Levels Of Metastasis-associated Lung Adenocarcinoma Transcript 1 Research Articles

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.

Hematopoietic Deficiency of the Long Noncoding RNA MALAT1 Promotes Atherosclerosis and Plaque Inflammation.

The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) on atherosclerosis was examined. The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E-deficient (Apoe-/-) MALAT1-deficient (Malat1-/-) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques. Apoe-/- Malat1-/- mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45+ cells compared with Apoe-/- Malat1+/+ control mice. Bone marrow transplantation of Apoe-/- Malat1-/- bone marrow cells in Apoe-/- Malat1+/+ mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1-/- mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1-/- mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis. Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1-/- mice were mainly caused by enhanced accumulation of hematopoietic cells.

Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Promotes Proliferation and Metastasis of Osteosarcoma Cells by Targeting c-Met and SOX4 via miR-34a/c-5p and miR-449a/b.

BackgroundMetastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a functional long non-coding RNA involved in many biologic processes. The study was aimed to explore the functional roles of MALAT1 in osteosarcoma progression.Material/MethodsA total of 76 osteosarcoma tissues and paired adjacent non-tumor tissues were collected from surgical resection. MALAT1, miRNAs, and genes mRNA expression levels were detected using quantitative real-time PCR (qRT-PCR). Protein expression level, cell proliferation, migration, and invasion were assessed using western blot, Cell Counting Kit-8 (CCK-8), wound-healing assay, and Matrigel invasion assay respectively. The target relationships among miRNAs, MALAT1, and mRNA were detected via dual-luciferase reporter assay.ResultsWe found that MALAT1 was frequently upregulated in osteosarcoma samples and cell lines and a high level of MALAT1 predicted poor overall survival in osteosarcoma patients. Knockdown of MALAT1 inhibited proliferation, migration, and invasion of osteosarcoma cells. Further study showed a positive correlation between MALAT1 and c-Met or SOX4 expression. Mechanistic investigations demonstrated that MALAT1, as a competing endogenous RNA (ceRNA), regulated osteosarcoma proliferation and metastasis through competitively binding to miR-34a/c-5p and miR-449a/b.ConclusionsTaken together, our study illustrates a new regulatory mechanism for MALAT1 and may provide a novel therapeutic strategy for the treatment of osteosarcoma.

Association of long non-coding RNA MIAT and MALAT1 expression profiles in peripheral blood of coronary artery disease patients with previous cardiac events.

Long non-coding RNAs (lncRNAs) are implicated in various cellular and pathological processes. Two lncRNAs, myocardial infarction-associated transcript (MIAT) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), may be involved in the pathogenesis of coronary artery disease (CAD). Here, we aimed to determine the relative circulating levels of MIAT and MALAT1 in 110 stable CAD patients and 117 controls and to correlate their levels with the clinical and laboratory data. Peripheral blood expression levels were quantified by Real-Time qPCR. The median MIAT expression level in CAD patients was significantly 12-fold higher than controls (p<0.001). Otherwise, the median MALAT1 expression level was comparable in patient and control groups. Both lncRNAs showed significantly higher relative expression levels in patients with positive history of previous cardiac ischemic events, and MIAT showed significantly higher expression in diabetic CAD patients. The area under the curve of MIAT (0.888 ± 0.02 with sensitivity 95.5% and specificity 72.7%), was significantly larger than that of MALAT1 (0.601 ± 0.04 with sensitivity 50% and specificity 63.6%) for detecting the presence of significant CAD. The current findings suggest that lncRNA MIAT could have a diagnostic significance in CAD patients. MALAT1 levels, however, are not sufficiently reliable to have much clinical use in our cases.

MALAT1 and BACH1 are prognostic biomarkers for triple-negative breast cancer.

The purpose of this study was to investigate the potential correlation between metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and the transcription factor BTB and CNC homology 1 (BACH1) and their clinicopathological significance in triple-negative breast cancer (TNBC). MALAT1 and BACH1 were detected by immunohistochemistry using TNBC tissue microarrays of 240 patients. The association between MALAT1 and BACH1 expression levels was statistically analyzed. Moreover, the prognostic roles as well as clinical and pathological significance of MALAT1 and BACH1 expression in TNBC were determined. Two-tailed Pearson correlation was used to examine the correlation of BACH1 and MALA1 expression. Comparisons of clinicopathological variables between different BACH1 and MALA1 expression groups were performed using χ2 tests. Overall survival (OS) and disease-free survival (DFS) curves were plotted with the Kaplan-Meier method and the differences in OS and DFS between three groups were compared by the log-rank test. Multiple comparisons were performed using χ2 tests for subsequent individual group comparisons. MALAT1 and BACH1 expression was significantly correlated with tumor-node-metastasis stage, distant metastasis, pathological stage, and survival outcomes of patients. Patients with high MALAT1 and BACH1 expression exhibited shorter overall survival and disease-free survival. These findings provide further insight into the expression pattern of MALAT1 and BACH1 in TNBC and suggest them as prognostic biomarkers for TNBC.

Long Noncoding RNA MALAT1 Regulates Hepatocellular Carcinoma Growth Under Hypoxia via Sponging MicroRNA-200a.

PurposeHepatocellular carcinoma (HCC) is a common cancer worldwide. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA (lncRNA), has been reported to be aberrantly expressed in hypoxic cancer cells. MALAT1 plays a significant role in many malignancies, including HCC. The aim of this study was to explore the role of MALAT1 in hypoxic HCC cells and its underlying regulatory mechanism.Materials and MethodsQuantitative reverse transcription PCR (qRT-PCR) assay was performed to detect the mRNA levels of MALAT1 and microRNA-200a (miR-200a) in HCC cells. Cell invasion and migration ability were evaluated by Transwell assay. Starbase v2.0 and luciferase reporter assay were employed to identify the association between MALAT1 and miR-200a. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively.ResultsMALAT1 levels were significantly upregulated in HCC cells under hypoxia. Hypoxia promoted proliferation, migration, and invasion, and blocked apoptosis in Hep3B cells, which were weakened by knockdown of MALAT1. Starbase v2.0 showed that MALAT1 and miR-200a have a complementarity region, and luciferase reporter assay verified that MALAT1 interacted with miR-200a in Hep3B cells. Moreover, MALAT1 negatively regulated the expression of miR-200a. miR-200a levels were dramatically downregulated in HCC cells under hypoxia. Upregulation of miR-200a inhibited proliferation, migration, and invasion, and induced apoptosis in Hep3B cells under hypoxia. Interestingly, downregulation of miR-200a partially reversed the tumor-suppressive effect of knockdown of MALAT1 on Hep3B cells in hypoxic condition.ConclusionLncRNA MALAT1 was involved in proliferation, migration, invasion, and apoptosis by interacting with miR-200a in hypoxic Hep3B cells, revealing a new mechanism of MALAT1 involved in hypoxic HCC progression.

Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos.

The single-wall carbon nanotube (SWCNT) is a new type of nanoparticle, which has been used to deliver multiple kinds of drugs into cells, such as proteins, oligonucleotides, and synthetic small-molecule drugs. The SWCNT has customizable dimensions, a large superficial area, and can flexibly bind with drugs through different modifications on its surface; therefore, it is an ideal system to transport drugs into cells. Long noncoding RNAs (lncRNAs) are a cluster of noncoding RNA longer than 200 nt, which cannot be translated to protein but play an important role in biological and pathophysiological processes. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved lncRNA. It was demonstrated that higher MALAT1 levels are related to the poor prognosis of various cancers, including multiple myeloma (MM). We have revealed that MALAT1 regulates DNA repair and cell death in MM; thus, MALAT1 can be considered as a therapeutic target for MM. However, the efficient delivery of the antisense oligo to inhibit/knockdown MALAT1 in vivo is still a problem. In this study, we modify the SWCNT with PEG-2000 and conjugate an anti-MALAT1 oligo to it, test the delivery of this compound in vitro, inject it intravenously into a disseminated MM mouse model, and observe a significant inhibition of MM progression, which indicates that SWCNT is an ideal delivery shuttle for anti-MALAT1 gapmer DNA.

LncRNA MALAT1 protects cardiomyocytes from isoproterenol-induced apoptosis through sponging miR-558 to enhance ULK1-mediated protective autophagy.

Investigating the molecular mechanisms of myocardial infarction (MI) and subsequent heart failure have gained considerable attention worldwide. Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been previously demonstrated to regulate the proliferation and metastasis of several tumors. However, little is known about the effects of MALAT1 in MI and in regulating the cell date after MI. In our study, first, it was shown that the expression levels of MALAT1 were increased in the MI samples compared with normal tissues using quantitative reverse-transcription polymerase chain reaction. Then, MALAT1 knockdown could significantly decrease the cell viability and increase the apoptotic rates in isoproterenol (ISO)-treated H9C2 cells. In addition, we screened the possible target and found that miR-558 is its direct target using dual luciferase reporter assay, indicating that MALAT1 functioned as decoys sponging miR-558. Transfection of miR-558 mimic decreased the cell viability and enhanced the apoptosis. Furthermore, we revealed that miR-558 could downregulate ULK1 expression and suppressed ISO-induced protective autophagy. Activation of MALAT1/miR-558/ULK1 pathway protected H9C2 cells from ISO-induced mitochondria-dependent apoptosis. Finally, we used MALAT1-knockout mice to further demonstrated that MALAT1 protected cardiomyocytes from apoptosis and partially improved the cardiac functions upon ISO treatment. In conclusion, we elucidated that lncRNA MALAT1 protected cardiomyocytes from ISO-induced apoptosis by sponging miR-558 thus promoting ULK1-dependent autophagy. Targeting lncRNA MALAT1 might become a potential strategy in protecting cardiomyocytes during MI.

MALAT1 lncRNA Induces Autophagy and Protects Brain Microvascular Endothelial Cells Against Oxygen–Glucose Deprivation by Binding to miR-200c-3p and Upregulating SIRT1 Expression

There is growing evidence that long noncoding RNAs (lncRNAs) play important roles in various biological processes. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the most highly upregulated lncRNAs in cerebral ischemia. However, the molecular mechanism of MALAT1 during cerebral ischemia is still unclear. This experiment is intended to investigate the role of MALAT1 in cerebral ischemia and its relationship with autophagy. Oxygen–glucose deprivation (OGD) in brain microvascular endothelial cells (BMECs) was used to mimic ischemic-like conditions in vitro. Real-time PCR, MTT, LDH assay and western blot were used to evaluate the levels of MALAT1, miR-200c-3p, SIRT1, cell survival and proteins. We found that the expression of MALAT1 and LC3BII were upregulated and p62 was downregulated by OGD. Inhibition of MALAT1 attenuated the autophagy activation and promoted cell death. We further revealed that MALAT1 downregulated the expression of miR-200c-3p by directly binding to miR-200c-3p. Furthermore, miR-200c-3p inhibited the autophagy and survival in BMECs by binding to 3′UTR of SIRT1, whereas MALAT1 overturned the inhibitory effect of miR-200c-3p. In conclusion, our study illuminated a novel Malat1-miR-200c-3p-SIRT1 pathway in the regulation of autophagy, in which, MALAT1 activates autophagy and promotes cell survival by binding to miR-200c-3p and upregulating SIRT1 expression.

Diagnostic potential of metastasis-associated-lung-adenocarcinoma-transcript-1 (MALAT-1) and TNFα and hnRNPL related immunoregulatory long non-coding RNA (THRIL) in systemic lupus erythematosus patients: Relation to disease activity

Aim of the workTo determine expression levels and diagnostic value of metastasis-associated-lung-adenocarcinoma-transcript-1 (MALAT-1) and TNFα and hnRNPL related immunoregulatory long non-coding RNA (THRIL) in systemic lupus erythematosus (SLE), and to assess their role in the clinical characteristics of SLE and disease activity. Patients and methodsStudy included 40 patients with SLE and 30 matched controls. SLE Disease Activity Index (SLEDAI) score was assessed. Expression levels of MALAT-1 and THRIL were detected in the serum by using Real-time polymerase chain reaction and 2−ΔΔCT method. ResultsMean age of patients was 40.1 ± 9 years (25–55 years), they were 38 females and 2 males and disease duration was 16.5 ± 3.9 years. Their mean SLEDAI was 5.8 ± 5.3. Expression levels of MALAT-1 and THRIL were found to be significantly upregulated in the serum of SLE patients compared with controls (set as 1). MALAT-1 fold change = 3.7 ± 3.8 (p = 0.009), and THRIL fold change = 3.6 ± 3.4 (p = 0.026). There were significant correlations between MALAT-1 with THRILL (r = 0.44, p = 0.005), proteinuria (r = 0.45, p = 0.006), erythrocyte sedimentation rate (r = 0.43, p = 0.006) and SLEDAI (r = 0.36, p = 0.024). No significant correlations were found between THRIL and study parameters. Sensitivity and specificity of MALAT-1 and THRIL were determined (sensitivity 67.5% and 65% respectively), (specificity 100% for both, total accuracy 80% and 81.4% respectively), and the combined effect of both increased sensitivity and total accuracy to 70% and 82.9% respectively. THRIL was a significant predictor for SLE disease (p = 0.02). ConclusionMALAT-1 and THRIL may be potential diagnostic biomarkers for SLE and only MALAT-1 may be valuable in detecting disease activity.

Expression changes of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 and nuclear factor etythroid-2 related factor 2 and their significance in lung tissues of hyperoxia-induced premature newborn rats

Objective To observe the expressions of long noncoding RNA(lncRNA)metastasis-associated lung adenocarcinoma transcript 1(MALAT1)and nuclear factor etythroid-2 related factor 2(Nrf2) in lung tissues of hyperoxia-exposed premature neonatal rats, and explore the role of MALAT1 and Nrf2 in hyperoxia-induced lung injury. Methods Pregnant Sprague-Dawley (SD) rats were given cesarean section on the 21st day of gestation.After feeding for 24 h, a total of 80 premature rats were randomly divided into the air group and hyperoxia group.The rats in the air group were fed in the indoor environment[fraction of inspiration O2 (FiO2)=210 mL/L] and those in the hyperoxia group were fed in a high-oxygen box (FiO2>850 mL/L). Eight premature rats from each group were sacrificed and lung tissue samples were collected at 5 experimental time points (1st, 4th, 7th, 10th, 14th day ), respectively.Hematoxylin-eosin staining was used to observe pathological changes in lung tissues.Real-time quantitative polyme-rase chain reaction (qPCR)and Western blot were used to detect the expression level of MALAT1and Nrf2. Results Compared with the air group, the degree of alveolarization in lung tissues of the hyperoxia group rats was reduced, and radial alveolar count (RAC) decreased on the 1st day, but there was no significant difference between 2 groups (P>0.05), when they decreased on the 4th(3.14±0.23), 7th(5.25±0.38), 10th(4.41±0.44), 14th(3.41±0.13) day of exposure, the differences were statistically significant (all P 0.05). Compared with the air group, the mRNA expression of Nrf2 of hyperoxia group preterm rats decreased after the 1st day(0.791±0.031) of exposure, increased after the 4th(0.977±0.189), 7th(1.369±0.100), 10th(1.094±0.104) day, and the differences were statistically significant (all P 0.05). The hyperoxia group had significantly higher expression of free Nrf2 protein and lower expression of Nrf2-Keap1 protein than those of the air group at all time points.Within the hyperoxia group, the RNA expression of MALAT1 was positively correlated with RAC and Nrf2 (r=0.517, 0.533, all P<0.001). Conclusions Lung injury is gradually aggravated over the time of hyperoxia exposure.The level of lncRNA MALAT1 is associated with the severity of lung injury and the level of Nrf2 mRNA, suggesting that lncRNA MALAT1 and the Nrf2 target gene signaling pathway might be involved in the development of hyperoxia-induced lung injury in neonatal premature rats together. Key words: Hyperoxia-induced lung injury; Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1; Nuclear factor etythroid-2 related factor 2; Rat, preterm

Knockdown of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 inhibits the proliferation and migration of bladder cancer cells by modulating the microRNA-34a/cyclin D1 axis.

Long non‑coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been demonstrated to participate in the development and progression of some common cancer types, including bladder cancer (BC). However, the regulatory mechanism of MALAT1 underlying BC growth and metastasis remains to be fully elucidated. The present study revealed that MALAT1 was significantly upregulated in BC tissues and cell lines compared with the adjacent non‑tumour tissues and the normal urinary tract epithelial cell line SV‑HUC‑1, respectively. The expression levels of MALAT1 were higher in stage III‑IV BC tissues when compared with that in stage I‑II tissues. Furthermore, knockdown of MALAT1 significantly inhibited BC cell proliferation and migration by targeting microRNA (miR)‑34a. The expression levels of miR‑34a were significantly decreased in BC tissues and cell lines compared with that of adjacent non‑tumour tissues and SV‑HUC‑1 cells. In addition, the expression of miR‑34a was inversely correlated with the expression of MALAT1 in BC tissues. The present study revealed that cyclin D1 (CCND1) was identified as a target gene of miR‑34a, and its expression was negatively mediated by miR‑34a in BC cells. Notably, the upregulation of CCND1 impaired the effect of MALAT1 inhibition on BC cell proliferation and migration. In addition, the expression levels of CCND1 were significantly increased in BC tissues and cell lines. In conclusion, the present findings demonstrated that the knockdown of lncRNA MALAT1 inhibits the proliferation and migration of BC cells by modulating the miR‑34a/CCND1 axis, suggesting that the MALAT1/miR‑34a/CCND1 axis may be a potential therapeutic target for BC treatment.

Knockdown of MALAT1 inhibits osteosarcoma progression via regulating the miR‑34a/cyclin D1 axis.

Long non-coding (lnc)RNAs have been demonstrated to be involved in the development of various types of cancers, such as osteosarcoma (OS). Long non-coding (lnc) RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) expression was reported to be highly expressed in OS and promoted the development of this disease; however, the underlying molecular mechanism by which MALAT1 promotes the progression of OS requires further investigation. In the present study, the expression of MALAT1 and miR-34a was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The abundance of cyclin D1 (CCND1) was detected by RT-qPCR and western blotting. Cell viability, migration and invasion were examined by MTT and Transwell assays. The interaction between miR-34a and MALAT1 or CCND1 was probed by a dual luciferase reporter assay and RNA immunoprecipitation. Xenograft tumor assay was performed to verify the roles of MALAT1 and miR-34a in tumor growth in vivo. The results demonstrated that MALAT1 and CCND1 mRNA expression levels were upregulated and miR-34a was downregulated in OS tissues and cells. Additionally, MALAT1 expression was correlated with tumor size, clinical stage and distant metastasis in patients with OS. In addition, MALAT1 promoted OS cell viability, invasion and migration, while MALAT1 silencing exhibited opposing effects. Moreover, MALAT1 functioned as a ceRNA to suppress miR-34a expression and in turn upregulate CCND1 in OS cells. Rescue experiments further demonstrated that MALAT1 knockdown partially reversed anti-miR-34a-mediated promotion on OS cell viability, migration and invasion; overexpression of CCND1 partially reversed the effects of MALAT1 silencing on OS progression. Furthermore, in vivo experiments also revealed that MALAT1 promoted OS tumor growth via miR-34a inhibition and upregulating the expression of CCND1. In conclusion, the present study suggested that MALAT1 exerted its oncogenic function in OS by regulating the miR-34a/CCND1 axis in OS, which may provide novel insight into the diagnosis and therapy for OS.

Long non-coding RNA MALAT1 and microRNA-499a expression profiles in diabetic ESRD patients undergoing dialysis: a preliminary cross-sectional analysis

Background: Circulating non-coding RNAs (ncRNAs) have been implicated in health and disease. This study aimed to evaluate the serum expression profile of microRNA-499a (miR-499a) and its selected bioinformatically predicted partner long-ncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) in diabetes-related end-stage renal disease (ESRD) patients and to correlate the expressions with the patients' clinicolaboratory data.Subjects and methods: Real-time quantitative polymerase chain reaction was applied in diabetics with and without ESRD (n = 90 for each).Results: Serum MALAT1 expression levels were increased in the ESRD group relative to diabetics without ESRD with median (quartile) values of 10.5 (1.41–126.7) (p < .001). However, miR-499a levels were decreased in more than half of ESRD patients with a median of 0.96 (0.13–3.14). Both MALAT1 and miR-499a expression levels were inversely correlated in the ESRD patient-group.Conclusions: MALAT1 up-regulation and miR-499 down-regulation might be involved in diabetic nephropathy-related ESRD pathogenesis. Functional validation studies are warranted to confirm the MALAT1/miR-499a partnership.

Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold

Structural studies of the 3'-end of the oncogenic long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) confirmed a unique triple-helix structure. This structure enables accumulation of the transcript, and high levels of MALAT1 are found in several cancers. Here, we synthesize a small molecule library based on an RNA-binding scaffold, diphenylfuran (DPF), screen it against a variety of nucleic acid constructs, and demonstrate for the first time that the MALAT1 triple helix can be selectively targeted with small molecules. Computational analysis revealed a trend between subunit positioning and composition on DPF shape and intramolecular interactions, which in turn generally correlated with selectivity and binding strengths. This work thus provides design strategies toward chemical probe development for the MALAT1 triple helix and suggests that comprehensive analyses of RNA-focused libraries can generate insights into selective RNA recognition.

Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold

AbstractStructural studies of the 3′‐end of the oncogenic long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) confirmed a unique triple‐helix structure. This structure enables accumulation of the transcript, and high levels of MALAT1 are found in several cancers. Here, we synthesize a small molecule library based on an RNA‐binding scaffold, diphenylfuran (DPF), screen it against a variety of nucleic acid constructs, and demonstrate for the first time that the MALAT1 triple helix can be selectively targeted with small molecules. Computational analysis revealed a trend between subunit positioning and composition on DPF shape and intramolecular interactions, which in turn generally correlated with selectivity and binding strengths. This work thus provides design strategies toward chemical probe development for the MALAT1 triple helix and suggests that comprehensive analyses of RNA‐focused libraries can generate insights into selective RNA recognition.

Functions and regulatory mechanisms of metastasis-associated lung adenocarcinoma transcript 1.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA whose transcript is around 8 kb in length. As an important stress response molecule, MALAT1 can be expressed differently under stress conditions, such as hypoxia, high glucose, hydrogen peroxide, ultraviolet irradiation, infection, and chemical stimulation. MALAT1 is involved in regulating multiple cell behaviors, such as proliferation, apoptosis, differentiation, migration, epithelial-mesenchymal transition, autophagy, and morphological maintenance. Extensive evidence show that MALAT1 plays critical roles in the physiopathological process of embryo implantation, angiogenesis, tissue inflammation, tumor progression, liver fibrosis, cardiovascular remodeling, and diabetes progression by regulating gene transcription, forming RNA-protein complexes with proteins as a structural component, regulating protein activity, assisting protein localization, mediating epigenetic changes, or by acting as a competing endogenous RNA. Furthermore, MALAT1 can affect the sensitivity of chemotherapy and radiotherapy; therefore, it could be used as a potential drug target for chemotherapy and radiotherapy sensitization. The levels of MALAT1 are reported to be overexpressed in most tumor tissues or sera, and the expression levels of MALAT1 often affect the tumor size, stage, lymph node metastasis, and distant invasion. Therefore, MALAT1 can be used as a biomarker for early diagnosis, severity assessment, or prognostic assessment. This review outlines the current understanding of the biological role and function of MALAT1. In the meantime, we have summarized the mechanisms involved in the reulation of MALAT1 expression and the mechanisms by which MALAT1 regulates the physiological and pathological processes.

Increased MALAT1 expression contributes to cisplatin resistance in non-small cell lung cancer.

Cisplatin-based chemotherapy is commonly used for the clinical treatment of patients with non-small cell lung cancer (NSCLC). However, the anti-tumor efficacy of cisplatin is limited by poor clinical response and the development of chemoresistance. At present, the underlying mechanism for cisplatin resistance remains unclear. In the present study, it was identified that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA that has been demonstrated to function as an oncogene, was increased in tumor tissues from patients with cisplatin-resistant NSCLC. In addition, the MALAT1 level was increased in A549rCDDP cells compared with the parental A549 cells. Silencing of MALAT1 sensitized A549rCDDP cells to cisplatin treatment, while overexpression of MALAT1 in A549 cells decreased their sensitivity towards cisplatin. Through analysis of the gene expression in patient samples, a decrease in miR-145 and an increase in Kruppel-like factor 4 (KLF4) in tumor tissues compared with adjacent normal tissues was observed. A negative association between MALAT1 and miR-145 was also identified in A549 cells and A549rCDDP cells. Furthermore, reverse transcription quantitative polymerase chain reaction and western blotting identified that KLF4 was positively and negatively regulated by MALAT1 and miR-145, respectively. The direct regulatory association between MALAT1 and miR-145 and the target gene KLF4 was additionally confirmed using a luciferase reporter assay. Knockdown of MALAT1 reversed cisplatin resistance in A549rCDDP cells. Taken together, these data indicated that MALAT1 decreased the sensitivity of NSCLC to cisplatin via the regulation of miR-145 and KLF4.

Knockdown of lncRNA MALAT1 attenuates acute myocardial infarction through miR-320-Pten axis

BackgroundLong noncoding RNA (LncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in the development of acute myocardial infarction (AMI). However, the molecular mechanism and biological function of MALAT1 in AMI remained unclear. MethodsThe expression levels of MALAT1, miR-320 and phosphatase and tensin homolog deleted on chromosome 10 (Pten) in a mouse model of AMI and sham-operated mice were determined by quantitative real-time PCR (qRT-PCR) and western blotting, respectively. The relationships between miR-320 and MALAT1, Pten were confirmed by luciferase reporter assay. The roles of MALAT1, miR-320 and Pten in myocardial apoptosis were evaluated using Annexin V-FITC/PI double-labeled flow cytometry. Echocardiographic evaluation, serum creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH), myocardial infarct size and myocardial apoptosis using terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were used to examine the impact of MALAT1 on myocardial injury. ResultsMALAT1 and Pten were highly expressed, while miR-320 was suppressed in MI group. Mechanistically, MALAT1 may serve as a sponge for miR-320 to upregulate Pten, a direct target of miR-320. Moreover, MALAT1 knockdown overturned the pro-apoptotic effect of miR-320 in vitro and in vivo. ConclusionMALAT1 knockdown attenuated myocardial apoptosis through suppressing Pten expression by sponging miR-320 in mouse AMI.

MALAT1 via microRNA-17 regulation of insulin transcription is involved in the dysfunction of pancreatic β-cells induced by cigarette smoke extract.

Cigarettes contain various chemicals with the potential to influence metabolic health. Exposure to cigarette smoke causes a dysfunction in pancreatic β-cells and impairs insulin production. However, the mechanisms for cigarette smoke-induced reduction of insulin remain largely unclear. Data from 558 patients with diabetes showed that, with smoking pack-years, homeostatic model assessment (HOMA)-β (a method for assessing β-cell function) decreased and that HOMA of insulin resistance increased. For β-cells (MIN6), cigarette smoke extract (CSE) increased the levels of thioredoxin-interacting protein (TXNIP) and the long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and downregulated the levels of the transcription factor, mafA, and microRNA (miR)-17. MALAT1, one of four lncRNAs predicted to regulate miR-17, was knocked down by small interfering RNA (siRNA). For these cells, an miR-17 mimic inhibited TXNIP and enhanced the production of insulin. Knockdown of MALAT1 induced an increase in miR-17, which suppressed TXNIP and promoted the production of insulin. In the sera of patients with diabetes who smoked, there were higher MALAT1 levels and lower miR-17 levels than in the sera of nonsmokers. Thus, CSE inhibits insulin production by upregulating TXNIP via MALAT1-mediated downregulation of miR-17, which provides an understanding of the processes involved in the reduced β-cells function caused by cigarette smoke.