strongly correlated with cancer events such as tumorigenesis, progression, metastasis, drug resistance, and treatment outcome in solid cancers. Recently, a series of studies has highlighted its potential role in hematological malignancies in terms of these events. Similar to solid cancers, MALAT1 can regulate various target genes via sponging and epigenetic mechanisms, but the miRNAs sponged by MALAT1 differ from those identified in solid cancers. In this review, we systematically describe the role and underlying mechanisms of MALAT1 in multiple types of hematological malignancies, including regulation of cell proliferation, metastasis, stress response, and glycolysis. Clinically, MALAT1 expression is related to poor treatment outcome and drug resistance, therefore exhibiting potential prognostic value in multiple myeloma, lymphoma, and leukemia. Finally, we discuss the evaluation of MALAT1 as a novel therapeutic target against cancer in preclinical studies.

Evaluation of the clinical significance of long non-coding RNA MALAT1 genetic variants in human lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most frequent histological subtype of lung cancer, which is the most common malignant tumor and the main cause of cancer-related mortality globally. Recent reports revealed that long non-coding RNA (lncRNA) of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in tumorigenesis and metastasis development in lung cancer. However, the contribution of MALAT1 genetic variants to the development of LUAD is unclear, especially in epidermal growth factor receptor (EGFR) mutation status. In this study, 272 LADC patients with different EGFR status were recruited to dissect the allelic discrimination of the MALAT1 polymorphisms at rs3200401, rs619586, and rs1194338. The findings of the study showed that MALAT1 polymorphisms rs3200401, rs619586, and rs1194338 were not associated to LUAD susceptibility; however, rs3200401 polymorphisms was significantly correlated to EGFR wild-type status and tumor stages in LUAD patients in dominant model (p=0.016). Further analyses using the datasets from The Cancer Genome Atlas (TCGA) revealed that lower MALAT1 mRNA levels were associated with the advanced stage, and lymph node metastasis in LADC patients. In conclusion, our results showed that MALAT1 rs3200401 polymorphisms dramatically raised the probability of LUAD development.

Predictive value of peripheral blood leukocytes-based methylation of Long non-coding RNA MALAT1 and H19 in the chemotherapy effect and prognosis of gastric cancer

BackgroundThe predictive value of the methylation of Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and H19 promoters in peripheral blood leukocytes as a non-invasive biomarker for the chemotherapy effect and prognosis gastric cancer (GC) is unclear. MethodsThe DNA methylation of H19 and MALAT1 between chemotherapy-sensitive and non-sensitive groups and between groups with better and worse survival of GC was compared using regression analyses. Several predictive nomograms were constructed. The genetic alteration of MALAT1 and H19 and the association between gene expression and immune status in GC were also investigated using bioinformatics analysis. ResultsHigher genetic methylations in peripheral blood were noticed in GC groups with poorer survival. The constructed nomograms presented strong predictive values for the chemotherapy effect and 3-year survival of disease-free survival, progression-free survival, and overall survival, with the area under the curve as 0.838, 0.838, 0.912, and 0.925, respectively. Significant correlations between MALAT1 or H19 expression and marker genes of immune checkpoints and immune pathways were noticed. The high infiltration of macrophages in H19-high and low infiltration of CD8+ T cells in MALAT1-high groups were associated with worse survival of GC. ConclusionsMALAT1 and H19 have the potential to predict the chemotherapy response and clinical outcomes of GC.

Exosomal long non-coding RNA MALAT1: a candidate of liquid biopsy in monitoring of Wilms' tumor.

Wilms' tumor (WT) is a rare kidney cancer that primarily affects children. Exosomes are extracellular vesicles that cargo nucleic acids, proteins,etc. for cellular communication. Long non-coding RNAs (lncRNAs) have utility as biomarkers for cancer diagnosis, prognosis, and disease monitoring. We hypothesize that expression of lncRNA, metastasis-associated lung adenocarcinoma transcript-1(MALAT1), is dysregulated and possibly trafficked within exosomes to influence the tissue microenvironment for metastasis and recurrence of WT. We investigated the expression of MALAT1 in thirty WT samples by qPCR. Exosomes were isolated using a precipitated and affinity-binding-based kit, and characterized using TEM, NTA, and DLS. Mean number of exosomes was 9.01×108/mL in primary culture, 1.64×108/mL in urine, and 4.65×108/plasma:400µl. Average yield of total RNA was 1.28µg (primary-culture supernatant:1ml), 1.47µg (Urine:1ml), 1.65µg (Plasma:400 µL). We quantified MALAT1 in exosomes derived from these sources in patients of WT. Expression of MALAT1 was significantly downregulated (p=0.008) in WT samples. This is the first study that demonstrated the presence of lncRNA MALAT1 in various invasive and non-invasive samples of patients with WT(primary tissue culture, urine, and plasma samples).

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.

Long noncoding RNA MALAT1; A novel and potential therapeutic target for Alzheimer’s disease

AbstractBackgroundAlzheimer disease (AD) is the most common form of dementia, characterized pathologically by amyloid plaques and neurofibrillary tangles. Despite considerable advances in the knowledge of AD pathogenesis, we know little about preventing or delaying the ongoing neurodegenerative process, indicating that there remain critical gaps in our understanding of disease mechanisms and opportunities for new treatment approaches. Long noncoding RNAs (lncRNAs) are larger than 200 nucleotides, structurally resemble mRNAs but do not encode proteins. LncRNAs participate in regulation of several physiological and pathophysiological processes by modulating gene expression and have been documented in several neurodegenerative diseases. Among them, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is a highly abundant and evolutionary conserved lncRNA and regulates a subset of genes involved in synaptic plasticity, cognitive function and memory.MethodTo test the hypothesis that lncRNA MALAT1 plays an important role in AD pathology, we quantified expression levels of lncRNA MALAT1 in the brains of age‐matched AD patients and cognitively normal controls (Non‐AD) by QRT‐PCR and RNAScope in situ hybridization assays, respectively. We further examined the lncRNA MALAT1 expressions and AD‐related neuropathology in the brains of 5XFAD transgenic mouse model of AD and their WT littermates using dual RNAScope/Immunofluorescence technique.ResultWe observed reduced expressions of lncRNA MALAT1 in the hippocampus of AD brains compared to the non‐AD control brains. Next, we found marked reduced expression of lncRNA MALAT1 in the brain of 5xFAD mice compared to non‐transgenic mice. Interestingly, decreased expression levels of lncRNA MALAT1 are correlated with AD‐related neuropathology and memory deficits in 5xFAD mice.ConclusionThese findings provided compelling evidence that AD is associated with altered expression of lncRNA MALAT1 which may influence several pathways related to neural damage and memory deficits in AD. Because expression patterns, interacting proteins, pathways, and biological functions of lncRNA MALAT1 are remain largely unexplored in AD, understanding how lncRNA MALAT1 regulates AD‐related neuropathology may allow development of effective therapies for this incurable disease.

The Long non-coding RNA MALAT1 functions as a competing endogenous RNA to regulate vascular remodeling by sponging miR-145-5p/HK2 in hypertension

ABSTRACT Long non-coding RNAs (LncRNAs) have been found to play a regulatory role in the pathophysiology of vascular remodeling-associated illnesses through the lncRNA-microRNA (miRNA) regulation axis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is thought to be involved in proliferation, migration, apoptosis, and calcification of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the regulatory role of MALAT1 on vascular remodeling in hypertension. Our data indicate that the expression of MALAT1 is significantly upregulated in hypertensive aortic smooth muscle. Knockdown of MALAT1 inhibited the proliferation, migration, and phenotypic transition of VSMCs induced by Ang II. Bioinformatics analysis was used to predict the complementary binding of miR-145-5p to the 3’-untranslated region of MALAT1. Besides, the expressions of MALAT1 and miR-145-5p were negatively correlated, while luciferase reporter assays and RNA immunoprecipitation assay validated the interaction between miR-145-5p and MALAT1. The proliferation, migration and phenotypic transformation of VSMCs induced by overexpression of MALAT1 were reversed in the presence of miR-145-5p. Furthermore, we verified that miR-145-5p could directly target and bind to hexokinase 2 (HK2) mRNA, and that HK2 expression was negatively correlated with miR-145-5p in VSMCs. Knockdown of HK2 significantly inhibited the effects of overexpression of MALAT1 on Ang II-induced VSMCs proliferation, migration and phenotypic transformation. Taken together, the MALAT1/miR-145-5p/HK2 axis may play a critical regulatory role in the vascular remodeling of VSMCs in hypertension.

Anti-apoptotic capacity of MALAT1 on hippocampal neurons correlates with CASP3 DNA methylation in a mouse model of autism.

Prior evidence has suggested the alleviatory effect of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on neuroinflammation in neurodegenerative diseases. This study primarily investigates the underlying mechanism of how the long non-coding RNA MALAT1 affects neuronal apoptosis in the hippocampus of mice with autism spectrum disorder (ASD). The findings demonstrate that CASP3 is highly expressed while MALAT1 is downregulated in the hippocampal neurons of autistic mice. MALAT1 mainly localizes within the cell nucleus and recruits DNA methyltransferases (including DNMT1, DNMT3a, and DNMT3b) to the promoter region of CASP3, promoting its methylation and further inhibiting its expression. In vitro experiments reveal that reducing MALAT1 expression promotes the expression of CASP3 and Bax while suppressing Bcl-2 expression, thereby enhancing cellular apoptosis. Conversely, increasing MALAT1 expression yields the opposite effect. Consequently, these results further confirm the role of MALAT1 in suppressing neuronal apoptosis in the hippocampus of mice with ASD through the regulation of CASP3 promoter methylation. Thus, this research unveils the significant roles of MALAT1 and CASP3 in the pathogenesis of ASD, offering new possibilities for future therapeutic interventions.

Long noncoding RNA MALAT1 is dynamically regulated in leader cells during collective cancer invasion

Cancer cells collectively invade using a leader-follower organization, but the regulation of leader cells during this dynamic process is poorly understood. Using a dual double-stranded locked nucleic acid (LNA) nanobiosensor that tracks long noncoding RNA (lncRNA) dynamics in live single cells, we monitored the spatiotemporal distribution of lncRNA during collective cancer invasion. We show that the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is dynamically regulated in the invading fronts of cancer cells and patient-derived spheroids. MALAT1 transcripts exhibit distinct abundance, diffusivity, and distribution between leader and follower cells. MALAT1 expression increases when a cancer cell becomes a leader and decreases when the collective migration process stops. Transient knockdown of MALAT1 prevents the formation of leader cells and abolishes the invasion of cancer cells. Taken together, our single-cell analysis suggests that MALAT1 is dynamically regulated in leader cells during collective cancer invasion.

Long non-coding RNA MALAT1 sponges miR-30c to promote the calcification of human vascular smooth muscle cells by regulating Runx2

Objectives Recent evidence suggested that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in the pathogenesis of vascular calcification (VC). In this study, we tried to explore the expression and role of a lncRNA, i.e., metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and a miRNA, i.e., miR-30c, in VC. Methods In vitro VC model was induced in human vascular smooth muscle cells (VSMCs) after 10 days culture in calcifying medium containing 2 mM Na2HPO4. Alizarin red S staining, calcium assay and western blot analysis of runt-related transcription factor 2 (Runx2) and alpha smooth muscle actin (α-SMA) were performed to evaluate VC. Knockdown of MALAT1 and up-regulation of MALAT1, miR-30c and Runx2 was performed to determine the impact of these molecules on VSMCs calcification. Dual-luciferase report assay was performed to confirm the relationship between MALAT1 and miR-30c or miR-30c and Runx2. In addition, quantitative reverse transcription PCR and western blot were used to determine gene and protein expression. Results MALAT1 was increased, while miR-30c was decreased in calcified VSMCs. Knockdown of MALAT1 suppressed VSMCs calcification; on the contrary, up-regulation of MALAT1 promoted VSMCs calcification. The effect of MALAT1 over-expression on VSMCs calcification was reversed by upregulation of miR-30c, which was reversed again by upregulation of Runx2. Dual-luciferase report assay confirmed that there is a direct interaction between MALAT1 and miR-30c, and Runx2 is a direct target of miR-30c. Conclusion MALAT1 over-expression promoted VSMCs calcification, which was at least partially through regulating the miR-30c/Runx2 axis.

The role of long non-coding RNA UCA1 and MALAT1 in bladder cancer patients

BackgroundBladder cancer (BC) is considered the most prevalent tumor of the urinary tract, and incidence rates are rising globally. Long noncoding RNAs (lncRNAs) can serve as biomarkers to help the diagnosis and anticipation of recurrence in cancer patients as they are implicated in carcinogenesis and tumor progression. This study targeted to investigate the expression of lncRNA as urothelial cancer associated 1 (UCA1) as well as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the diagnosis of BC. Subjects and methodsThe study included 70 BC patients, 70 benign urinary tract diseases and 70 controls. The UCA1 and MALAT1 expressions were studied utilizing quantitative real-time polymerase chain reaction. ResultsThe UCA1 and MALAT1 expression were significantly increased in patients with BC than patients with chronic cystitis and controls (p < 0.001). The sensitivity and specificity for the diagnosis of BC for UCA1(87.14%, 97.14% respectively) and MALAT1 (92.86%, 90% respectively). Multivariate logistic regression analysis showed that UCA1 and MALAT1 were risk factors for the development of BC where the odds ratio (OR) for UCA1 was 1.262 (CI 1.004–1.587) and MALAT1 was 2.201(CI 1.036–4.676). ConclusionUCA1 and MALAT1 could be potential diagnostic biomarkers with good specificity and sensitivity in bladder cancer.

Structural Analysis of MALAT1 long non-coding RNA in cells and in evolution.

Although not canonically polyadenylated, the long non-coding RNA MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) is stabilized by a highly conserved 76 nucleotide triple helix structure on its 3' end. The entire MALAT1 transcript is over 8,000 nucleotides long in humans. The strongest structural conservation signal in MALAT1 (as measured by co-variation of base-pairs) is in the triple helix structure. Primary sequence analysis of co-variation alone does not reveal the degree of structural conservation of the entire full-length transcript, however. Furthermore, RNA structure is often context dependent; RNA binding proteins that are differentially expressed in different cell types may alter structure. We investigate here the in cell and cell free structures of the full-length human and green monkey (Chlorocebus sabaeus) MALAT1 transcripts in multiple tissue-derived cell lines using SHAPE chemical probing. Our data reveal levels of uniform structural conservation in different cell lines, in cells and cell free, and even between species, despite significant differences in primary sequence. The uniformity of the structural conservation across the entire transcript suggests that, despite seeing co-variation signals only in the triple helix junction of the lncRNA, the rest of the transcript's structure is remarkably conserved at least in primates and across multiple cell types and conditions.

Long noncoding RNA MALAT1 inhibition attenuates sepsis-induced acute lung injury through modulating the miR-129-5p/PAX6/ZEB2 axis.

This research aimed to investigate the role of the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-129-5p (miR-129-5p)/paired box gene 6 (PAX6) axis in sepsis-induced acute lung injury (ALI). MLE-12 cells and C57BL/6 mice were induced by LPS to establish lung injury in in vitro and in vivo models. Cell viability and apoptosis were measured by cell counting kit-8 assay and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining, respectively. Levels of inflammatory cytokines in cell supernatants and bronchoalveolar lavage fluid (BALF) were detected by ELISA. Lung injury was evaluated by lung wet weight-to-dry weight ratio and hematoxylin-eosin staining. MALAT1, PAX6, and zinc finger E-box-binding homeobox 2 (ZEB2) expression was elevated and miR-129-5p expression was reduced in the serum of patients with sepsis-induced ALI, LPS-induced MLE-12 cells, and lung tissues of ALI mice. MALAT1 interference delayed the LPS-induced cell proliferation decrease, apoptosis increase, and inflammatory factor increase. miR-129-5p inhibition could reverse the delaying effect of MALAT1 interference on LPS-induced lung cell injury. PAX6 overexpression (oe) reversed the inhibitory effect of miR-129-5p oe on LPS-induced lung cell injury. Downregulating MALAT1 reduced pulmonary edema, inflammatory cytokine levels, lung injury, and apoptosis in ALI mice. Moreover, miR-129-5p suppression or PAX6 oe reversed the delaying effect of MALAT1 interference on sepsis-induced ALI. MALAT1 aggravates sepsis-induced ALI via the miR-129-5p/PAX6/ZEB2 axis.

Upregulation of Long Noncoding RNA MALAT1 in Colorectal Cancer Promotes Radioresistance and Aggressive Malignance.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a conserved transcript with 8000 nt, is highly associated with malignancy of numerous cancer types. However, the function of MALAT1 plays in regulating the response to radiotherapy in colorectal cancer (CRC) remains unclear. Thus, the object of this study is to investigate the functions of MALAT1 in CRC radioresistance. First, the expression of MALAT1 in colon adenocarcinoma (COAD) was analyzed through the Cancer Genome Atlas (TCGA) database. Then, we detected the expression level of MALAT1 in tumor tissues and CRC cell lines and analyzed the relevance of MALAT1 and clinicopathological parameters. In the end, the effect of silencing MALAT1 on the radiosensitivity of CRC cells was investigated, and its potential mechanism was preliminarily illustrated. The analysis of TCGA data showed that MALAT1 was closely related to the type of tumor, and high expression of MALAT1 was remarkably relevant to poor outcome. MALAT1 was highly expressed in CRC tissues and cell lines and related to tumor stages. Knockdown of MALAT1 could significantly suppress colony survival, proliferation, and migration and increase apoptosis, G2/M phase arrest, and formation of gamma-H2AX foci in HCT116, whether in combination with X-rays or not. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated that the regulated proteins were principally enriched in the glycosaminoglycan degradation pathway after silencing MALAT1. Our results implied that MALAT1 was highly expressed in CRC and associated with tumor stage and prognosis. Silencing MALAT1 can increase HCT116 cell radiosensitivity, which may be potentially influenced by glycosaminoglycan degradation pathway.

Focus on long non-coding RNA MALAT1: Insights into acute and chronic lung diseases.

Acute lung injury (ALI) is a pulmonary illness with a high burden of morbidity and mortality around the world. Chronic lung diseases also represent life-threatening situations. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a type of long non-coding RNA (lncRNA) and is highly abundant in lung tissues. MALAT1 can function as a competitive endogenous RNA (ceRNA) to impair the microRNA (miRNA) inhibition on targeted messenger RNAs (mRNAs). In this review, we summarized that MALAT1 mainly participates in pulmonary cell biology and lung inflammation. Therefore, MALAT1 can positively or negatively regulate ALI and chronic lung diseases (e.g., chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), pulmonary fibrosis, asthma, and pulmonary hypertension (PH)). Besides, we also found a MALAT1-miRNA-mRNA ceRNA regulatory network in acute and chronic lung diseases. Through this review, we hope to cast light on the regulatory mechanisms of MALAT1 in ALI and chronic lung disease and provide a promising approach for lung disease treatment.

Functional roles of long noncoding RNA MALAT1 in gynecologic cancers.

Gynecologic cancers are reproductive disorders characterized by pelvic pain and infertility. The identification of new predictive markers and therapeutic targets for the treatment of gynecologic cancers is urgently necessary. One of the recent successes in gynecologic cancers research is identifying the role of signaling pathways in the pathogenesis of the disease. Recent experiments showed long noncoding RNAs (lncRNA) can be novel therapeutic approaches for the diagnosis and treatment of gynecologic cancers. LncRNA are transcribed RNA molecules that play pivotal roles in multiple biological processes by regulating the different steps of gene expression. Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) is a well-known lncRNA that plays functional roles in gene expression, RNA processing, and epigenetic regulation. High expression of MALAT1 is closely related to numerous human diseases. It is generally believed that MALAT1 expression is associated with cancer cell growth, autophagy, invasion, and metastasis. MALAT1 by targeting multiple signaling pathways and microRNAs (miRNAs) could contribute to the pathogenesis of gynecologic cancers. In this review, we will summarize functional roles of MALAT1 in the most common gynecologic cancers, including endometrium, breast, ovary, and cervix.

Long Noncoding RNA MALAT1 Promotes Laryngocarcinoma Development by Targeting miR-708-5p/BRD4 Axis to Regulate YAP1-Mediated Epithelial-Mesenchymal Transition.

Objective The objective of this study was to investigate whether long noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) contributes to laryngocarcinoma development via regulating the Yes-associated protein 1- (YAP1-) mediated epithelial-mesenchymal transition (EMT) and the underlying mechanism. Methods The effects of MALAT1 suppression and BET inhibitor JQ1 on the malignant phenotypes and cancer stem cell- (CSC-) like properties of laryngocarcinoma cells as well as the expression of bromodomain-containing protein 4 (BRD4), YAP1, and EMT markers were investigated. Moreover, the relationships between MALAT1 and miR-708-5p as well as between miR-708-5p and BRD4 were explored. Furthermore, whether MALAT1 regulated the malignant phenotypes of laryngocarcinoma cells via sponging miR-708-5p to target BRD4 was revealed by both in vitro and in vivo experiments. Results MALAT1 suppression inhibited the malignant phenotypes of laryngocarcinoma cells, such as decreased proliferation, promoted apoptosis, suppressed migration, and inhibited the CSC properties. Suppression of MALAT1 increased miR-708-5p expression and decreased the expression of BRD4 and YAP1 and inhibited EMT. Moreover, there were target relationships between MALAT1 and miR-708-5p as well as between miR-708-5p and BRD4. miR-708-5p overexpression and MALAT1 suppression had synergistic inhibitory effects on the malignant phenotypes of laryngocarcinoma cells and the expression of BRD4, YAP1, and EMT. Furthermore, in vivo experiments confirmed that MALAT1/miR-708-5p regulated tumorigenicity by regulating BRD4 and YAP1-mediated EMT. Conclusions Our results indicate that suppression of MALAT1 may inhibit laryngocarcinoma development by sponging miR-708-5p/BRD4 to regulate YAP1-mediated EMT. Targeting MALAT1/miR-708-5p/BRD4 axis may provide a promising therapeutic strategy for laryngocarcinoma.

Significant role of long non-coding RNA MALAT1 in deep vein thrombosis via the regulation of vascular endothelial cell physiology through the microRNA-383-5p/BCL2L11 axis

ABSTRACT Deep vein thrombosis (DVT) is a vascular disease. The long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is positively expressed in DVT tissues, and regulates the biological behavior of endothelial progenitor cells. Here, we explored whether MALAT1 affected the physiology of human vascular endothelial cells (HUVECs) and analyzed its underlying mechanism. To overexpress/silence the expression of MALAT1 in HUVECs, MALAT1-plasmid/MALAT1-small interfering RNA (siRNA) was used. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and flow cytometry analyses were performed to observe the cell viability and apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to determine the apoptosis-related protein and gene expression levels. We used Starbase software to predict the associations among MALAT1, microRNA (miR)-383-5p, and BCL2-like 11 (BCL2L11). Luciferase reporter assay was used to validate their relationship. Compared to the control vector group, MALAT1-plasmid suppressed the viability and induced apoptosis of HUVECs, while improving Bcl-2-associated X protein (Bax) expression and decreasing Bcl-2 expression. There was an interaction between MALAT1 and miR-383-5p. Compared to the control siRNA group, MALAT1-siRNA increased the cell viability, reduced cell apoptosis, upregulated Bcl-2 expression, and suppressed Bax expression. These changes were reversed by the miR-383-5p inhibitor. Additionally, we verified that BCL2L11 is a target of miR-383-5p. miR-383-5p improved the cell proliferation, while decreasing cell apoptosis in HUVECs by targeting BCL2L11. Therefore, the lncRNA-MALAT1/miR-383-5p/BCL2L11 axis may be effective for DVT treatment.

Long non-coding RNA MALAT1 aggravated liver ischemia-reperfusion injury via targeting miR-150-5p/AZIN1

ABSTRACT Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in the process of renal ischemia-reperfusion (IR) injury and myocardial IR injury. However, its mechanism in liver IR injury is not clear. IR and hypoxia/reoxygenation (H/R) model were built on C57BL/6 mice. Blood samples were obtained from the inferior vena cava of the model mice. MALAT1 expression was detected in IR model and H/R model. Supported by experimental results, the impacts of MALAT1 on viability, apoptosis, and inflammation of H/R model cells were detected. The correlation between MALAT1 and downstream genes was analyzed by mechanism assays. MALAT1 was detected to be upregulated in IR model and H/R model. MALAT1 knockdown had inhibitory effects on apoptosis and inflammatory reaction while promoting liver cell viability in H/R condition. Meanwhile, MALAT1 targeted miR-150-5p to regulate antizyme inhibitor 1 (AZIN1) in liver cells. Finally, MALAT1 regulated viability, apoptosis, and inflammatory reaction of liver cells by targeting miR-150-5p and AZIN1. To conclude, MALAT1 targeted miR-150-5p/AZIN1 to accelerate liver IR injury, suggesting that MALAT1 might be a novel target for liver IR injury.