Novel tRNA-like transcripts from the NEAT1-MALAT1 genomic region critically influence human innate immunity and macrophage functions
Martina GastVanasa NageswaranAndreas W. KußAna TzvetkovaXiaomin WangLiliana H. MochmannPegah Ramezani-RadStefan WeißStefan SimmTanja ZellerHenry VoelzkeWolfgang HoffmannUwe VölkerStefan FelixMarcus DörrAntje BelingCarsten SkurkD LeistnerBernhard RauchTetsuro HiroseBettina HeideckerKarin KlingelShinichi NakagawaWolfram C. PollerFilip K. ŚwirskiArash HaghikiaWolfgang Poller
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Abstract The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. NEAT1-/- and MALAT1-/- mice display massive atherosclerosis and vascular inflammation. Here, we identify the tRNA-like molecules as critical components of innate immunity. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell-cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining the tRNA-like molecules’ first described biological functions. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.Keywords:
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Increasing evidences suggest that long noncoding RNAs (lncRNAs) play critical roles in the pathogenesis of coronary artery disease (CAD). However, the association between lncRNAs expression profiles and unstable angina (UA) remained poorly known. Thus, the present study aims to investigate expression patterns, biological functions, and diagnostic value of lncRNAs in UA.The present study explored the lncRNA and mRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of UA patients and normal coronary artery (NCA) controls using RNA-seq. The biological function of differentially expressed lncRNAs was analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The expression of the selected lncRNAs was validated in another 44 UA patients and 46 NCA controls. Receiver operating characteristic curve (ROC) was performed to evaluate the diagnostic value of lncRNAs for UA.A total of 98 lncRNAs and 615 mRNAs were observed differentially expressed in PBMCs of UA patients as compared to NCA controls. The 10 most upregulated lncRNAs were LNC_000226, DANCR, RP1-167A14.2, LNC_002091, LNC_001526, LNC_001165, LNC_002772, LNC_000088, LNC_001226, and FAM157C, and the 10 most downregulated lncRNAs were RP11-734I18.1, RP11-185E8.1, RP11-360I2.1, LNC_001302, LNC_001287, RN7SL471P, LNC_000914, LINC01506, RP11-160E2.6, and LNC_000995. LNC_000226 and MALAT1 have high area under the curve values (AUC) for distinguishing UA from NCA patients (0.810 and 0.799, respectively), and the combination of MALAT1 and LNC_000226 increased the AUC value to 0.878.The present study added our understanding about the lncRNA expression profile in UA patients and provided potential biomarkers for the diagnosis of UA.
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Our genome consists not only of protein-coding DNA, but also of the non-coding part that plays a very important role in the regulation of all cellular processes. A part of the non-coding genome comes with non-coding RNAs (ncRNAs), and disruption of the functional activity of these RNAs may be associated with oncogenesis in various cancer types. There exist two types of ncRNAs: small and long non-coding RNAs, which are classified according to their transcript length. Long non-coding metastasis-associated lung adenocarcinoma transcript 1, MALAT1 RNA (NEAT2), is a long non-coding RNA of particular interest. The aforementioned transcript takes part in the regulation of numerous cellular processes and pathogenesis of different malignant tumors, including breast tumors. This review focuses on experimental and clinical studies into the role of MALAT1 in carcinogenesis and the progression of breast cancer.
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Glioma is the most common malignant central nervous system tumor with significant mortality and morbidity. Despite considerable advances, the exact molecular pathways involved in tumor progression are not fully elucidated, and patients commonly face a poor prognosis. Long non-coding RNAs (lncRNAs) have recently drawn extra attention for their potential roles in different types of cancer as well as non-malignant diseases. More than 200 lncRNAs have been reported to be associated with glioma. We aimed to assess the roles of the most investigated lncRNAs in different stages of tumor progression and the mediating molecular pathways in addition to their clinical applications. lncRNAs are involved in different stages of tumor formation, invasion, and progression, including regulating the cell cycle, apoptosis, autophagy, epithelial-to-mesenchymal transition, tumor stemness, angiogenesis, the integrity of the blood-tumor-brain barrier, tumor metabolism, and immunological responses. The well-known oncogenic lncRNAs, which are upregulated in glioma, are H19 , HOTAIR , PVT1 , UCA1 , XIST , CRNDE , FOXD2-AS1 , ANRIL , HOXA11-AS , TP73-AS1 , and DANCR . On the other hand, MEG3 , GAS5 , CCASC2 , and TUSC7 are tumor suppressor lncRNAs, which are downregulated. While most studies reported oncogenic effects for MALAT1 , TUG1 , and NEAT1 , there are some controversies regarding these lncRNAs. Expression levels of lncRNAs can be associated with tumor grade, survival, treatment response (chemotherapy drugs or radiotherapy), and overall prognosis. Moreover, circulatory levels of lncRNAs, such as MALAT1, H19, HOTAIR, NEAT1, TUG1, GAS5, LINK-A , and TUSC7 , can provide non-invasive diagnostic and prognostic tools. Modulation of expression of lncRNAs using antisense oligonucleotides can lead to novel therapeutics. Notably, a profound understanding of the underlying molecular pathways involved in the function of lncRNAs is required to develop novel therapeutic targets. More investigations with large sample sizes and increased focus on in-vivo models are required to expand our understanding of the potential roles and application of lncRNAs in glioma.
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Long noncoding RNAs (lncRNAs) represent a large subgroup of RNA transcripts that lack the function of coding proteins and may be essential universal genes involved in carcinogenesis and metastasis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNAMALAT1) is overexpressed in various human tumors, including gliomas. However, the biological function and molecular mechanism of action of lncRNA-MALAT1 in gliomas have not yet been systematically elucidated. Accumulating evidence suggests that the abnormal expression of lncRNA-MALAT1 in gliomas is associated with various physical properties of the glioma, such as tumor growth, metastasis, apoptosis, drug resistance, and prognosis. Furthermore, lncRNAs, as tumor progression and prognostic markers in gliomas, may affect tumorigenesis, proliferation of glioma stem cells, and drug resistance. In this review, we summarize the knowledge on the biological functions and prognostic value of lncRNA-MALAT1 in gliomas. This mini-review aims to deepen the understanding of lncRNA-MALAT1 as a novel potential therapeutic target for the individualized precision treatment of gliomas.
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Accumulating evidence suggested that lncRNA MALAT1 plays critical roles in the commencement and progression of malignant cancers. Nevertheless, the function of MALAT1 in colorectal cancer (CRC) remains largely unknown. In the present study, we reported that MALAT1 expression is significantly upregulated in CRC and correlated with advanced TNM stage, lymph node metastasis, and worse prognosis in patients. Functional assays revealed that MALAT1 knockdown reduced CRC cell growth and invasion abilities in vitro. Mechanistically, we discovered that MALAT1 may serve as a competing endogenous RNA (ceRNA) to miR-508-5p in CRC progression. Bioinformatics analysis and luciferase assays confirmed that RAB14 acts as a target of miR-508-5p. In addition, downregulation of RAB14 reduced the progression of CRC. Collectively, our findings indicated that MALAT1 could promote CRC progress by sponging miR-508-5p and enhancing RAB14 expression, which provides a therapeutic target in CRC treatment.
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Non-coding RNAs are becoming major players in disease pathogenesis such as cancer. Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a nuclear enriched long non-coding RNA that is generally overexpressed in patient tumors and metastases. Overexpression of MALAT1 has been shown to be positively correlated with tumor progression and metastasis in a large number of tumor types including breast tumors. Surprisingly, a recent report by Kim et al shows a metastasis suppressive role for Malat1. Here, we discuss these results in the context of a large body of published literature that support a pro-tumorigenic role for MALAT1 in order to gain potential insights into the basis of these observed differences.
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Background: Long noncoding RNAs (lncRNAs) have recently been recognized as a new layer of biological regulation. They participate in mRNA regulation and may be useful as prognostic factors and drug targets. Colorectal cancer (CRC) is a common tumor that is characterized by its high mortality rate. Despite improvements in screening of CRC, the prognosis is still poor. Therefore, there is an urgent need to develop effective biomarkers for the detection of CRC. This study was designed to measure the expression of several oncogenic lncRNAs, including PANDAR, MALAT1, PCAT6, CCAT1, UCA1, MEG3, CCAT2, and BCAR4, in blood samples of healthy individuals and CRC patients. Methods: Total RNA was isolated from whole blood of 63 CRC patients and 40 controls and the expression of the lncRNAs was determined by real-time polymerase chain reaction and measured by REST2009 software. All p-values <0.05 were considered statistically significant. Results: The results showed that the expression levels of MALAT1, CCAT1, and PANDAR were significantly upregulated with 1.86, 4.54, and 4.68-fold higher levels (p < 0.05), respectively, in the blood of CRC patients compared to the controls. However, the other lncRNAs examined were not significantly expressed differentially in CRC blood samples. Conclusion: The findings of this study suggest that the expression of MALAT1, CCAT1, and PANDAR in blood could serve as potential biomarkers for CRC prognosis.
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In recent year, increasing evidence suggests that noncoding RNAs play important roles in the regulation of tissue homeostasis and pathophysiological conditions. Besides small noncoding RNAs (eg, microRNAs), >200-nucleotide long transcripts, namely long noncoding RNAs (lncRNAs), can interfere with gene expressions and signaling pathways at various stages. In the cardiovascular system, studies have detected and characterized the expression of lncRNAs under normal physiological condition and in disease states. Several lncRNAs are regulated during acute myocardial infarction (eg, Novlnc6 ) and heart failure (eg, Mhrt ), whereas others control hypertrophy, mitochondrial function and apoptosis of cardiomyocytes. In the vascular system, the endothelial-expressed lncRNAs (eg, MALAT1 and Tie-1-AS) can regulate vessel growth and function, whereas the smooth-muscle–expressed lncRNA smooth muscle and endothelial cell–enriched migration/differentiation-associated long noncoding RNA was recently shown to control the contractile phenotype of smooth muscle cells. This review article summarizes the data on lncRNA expressions in mouse and human and highlights identified cardiovascular lncRNAs that might play a role in cardiovascular diseases. Although our understanding of lncRNAs is still in its infancy, these examples may provide helpful insights how lncRNAs interfere with cardiovascular diseases.
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