Whole blood transcriptomic investigation identifies long non-coding RNAs as regulators in sepsis
Lixin ChengChuanchuan NanLin KangNing ZhangSheng LiuHuaisheng ChenChengying HongYoulian ChenZhen LiangXueyan Liu
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Abstract Background Sepsis is a fatal disease referring to the presence of a known or strongly suspected infection coupled with systemic and uncontrolled immune activation causing multiple organ failure. However, current knowledge of the role of lncRNAs in sepsis is still extremely limited. Methods We performed an in silico investigation of the gene coexpression pattern for the patients response to all-cause sepsis in consecutive intensive care unit (ICU) admissions. Sepsis coexpression gene modules were identified using WGCNA and enrichment analysis. lncRNAs were determined as sepsis biomarkers based on the interactions among lncRNAs and the identified modules. Results Twenty-three sepsis modules, including both differentially expressed modules and prognostic modules, were identified from the whole blood RNA expression profiling of sepsis patients. Five lncRNAs, FENDRR, MALAT1, TUG1, CRNDE, and ANCR, were detected as sepsis regulators based on the interactions among lncRNAs and the identified coexpression modules. Furthermore, we found that CRNDE and MALAT1 may act as miRNA sponges of sepsis related miRNAs to regulate the expression of sepsis modules. Ultimately, FENDRR, MALAT1, TUG1, and CRNDE were reannotated using three independent lncRNA expression datasets and validated as differentially expressed lncRNAs. Conclusion The procedure facilitates the identification of prognostic biomarkers and novel therapeutic strategies of sepsis. Our findings highlight the importance of transcriptome modularity and regulatory lncRNAs in the progress of sepsis.Keywords:
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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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2b, in which the micro-CT image used as the representative image for male Malat1-/in Fig. 2a was duplicated and presented as the representative image for the female Malat1+/+ mice.
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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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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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Non-coding RNAs (ncRNAs) are reported to be expressed in human cancer, including pancreatic ductal adenocarcinoma (PDAC). They affect the growth, migration and invasion of tumor cells by regulating cell cycle and apoptosis, as well as play an important role on epigenetic modification, transcription and post-transcriptional regulation. However, whether ncRNAs alteration results in PDAC remains largely unknown. Because of this, analysis based on existing data on ncRNAs, which are crucial for modulating pancreatic tumorigenesis, will be important for the future research on PDAC. We identify non-coding RNAs with tumor-promoting function: HOTAIR, HOTTIP, MALAT1, lncRNA H19, lncRNA PVT1, circ-RNA ciRS-7, circ-0030235, circ-RNA_100782, circ-LDLRAD3, circ-0007534, circRHOT1, circZMYM2, circ-IARS, circ-RNA PDE8A, miR-21, miR-155, miR-221/222, miR-196b, miR-10a. While others including GAS5, MEG3 and lncRNA ENST00000480739, has_circ_0001649, miR-34a, miR-100, miR-217, miR-143 inhibit the proliferation and invasion of PDAC. Hence, we summarized the function of ncRNAs' role in the occurrence, development and metastasis of PDAC, aiming to provide guidance for the clinical diagnosis and treatment of PDAC.
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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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