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Wei Y, Jia H, Guo X, Zhang H, Yang X, Can C, He N, Wu H, Liu W, Ma D. A novel LncRNA risk model for disulfidptosis-related prognosis prediction and response to chemotherapy in acute myeloid leukemia. Sci Rep 2025; 15:16995. [PMID: 40379722 PMCID: PMC12084325 DOI: 10.1038/s41598-025-01730-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 05/07/2025] [Indexed: 05/19/2025] Open
Abstract
Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is characterized by its heterogeneity, which contributes to a poor prognosis and high recurrence rate. Recently, a unique form of cell death, called disulfidptosis, has been identified, which could transforming our understanding of and strategy for cancer treatment. Consequently, further inquiry is necessary to explore the possible link between disulfidptosis and AML. To facilitate this analysis, the researchers obtained single-cell RNA sequencing (scRNA-seq) data from AML patients using the Gene Expression Omnibus (GEO) database. By applying the Cox proportional hazards model and least absolute shrinkage and selection operator (LASSO) regression analysis, we created a signature of disulfidptosis-related long non-coding RNAs (DRLs). This predictive model was established based on six specific DRLs (AC005076.1, AP002807.1, HDAC4-AS1, L3MBTL4-AS1, LINC01694, and THAP9-AS1). The utility of this model in forecasting the prognosis of AML patients was corroborated by the receiver operating characteristic (ROC) curve. Moreover, significant variations in the biological functions and signaling pathways were discovered by gene ontology (GO) and Gene Set Enrichment Analysis (GSEA). To further investigate the relationship between immune infiltration, the study assessed variations in immune checkpoint expression and immune cell subset infiltration. Additionally, we used real-time quantitative PCR (RT-qPCR) to detect lncRNA expression in AML and healthy control to substantiate our analysis results. In conclusion, the results of this study may help discover novel therapeutic targets and prognostic biomarkers for AML, paving the way for customized precision chemotherapy.
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MESH Headings
- Humans
- RNA, Long Noncoding/genetics
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/mortality
- Prognosis
- Female
- Male
- ROC Curve
- Middle Aged
- Gene Expression Regulation, Leukemic
- Biomarkers, Tumor/genetics
- Proportional Hazards Models
- Disulfidptosis
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Affiliation(s)
- Yihong Wei
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Hexiao Jia
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Xiaodong Guo
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Hailei Zhang
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Xinyu Yang
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Can Can
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Na He
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Hanyang Wu
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Wancheng Liu
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Daoxin Ma
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China.
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2
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Weise A, Ornellas AA, Alves G, Pentzold C, Holler J, Wolter M, Jamali E, Theis B, Liehr T. Satellite DNA Amplification in Advanced Prostate Cancer Is Largely Independent From Euchromatic and Oncogene Amplicons. J Histochem Cytochem 2025; 73:109-113. [PMID: 40097918 PMCID: PMC11915227 DOI: 10.1369/00221554251323657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 02/11/2025] [Indexed: 03/19/2025] Open
Abstract
Recently, we were able to show that satellite DNA amplification (satDNA-AMP) is present in advanced prostate cancer. A chromosome microarray study provided first evidence that satDNA-AMP appears to be largely independent of centromere-near/pericentric euchromatic copy number alterations. Therefore, it might be carefully suggested that satDNA-AMP could be a new and independent marker for advanced tumor progression.
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Affiliation(s)
- Anja Weise
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | | | - Gilda Alves
- Circulating Biomarkers Laboratory, Faculty of Medical Sciences, Department of General Pathology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Constanze Pentzold
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Jenny Holler
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Melanie Wolter
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Elena Jamali
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Bernhard Theis
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Thomas Liehr
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany
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3
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Passos GA, Genari AB, Assis AF, Monteleone-Cassiano AC, Donadi EA, Oliveira EH, Duarte MJ, Machado MV, Tanaka PP, Mascarenhas R. The Thymus as a Mirror of the Body's Gene Expression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1471:247-268. [PMID: 40067590 DOI: 10.1007/978-3-031-77921-3_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
The thymus, a complex organ formed by different cell types that establish close interaction, serves a unique function of significant interest. The role played by the thymic stroma is not only a connective tissue or a support structure, but it also involves the stromal thymic epithelial cells (TECs) establishing physical and functional interaction with developing thymocytes. This interaction culminates in the induction of central tolerance, a function that sets this organ apart. The role played by the medullary thymic epithelial cells (mTECs) is noteworthy and is the focus of many studies. The transcriptome of mTEC cells is also very complex. These cells express nearly the functional genome without altering morphological and functional features. Among the thousand mRNAs expressed, a particular set encodes all peripheral tissue antigens (PTAs), representing the body's different tissues and organs. The consequence of ectopic proteins translated from these mRNAs in the thymus is immunological and is associated with self-nonself-discrimination and induction of central tolerance. Due to the wide variety of PTAs, this process was termed promiscuous gene expression (PGE), whose control is shared between autoimmune regulator (human AIRE/murine Aire), a transcriptional modulator, and forebrain-expressed zinc finger 2 (FEZF2/Fezf2), a transcription factor. Therefore, this molecular-genetic process is closely linked to eliminating autoreactive thymocytes in the thymus through negative selection. In this chapter, we review PGE in mTECs and its immunologic implication, the role of the Aire and Fezf2genes, the role of Aire on the expression of miRNAs in mTECs, its consequence on PGE and the manipulation of the Aire expression either by siRNA or by genome editing using the Crispr-Cas9 system.
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Affiliation(s)
- Geraldo A Passos
- Laboratory of Genetics and Molecular Biology, Department of Basic and Oral Biology, Ribeirão Preto School of Dentistry (FORP-USP), University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Adriana B Genari
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Amanda F Assis
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Ana C Monteleone-Cassiano
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Eduardo A Donadi
- Department of Clinical Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Ernna H Oliveira
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Max J Duarte
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Mayara V Machado
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Pedro P Tanaka
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Romário Mascarenhas
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
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4
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Li P, Liu ZP. Structure-Based Prediction of lncRNA-Protein Interactions by Deep Learning. Methods Mol Biol 2025; 2883:363-376. [PMID: 39702717 DOI: 10.1007/978-1-0716-4290-0_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
The interactions between long noncoding RNA (lncRNA) and protein play crucial roles in various biological processes. Computational methods are essential for predicting lncRNA-protein interactions and deciphering their mechanisms. In this chapter, we aim to introduce the fundamental framework for predicting lncRNA-protein interactions based on three-dimensional structure information. With the increasing availability of lncRNA and protein molecular tertiary structures, the feasibility of using deep learning methods for automatic representation and learning has become evident. This chapter outlines the key steps in predicting lncRNA-protein interactions using deep learning, including three common non-Euclidean data representations for lncRNA and proteins, as well as neural networks tailored to these specific data characteristics. We also highlight the advantages and challenges of structure-based prediction of lncRNA-protein interactions with geometric deep learning methods.
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Affiliation(s)
- Pengpai Li
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, China
| | - Zhi-Ping Liu
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, China.
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5
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Shen JJ, Li MC, Tian SQ, Chen WM. Long non-coding RNA GATA6-AS1 is mediated by N6-methyladenosine methylation and inhibits the proliferation and metastasis of gastric cancer. World J Gastrointest Oncol 2024; 16:1019-1028. [PMID: 38577476 PMCID: PMC10989367 DOI: 10.4251/wjgo.v16.i3.1019] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/16/2023] [Accepted: 01/17/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND Through experimental research on the biological function of GATA6-AS1, it was confirmed that GATA6-AS1 can inhibit the proliferation, invasion, and migration of gastric cancer cells, suggesting that GATA6-AS1 plays a role as an anti-oncogene in the occurrence and development of gastric cancer. Further experiments confirmed that the overexpression of fat mass and obesity-associated protein (FTO) inhibited the expression of GATA6-AS1, thereby promoting the occurrence and development of gastric cancer. AIM To investigate the effects of GATA6-AS1 on the proliferation, invasion and migration of gastric cancer cells and its mechanism of action. METHODS We used bioinformatics methods to analyze the Cancer Genome Atlas (https://portal.gdc.cancer.gov/. The Cancer Genome Atlas) and download expression data for GATA6-AS1 in gastric cancer tissue and normal tissue. We also constructed a GATA6-AS1 lentivirus overexpression vector which was transfected into gastric cancer cells to investigate its effects on proliferation, migration and invasion, and thereby clarify the expression of GATA6-AS1 in gastric cancer and its biological role in the genesis and development of gastric cancer. Next, we used a database (http://starbase.sysu.edu.cn/starbase2/) to analysis GATA6-AS1 whether by m6A methylation modify regulation and predict the methyltransferases that may methylate GATA6-AS1. Furthermore, RNA immunoprecipitation experiments confirmed that GATA6-AS1 was able to bind to the m6A methylation modification enzyme. These data allowed us to clarify the ability of m6A methylase to influence the action of GATA6-AS1 and its role in the occurrence and development of gastric cancer. RESULTS Low expression levels of GATA6-AS1 were detected in gastric cancer. We also determined the effects of GATA6-AS1 overexpression on the biological function of gastric cancer cells. GATA6-AS1 had strong binding ability with the m6A demethylase FTO, which was expressed at high levels in gastric cancer and negatively correlated with the expression of GATA6-AS1. Following transfection with siRNA to knock down the expression of FTO, the expression levels of GATA6-AS1 were up-regulated. Finally, the proliferation, migration and invasion of gastric cancer cells were all inhibited following the knockdown of FTO expression. CONCLUSION During the occurrence and development of gastric cancer, the overexpression of FTO may inhibit the expression of GATA6-AS1, thus promoting the proliferation and metastasis of gastric cancer.
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Affiliation(s)
- Jun-Jie Shen
- Department of Oncology, Jiangxi Hospital of Integrated Chinese and Western Medicine, Nanchang 330000, Jiangxi Province, China
| | - Min-Chang Li
- Department of Hepatopancreatobiliary Surgery, Jiangxi Hospital of Integrated Chinese and Western Medicine, Nanchang 330000, Jiangxi Province, China
| | - Shao-Qi Tian
- Clinical Medical School, Jining Medical University, Jining 272000, Shandong Province, China
| | - Wen-Ming Chen
- Department of Oncology, Jining No.1 People’s Hospital, Jining 272011, Shandong Province, China
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6
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Alluli A, Rijnbout St James W, Eidelman DH, Baglole CJ. Dynamic relationship between the aryl hydrocarbon receptor and long noncoding RNA balances cellular and toxicological responses. Biochem Pharmacol 2023; 216:115745. [PMID: 37597813 DOI: 10.1016/j.bcp.2023.115745] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 08/21/2023]
Abstract
The aryl hydrocarbon receptor (AhR) is a cytosolic transcription factor activated by endogenous ligands and xenobiotic chemicals. Once the AhR is activated, it translocates to the nucleus, dimerizes with the AhR nuclear translator (ARNT) and binds to xenobiotic response elements (XRE) to promote gene transcription, notably the cytochrome P450 CYP1A1. The AhR not only mediates the toxic effects of environmental chemicals, but also has numerous putative physiological functions. This dichotomy in AhR biology may be related to reciprocal regulation of long non-coding RNA (lncRNA). lncRNA are defined as transcripts more than 200 nucleotides in length that do not encode a protein but are implicated in many physiological processes such as cell differentiation, cell proliferation, and apoptosis. lncRNA are also linked to disease pathogenesis, particularly the development of cancer. Recent studies have revealed that AhR activation by environmental chemicals affects the expression and function of lncRNA. In this article, we provide an overview of AhR signaling pathways activated by diverse ligands and highlight key differences in the putative biological versus toxicological response of AhR activation. We also detail the functions of lncRNA and provide current data on their regulation by the AhR. Finally, we outline how overlap in function between AhR and lncRNA may be one way in which AhR can be both a regulator of endogenous functions but also a mediator of toxicological responses to environmental chemicals. Overall, more research is still needed to fully understand the dynamic interplay between the AhR and lncRNA.
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Affiliation(s)
- Aeshah Alluli
- Meakins-Christie Laboratories, McGill University, Canada; Translational Research in Respiratory Diseases Program at the Research Institute of the McGill University Health Centre, Canada; Department of Pathology, McGill University, Canada
| | - Willem Rijnbout St James
- Meakins-Christie Laboratories, McGill University, Canada; Translational Research in Respiratory Diseases Program at the Research Institute of the McGill University Health Centre, Canada; Department of Pathology, McGill University, Canada
| | - David H Eidelman
- Meakins-Christie Laboratories, McGill University, Canada; Department of Medicine, McGill University, Canada
| | - Carolyn J Baglole
- Meakins-Christie Laboratories, McGill University, Canada; Translational Research in Respiratory Diseases Program at the Research Institute of the McGill University Health Centre, Canada; Department of Pathology, McGill University, Canada; Department of Medicine, McGill University, Canada; Department of Pharmacology and Therapeutics, McGill University, Canada.
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7
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Wang P, Paquet ÉR, Robert C. Comprehensive transcriptomic analysis of long non-coding RNAs in bovine ovarian follicles and early embryos. PLoS One 2023; 18:e0291761. [PMID: 37725621 PMCID: PMC10508637 DOI: 10.1371/journal.pone.0291761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 09/05/2023] [Indexed: 09/21/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have been the subject of numerous studies over the past decade. First thought to come from aberrant transcriptional events, lncRNAs are now considered a crucial component of the genome with roles in multiple cellular functions. However, the functional annotation and characterization of bovine lncRNAs during early development remain limited. In this comprehensive analysis, we review lncRNAs expression in bovine ovarian follicles and early embryos, based on a unique database comprising 468 microarray hybridizations from a single platform designed to target 7,724 lncRNA transcripts, of which 5,272 are intergenic (lincRNA), 958 are intronic, and 1,524 are antisense (lncNAT). Compared to translated mRNA, lncRNAs have been shown to be more tissue-specific and expressed in low copy numbers. This analysis revealed that protein-coding genes and lncRNAs are both expressed more in oocytes. Differences between the oocyte and the 2-cell embryo are also more apparent in terms of lncRNAs than mRNAs. Co-expression network analysis using WGCNA generated 25 modules with differing proportions of lncRNAs. The modules exhibiting a higher proportion of lncRNAs were found to be associated with fewer annotated mRNAs and housekeeping functions. Functional annotation of co-expressed mRNAs allowed attribution of lncRNAs to a wide array of key cellular events such as meiosis, translation initiation, immune response, and mitochondrial related functions. We thus provide evidence that lncRNAs play diverse physiological roles that are tissue-specific and associated with key cellular functions alongside mRNAs in bovine ovarian follicles and early embryos. This contributes to add lncRNAs as active molecules in the complex regulatory networks driving folliculogenesis, oogenesis and early embryogenesis all of which are necessary for reproductive success.
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Affiliation(s)
- Pengmin Wang
- Département des sciences animales, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, Québec City, Québec, Canada
| | - Éric R. Paquet
- Département des sciences animales, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, Québec City, Québec, Canada
| | - Claude Robert
- Département des sciences animales, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, Québec City, Québec, Canada
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8
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Franco PIR, Neto JRDC, de Menezes LB, Machado JR, Miguel MP. Revisiting the hallmarks of cancer: A new look at long noncoding RNAs in breast cancer. Pathol Res Pract 2023; 243:154381. [PMID: 36857948 DOI: 10.1016/j.prp.2023.154381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/16/2023] [Indexed: 02/19/2023]
Abstract
Breast cancer is one of the leading causes of death in women worldwide. The increasing understanding of the molecular mechanisms underlying its heterogeneity favors a better understanding of tumor biology and consequently the development of better diagnostic and treatment techniques. The advent of tumor genome sequencing techniques has highlighted more participants in the process, in addition to protein-coding genes. Thus, it is now known that long noncoding RNAs, previously described as transcriptional noise with no biological function, are intimately associated with tumor development. In breast cancer, they are abnormally expressed and closely associated with tumor progression, which makes them attractive diagnostic biomarkers and prognostic and specific therapeutic targets. Therefore, a thorough understanding of the regulatory mechanisms of long noncoding RNAs in breast cancer is essential for the search for new treatment strategies. In this review, we summarize the major long noncoding RNAs and their association with the cancer characteristics of the ability to sustain proliferative signaling, evasion of growth suppressors, replicative immortality, activation of invasion and metastasis, induction of angiogenesis, resistance to cell death, reprogramming of energy metabolism, genomic instability and sustained mutations, promotion of tumor inflammation, and evasion of the immune system. In addition, we report and suggest how they can be used as prognostic biomarkers and possible therapeutic targets.
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Affiliation(s)
- Pablo Igor Ribeiro Franco
- Instituto de Patologia Tropical e Saúde Pública, Programa de Pós-Graduação em Medicina Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil.
| | - José Rodrigues do Carmo Neto
- Instituto de Patologia Tropical e Saúde Pública, Programa de Pós-Graduação em Medicina Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil
| | - Liliana Borges de Menezes
- Setor de Patologia Geral, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil; Escola de Veterinária e Zootecnia, Programa de Pós-Graduação em Ciência Animal, Universidade Federal de Goiás, Goiânia, GO, Brazil
| | - Juliana Reis Machado
- Instituto de Patologia Tropical e Saúde Pública, Programa de Pós-Graduação em Medicina Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil; Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | - Marina Pacheco Miguel
- Setor de Patologia Geral, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil; Escola de Veterinária e Zootecnia, Programa de Pós-Graduação em Ciência Animal, Universidade Federal de Goiás, Goiânia, GO, Brazil
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Eptaminitaki GC, Zaravinos A, Stellas D, Panagopoulou M, Karaliota S, Baltsavia I, Iliopoulos I, Chatzaki E, Iliopoulos D, Baritaki S. Genome-Wide Analysis of lncRNA-mRNA Co-Expression Networks in CD133+/CD44+ Stem-like PDAC Cells. Cancers (Basel) 2023; 15:cancers15041053. [PMID: 36831395 PMCID: PMC9954787 DOI: 10.3390/cancers15041053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the second most prevalent gastrointestinal malignancy and the most common type of pancreatic cancer is linked with poor prognosis and, eventually, with high mortality rates. Early detection is seldom, while tumor heterogeneity and microarchitectural alterations benefit PDAC resistance to conventional therapeutics. Although emerging evidence suggest the core role of cancer stem cells (CSCs) in PDAC aggressiveness, unique stem signatures are poorly available, thus limiting the efforts of anti-CSC-targeted therapy. Herein, we report the findings of the first genome-wide analyses of mRNA/lncRNA transcriptome profiling and co-expression networks in PDAC cell line-derived CD133+/CD44+ cells, which were shown to bear a CSC-like phenotype in vitro and in vivo. Compared to CD133-/CD44- cells, the CD133+/CD44+ population demonstrated significant expression differences in both transcript pools. Using emerging bioinformatic tools, we performed lncRNA target coding gene prediction analysis, which revealed significant Gene Ontology (GO), pathway, and network enrichments in many dyregulated lncRNA nearby (cis or trans) mRNAs, with reported involvement in the regulation of CSC phenotype and functions. In this context, the construction of lncRNA/mRNA networks by ingenuity platforms identified the lncRNAs ATF2, CHEK1, DCAF8, and PAX8 to interact with "hub" SC-associated mRNAs. In addition, the expressions of the above lncRNAs retrieved by TCGA-normalized RNAseq gene expression data of PAAD were significantly correlated with clinicopathological features of PDAC, including tumor grade and stage, nodal metastasis, and overall survival. Overall, our findings shed light on the identification of CSC-specific lncRNA signatures with potential prognostic and therapeutic significance in PDAC.
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Affiliation(s)
- Giasemi C. Eptaminitaki
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Apostolos Zaravinos
- Basic and Translational Cancer Research Center (BTCRC), Genomics and Systems Biology Laboratory, Cancer Genetics, Nicosia 1516, Cyprus
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 2404, Cyprus
| | - Dimitris Stellas
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
| | - Sevasti Karaliota
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ismini Baltsavia
- Laboratory of Computational Biology, Division of Basic Sciences, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ioannis Iliopoulos
- Laboratory of Computational Biology, Division of Basic Sciences, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
| | | | - Stavroula Baritaki
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece
- Correspondence: ; Tel.: +30-281-039-4727
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10
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Lightfoot HL, Smith GF. Targeting RNA with small molecules-A safety perspective. Br J Pharmacol 2023. [PMID: 36631428 DOI: 10.1111/bph.16027] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 06/30/2022] [Accepted: 12/20/2022] [Indexed: 01/13/2023] Open
Abstract
RNA is a major player in cellular function, and consequently can drive a number of disease pathologies. Over the past several years, small molecule-RNA targeting (smRNA targeting) has developed into a promising drug discovery approach. Numerous techniques, tools, and assays have been developed to support this field, and significant investments have been made by pharmaceutical and biotechnology companies. To date, the focus has been on identifying disease validated primary targets for smRNA drug development, yet RNA as a secondary (off) target for all small molecule drug programs largely has been unexplored. In this perspective, we discuss structure, target, and mechanism-driven safety aspects of smRNAs and highlight how these parameters can be evaluated in drug discovery programs to produce potentially safer drugs.
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Affiliation(s)
- Helen L Lightfoot
- Safety and Mechanistic Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Graham F Smith
- Data Science and AI, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
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Chen W, Chen W, Liu P, Qian S, Tao S, Huang M, Xu W, Li C, Chen X, Lin H, Qin Z, Lu J, Xie S. Role of lncRNA Has2os in Skeletal Muscle Differentiation and Regeneration. Cells 2022; 11:3497. [PMID: 36359891 PMCID: PMC9655701 DOI: 10.3390/cells11213497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/28/2022] [Accepted: 11/03/2022] [Indexed: 09/26/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) regulate a series of physiological processes and play an important role in development, metabolism and disease. Our previous studies showed that lncRNAs involved in skeletal muscle differentiation. Here, we demonstrated that lncRNA Has2os is highly expressed in skeletal muscle and significantly elevated during skeletal cell differentiation. The knockdown of Has2os inhibited myocyte fusion and impeded the expression of the myogenic factors MyHC and Mef2C. Mechanically, Has2os regulates skeletal muscle differentiation by inhibiting the JNK/MAPK signaling pathway. Furthermore, we also revealed that Has2os is involved in the early stage of regeneration after muscle injury, and the JNK/MAPK signaling pathway is activated at both protein and mRNA levels during early repair. Our results demonstrate the new function of lncRNA Has2os, which plays crucial roles during skeletal muscle differentiation and muscle regeneration, providing a basis for the therapy of lncRNA-related muscle diseases.
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Affiliation(s)
- Wanxin Chen
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Weicai Chen
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Peng Liu
- Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Shiyu Qian
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Shuang Tao
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Mengchun Huang
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Wanyi Xu
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Cuiping Li
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Xiaoyan Chen
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Huizhu Lin
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Zhenshu Qin
- Department of Trauma Orthopaedics, Chenzhou First People’s Hospital Affiliated to South China University, Chenzhou 423000, China
| | - Jianxi Lu
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Shujuan Xie
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
- Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
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12
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Chen W, Ma C, Dong Y, Li S. The bovine Prader-Willi/Angelman imprinted domain has four Sno-lncRNAs types. Anim Genet 2022; 53:685-689. [PMID: 35844032 DOI: 10.1111/age.13244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/14/2022] [Accepted: 07/06/2022] [Indexed: 11/30/2022]
Abstract
Sno-lncRNAs are intron-derived long noncoding RNAs (lncRNAs) with snoRNA ends. Sno-lncRNAs were first discovered in the human Prader-Willi (PWS)/Angelman (AS) imprinted domain. Here, we report the identification and characterization of four sno-lncRNA types (sno-lncRNA1, sno-lncRNA2, sno-lncRNA3, and sno-lncRNA4) in the bovine PWS/AS imprinted domain. Reverse transcription-PCR first determined the cDNA sequences of the four bovine sno-lncRNAs. A gene structure analysis showed that sno-lncRNA1 lacks introns, but sno-lncRNA2 and sno-lncRNA3 have one and two introns respectively. The three sno-lncRNAs have similar snoRNA ends. Moreover, the three have similar snoRNAs at their 5' and 3' ends. The head-to-tail orientation has six sno-lncRNA copies arranged between bovine SNORD116-6 and SNORD116-12. Moreover, only a copy of sno-lncRNA4 was located between SNORD116-3 and SNORD116-4. The expression of the four sno-lncRNAs was analyzed in the bovine heart, liver, spleen, lung, kidney, muscle, fat, brain, and placenta tissues. The monoallelic expression of sno-lncRNA4 was determined in bovine tissues. The results showed that the four sno-lncRNAs are widely expressed in the nine tissues, although sno-lncRNA3 and sno-lncRNA4 were undetected in the placenta. Moreover, an informative single nucleotide polymorphism (rs448706424) revealed the allelic expression of sno-lncRNA4 in exon 2 of sno-lncRNA4. The bovine genome had six copies of sno-lncRNA1, sno-lncRNA2, and sno-lncRNA3, but their allelic expression was not identified.
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Affiliation(s)
- Weina Chen
- College of Traditional Chinese Medicine, Hebei University, Baoding, China
| | - Chao Ma
- Baoding NO.2 Hospital, Baoding, China
| | - Yanqiu Dong
- Department of Biochemistry and Molecular Biology, College of Life Science, Hebei Agriculture University, Baoding, China
| | - Shijie Li
- Department of Biochemistry and Molecular Biology, College of Life Science, Hebei Agriculture University, Baoding, China
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Wang C, Duan M, Lin J, Wang G, Gao H, Yan M, Chen L, He J, Liu W, Yang F, Zhu S. LncRNA and mRNA expression profiles in brown adipose tissue of obesity-prone and obesity-resistant mice. iScience 2022; 25:104809. [PMID: 35992072 PMCID: PMC9382264 DOI: 10.1016/j.isci.2022.104809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/10/2022] [Accepted: 07/15/2022] [Indexed: 11/28/2022] Open
Abstract
Obesity-prone or obesity-resistant phenotypes can exist in individuals who consume the same diet type. Brown adipose tissue functions to dissipate energy in response to cold exposure or overfeeding. Long noncoding RNAs play important roles in a wide range of biological processes. However, systematic examination of lncRNAs in phenotypically divergent mice has not yet been reported. Here, the lncRNA expression profiles in BAT of HFD-induced C57BL/6J mice were investigated by high-throughput RNA sequencing. Genes that play roles in thermogenesis and related pathways were identified. We found lncRNA (Gm44502) may play a thermogenic role in obesity resistance by interacting with six mRNAs. Our results also indicated that seven differentially expressed lncRNAs (4930528G23Rik, Gm39490, Gm5627, Gm15551, Gm16083, Gm36860, Gm42002) may play roles in reducing heat production in obesity susceptibility by interacting with seven differentially expressed mRNAs. The screened lncRNAs may participate in the pathogenesis of weight regulation and provide insight into obesity therapy.
First lncRNA profiles in BAT of OR and OP mice via bioinformatic analysis Gm44502 may play a thermogenic role by interacting with 6 mRNAs 7 DElncRNAs may reduce thermogenesis by interacting with 7 DEmRNAs Validation of expression changes of candidate genes in BAT by in vivo or in vitro
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Affiliation(s)
- Congcong Wang
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - Meng Duan
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - Jinhua Lin
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - Guowei Wang
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - He Gao
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - Mengsha Yan
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - Lin Chen
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - Jialing He
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
| | - Wei Liu
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Fei Yang
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
- Corresponding author
| | - Shankuan Zhu
- Chronic Disease Research Institute, The Children’s Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, 866 Yu-hang-tang Road, Hangzhou, Zhejiang 310058, China
- Corresponding author
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Trigiante G, Blanes Ruiz N, Cerase A. Emerging Roles of Repetitive and Repeat-Containing RNA in Nuclear and Chromatin Organization and Gene Expression. Front Cell Dev Biol 2021; 9:735527. [PMID: 34722514 PMCID: PMC8552494 DOI: 10.3389/fcell.2021.735527] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022] Open
Abstract
Genomic repeats have been intensely studied as regulatory elements controlling gene transcription, splicing and genome architecture. Our understanding of the role of the repetitive RNA such as the RNA coming from genomic repeats, or repetitive sequences embedded in mRNA/lncRNAs, in nuclear and cellular functions is instead still limited. In this review we discuss evidence supporting the multifaceted roles of repetitive RNA and RNA binding proteins in nuclear organization, gene regulation, and in the formation of dynamic membrane-less aggregates. We hope that our review will further stimulate research in the consolidating field of repetitive RNA biology.
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Affiliation(s)
| | | | - Andrea Cerase
- Centre for Genomics and Child Health, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
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15
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Yin RH, Guo ZB, Zhou YY, Wang C, Yin RL, Bai WL. LncRNA-MEG3 Regulates the Inflammatory Responses and Apoptosis in Porcine Alveolar Macrophages Infected with Haemophilus parasuis Through Modulating the miR-210/TLR4 Axis. Curr Microbiol 2021; 78:3152-3164. [PMID: 34191053 DOI: 10.1007/s00284-021-02590-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 06/22/2021] [Indexed: 12/16/2022]
Abstract
Haemophilus parasuis (H. parasuis, HPS) can elicit serious inflammatory responses and cause enormous economic loss to swine industry worldwide. However, the factors responsible for systemic infection and inflammatory responses of HPS have not yet been fully clarified. In this study, we found that lncRNA-MEG3 was significantly up-regulated in porcine alveolar macrophages (PAMs) infected with HPS. The gain- and loss-of-function analysis confirmed that lncRNA-MEG3 participated in the inflammatory responses and apoptosis in HPS-infected PAMs, which was assessed via several inflammatory cytokine genes (TNF-α, IL-1β, and IL-6) and apoptotic factors (Bcl-2, Bax, and C-caspase-3). Based on biotin-labeled RNA pull-down assay, we found that lncRNA-MEG3 bound with miR-210 in HPS-infected PAMs. Based on both overexpression and knockdown analysis of lncRNA-MEG3, our results indicated that lncRNA-MEG3 promoted the expression of TLR4 in HPS-infected PAMs. Using dual-luciferase reporter assays, we showed that lncRNA-MEG3 positively regulated the expression of TLR4 gene in HPS-infected PAMs through miR-210 pathway. Taken together, our results indicated that lncRNA-MEG3 participated in the inflammatory responses and apoptosis in HPS-infected PAMs through modulating the miR-210/TLR4 axis. The results from this investigation provided significant information for a novel target to control HPS infection in swine.
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Affiliation(s)
- Rong H Yin
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, College of Aninal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Zhong B Guo
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, College of Aninal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Yuan Y Zhou
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, College of Aninal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Chao Wang
- Liaoning Agricultural Technical College, Yingkou, 115009, China
| | - Rong L Yin
- Research Academy of Animal Husbandry and Veterinary Medicine Sciences of Jilin Province, Changchun, 130062, China
| | - Wen L Bai
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, College of Aninal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China.
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16
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Lv S, Qu X, Qu Y, Wang Y. LncRNA NEAT1 Knockdown Alleviates Lipopolysaccharide-Induced Acute Lung Injury by Modulation of miR-182-5p/WISP1 Axis. Biochem Genet 2021; 59:1631-1647. [PMID: 34046810 DOI: 10.1007/s10528-021-10081-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/15/2021] [Indexed: 10/21/2022]
Abstract
Accumulating evidence has demonstrated the vital roles of long non-coding RNAs (lncRNAs) in acute lung injury (ALI). In this study, we aimed to explore the effect of Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) on ALI development. The ALI mice and cell models were constructed using lipopolysaccharide (LPS)-induced method. The concentrations of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA). The levels of TNF-α mRNA, IL-6 mRNA, IL-1β mRNA, NEAT1, miR-182-5p, and WNT-inducible secreted protein 1 (WISP1) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay. The level of lactate dehydrogenase (LDH) and the activity of caspase-3 were measured by specific kits. The interaction between miR-182-5p and NEAT1 or WISP1 was investigated by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Protein levels were measured by Western blot assay. NEAT1 level was elevated in LPS-induced ALI mice and LPS-stimulated MH-S cells. LPS treatment repressed MH-S cell viability and promoted apoptosis and inflammation, while NEAT1 silencing restored the impacts. For mechanism analysis, NEAT1 was identified as the sponge for miR-182-5p to positively regulate WISP1 expression. Moreover, NEAT1 knockdown could accelerate cell viability and inhibit cell apoptosis and inflammation in LPS-induced MH-S cells by elevating miR-182-5p and decreasing WISP1 in LPS-exposed MH-S cells. In addition, NEAT1 deficiency blocked the activation of NF-κB pathway caused by LPS in MH-S cells. NEAT1 overexpression restrained cell viability and facilitated cell apoptosis and inflammation in LPS-exposed MH-S cells through miR-182-5p/WISP1 axis.
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Affiliation(s)
- Sensen Lv
- Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital (Headquarters), No.1 Jiaozhou Road, Shibei District, Qingdao, 266011, Shandong, China
| | - Xiaolu Qu
- Department of Critical Care Medicine, Qingdao Municipal Hospital (East Brach), No.5 Donghai Middle Road, Shinan District, Qingdao, 266071, Shandong, China
| | - Yan Qu
- Department of Critical Care Medicine, Qingdao Municipal Hospital (East Brach), No.5 Donghai Middle Road, Shinan District, Qingdao, 266071, Shandong, China.
| | - Yun Wang
- Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital (Headquarters), No.1 Jiaozhou Road, Shibei District, Qingdao, 266011, Shandong, China.
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Long non‑coding RNA‑DUXAP8 regulates TOP2A in the growth and metastasis of osteosarcoma via microRNA‑635. Mol Med Rep 2021; 24:511. [PMID: 33982765 PMCID: PMC8134877 DOI: 10.3892/mmr.2021.12150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OS) is a malignant disease with high morbidity and mortality rates in children and adolescents. Evidence has indicated that long non-coding RNAs (lncRNAs) may serve important roles in human cancer progression, including OS. In the present study, the role of lnc-double homeobox A pseudogene 8 (DUXAP8) in the development of OS was identified. The expression of lncRNA-DUXAP8 was determined by reverse transcription-quantitative polymerase chain reaction in OS tissues. Cell proliferation was evaluated using Cell Counting kit-8 and colony formation assays, and Transwell assays were conducted to measure cell invasion. Cell migration was evaluated using a wound healing assay. The binding site between lnc-DUXAP8 and miR-635 RNAs was investigated using a luciferase reporter assay. The expression of lnc-DUXAP8 was significantly upregulated in OS samples and OS cell lines compared with normal tissues. High expression of lncRNA DUXAP8 was associated with shorter overall survival times. Knockdown of lncRNA DUXAP8 inhibited proliferation, migration and invasion in OS cells. Notably, mechanistic investigation revealed that lncRNA DUXAP8 predominantly acted as a competing endogenous RNA in OS by regulating the miR-635/topoisomerase alpha 2 (TOP2A) axis. lncRNA DUXAP8 is upregulated in OS, and lncRNA DUXAP8-knockdown serves a vital antitumor role in OS cell progression through the miR-635/TOP2A axis. The results of the present study suggested that lncRNA DUXAP8 may be a novel, promising biomarker for the diagnosis and prognosis of OS.
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DLX6 Antisense RNA 1 Modulates Glucose Metabolism and Cell Growth in Gastric Cancer by Targeting microRNA-4290. Dig Dis Sci 2021; 66:460-473. [PMID: 32239379 DOI: 10.1007/s10620-020-06223-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/18/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most commonly diagnosed malignancy worldwide. DLX6 antisense RNA 1 (DLX6-AS1) is a long noncoding RNA (lncRNA) that exhibits oncogenic effects on multiple human carcinomas. AIMS This study aimed to investigate the regulatory effect of DLX6-AS1 in GC progression. METHODS The expression of DLX6-AS1 in GC tissues and cell lines was examined. The cell viability, number of clones, and apoptosis, aerobic glycolysis, and mitochondrial respiration was assessed. The effect of DLX6-AS1 on tumor growth in nude mice was also evaluated. RESULTS DLX6-AS1 was overexpressed in GC tissues and cell lines. DLX6-AS1 knockdown by short hairpin RNA (shRNA) significantly inhibited cell viability and colony formation, and induced apoptosis. DLX6-AS1 silencing impaired aerobic glycolysis but stimulated mitochondrial respiration in GC cells. miR-4290 was confirmed as a downstream target of DLX6-AS1, and their expression levels were inversely correlated. GC cells expressing sh-DLX6-AS1 showed significantly lower level of 3-phosphoinositide-dependent protein kinase 1 (PDK1), a target of miR-4290, compared to cells expressing control shRNA. In addition, the suppressed GC cell malignancy upon DLX6-AS1 knockdown could be prominently reversed by PDK1 overexpression. Meanwhile, PDK1 overexpression enhanced aerobic glycolysis but repressed mitochondrial respiration under sh-DLX6-AS1 treatment. Furthermore, DLX6-AS1 knockdown significantly delayed the tumor growth in a mouse xenograft model inoculated with GC cells. CONCLUSIONS LncRNA DLX6-AS1 regulated tumor growth and aerobic glycolysis in GC by targeting miR-4290 and PDK1, suggesting DLX6-AS1 might serve as a novel potential therapeutic target for GC treatment from bench to clinic.
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Silence of Long Noncoding RNA SNHG14 Alleviates Ischemia/Reperfusion-Induced Acute Kidney Injury by Regulating miR-124-3p/MMP2 Axis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8884438. [PMID: 33490282 PMCID: PMC7803415 DOI: 10.1155/2021/8884438] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/30/2020] [Accepted: 12/19/2020] [Indexed: 12/21/2022]
Abstract
Purpose Ample evidence has proved that lncRNAs are pivotal regulators in acute kidney injury (AKI). Here, we focus on the role and mechanism of lncRNA SNHG14 in ischemia/reperfusion- (I/R-) caused AKI. Methods I/R and hypoxia/reoxygenation (H/R) were applied to induce rats and HK-2 cells to establish AKI models in vivo and in vitro. Relative expression of SNHG14, miR-124-3p, and MMP2 was determined by qRT-PCR. HE staining was used to evaluate pathological changes in renal tissues, and acute tubular necrosis (ATN) score was calculated. Renal function was evaluated by measuring serum creatinine content and blood urea nitrogen content. Levels of IL-1β, IL-6, and TNF-α were measured by ELISA. Cell viability was examined by MTT assay. Oxidative stress was assessed by measuring SOD, MDA, and ROS levels. The target of SNHG14 or miR-124-3p was verified by DLR assay. Protein expression of MMP2 was examined by western blot. Results SNHG14 was boosted in renal tissues of I/R-stimulated rats and H/R-induced HK-2 cells, while miR-124-3p was diminished in H/R-stimulated HK-2 cells. Si-SNHG14 or miR-124-3p mimics repressed inflammation and oxidative stress and enhanced cell viability in H/R-stimulated HK-2 cells. Sh-SNHG14 mitigated I/R-induced AKI in rats. MiR-124-3p was targeted by SNHG14, and MMP2 was targeted by miR-124-3p. Inhibition of miR-124-3p or upregulation of MMP2 reversed inhibitory effects of SNHG14 silence on inflammation and oxidative stress as well as the promoting effect of SNHG14 silence on cell viability in H/R-induced HK-2 cells. Conclusion Knockdown of SNHG14 alleviated I/R-induced AKI by miR-124-3p-mediated downregulation of MMP2.
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20
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Liu X, Wang C. Long non-coding RNA ATB is associated with metastases and promotes cell invasion in colorectal cancer via sponging miR-141-3p. Exp Ther Med 2020; 20:261. [PMID: 33199986 PMCID: PMC7664613 DOI: 10.3892/etm.2020.9391] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/21/2020] [Indexed: 12/15/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) serve crucial roles in cancer development and progression. lncRNA-activated by transforming growth factor-β (lncRNA-ATB) mediates cell proliferation. However, the association between lncRNA-ATB and human colorectal cancer (CRC) is not completely understood. Therefore, the present study aimed to investigate the role of lncRNA-ATB in CRC, as well as the underlying mechanism. 50 pairs of tumor tissues and adjacent normal tissues from patients with primary CRC were collected. The expression of lncRNA-ATB and microRNA (miR)-141-3p in CRC tissues, adjacent normal tissues and cell lines was detected using reverse transcription-quantitative PCR. CCK-8, colony formation, Transwell, western blot, dual luciferase reporter gene, RNA immunoprecipitation and immunohistochemistry staining assays were conducted to assess the biological function of lncRNA-ATB and miR-141-3p in CRC progression. lncRNA-ATB was upregulated in CRC tissues and cell lines compared with healthy tissues and cells, respectively. Moreover, high expression of lncRNA-ATB was significantly associated with advanced TNM stage and metastasis in CRC. In addition, the results indicated that lncRNA-ATB expression predicted the prognosis and overall survival of patients with CRC. Compared with small interfering RNA-negative control, lncRNA-ATB knockdown inhibited CRC cell proliferation, migration and invasion, whereas, compared with vector, lncRNA-ATB overexpression promoted CRC cell proliferation, migration and invasion. Furthermore, the in vivo experiment suggested that lncRNA-ATB knockdown inhibited tumor growth. The results also indicated that lncRNA-ATB may contribute to CRC progression via binding to tumor suppressor microRNA-141-3p. Collectively, the present study suggested a crucial role of lncRNA-ATB in CRC tumorigenesis, suggesting that lncRNA-ATB may serve as an important marker for the diagnosis and development of CRC.
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Affiliation(s)
- Xianming Liu
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Cunchuan Wang
- Department of Gastrointestinal Surgery, Guangzhou Overseas Chinese Hospital, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
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21
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Yin RH, Zhao SJ, Wang ZY, Zhu YB, Yin RL, Bai M, Fan YX, Wang W, Bai WL. LncRNA-599547 contributes the inductive property of dermal papilla cells in cashmere goat through miR-15b-5p/Wnt10b axis. Anim Biotechnol 2020; 33:493-507. [PMID: 32808845 DOI: 10.1080/10495398.2020.1806860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The lncRNA-599547 (619-nt in length) is identified in secondary hair follicle (SHF) of cashmere goat, but its functional roles in regulating the inductive property of dermal papilla cells (DPCs) remains unknown. We found that lncRNA-599547 had significantly higher expression in dermal papilla of cashmere goat SHF at anagen than its counterpart at telogen. The overexpression of lncRNA-599547 led to a significant increase of ALP and LEF1 expression in DPCs (p < 0.05), whereas, the siLncRNA-1 mediated silencing of lncRNA-599547 significantly down-regulated the expression of ALP and LEF1 in DPCs (p < 0.05). Based on biotin-labeled RNA pull-down assay, we found that lncRNA-599547 directly interacted with chi-miR-15b-5p in DPCs. Based on both overexpression and silencing analysis of lncRNA-599547, our results indicate that lncRNA-599547 promotes the expression of Wnt10b in DPCs but without modulating its promoter methylation level. Using the mRNA-3'UTR fragments of goat Wnt10b containing the predicted binding sites of chi-miR-15b-5p in Dual-luciferase Reporter Assays, we show that lncRNA-599547 modulates the expression of Wnt10b at the chi-miR-15b-5p mediated post-transcriptional level. Taken together, our results indicate that lncRNA-599547 sponges miR-15b-5p to positively regulate the expression of Wnt10 gene, and thereby contributes the inductive property of DPCs in cashmere goat.
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Affiliation(s)
- Rong H Yin
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, P. R. China
| | - Su J Zhao
- Sichuan Animal Science Academy, Chengdu, Sichuan, China.,Animal Breeding and Genetics Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Ze Y Wang
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, P. R. China
| | - Yu B Zhu
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, P. R. China
| | - Rong L Yin
- Research Academy of Animal Husbandry and Veterinary Medicine Sciences of Jilin Province, Changchun, China
| | - Man Bai
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, P. R. China
| | - Yi X Fan
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, P. R. China
| | - Wei Wang
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, P. R. China
| | - Wen L Bai
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, P. R. China
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22
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Chen H, Hu X, Li R, Liu B, Zheng X, Fang Z, Chen L, Chen W, Min L, Hu S. LncRNA THRIL aggravates sepsis-induced acute lung injury by regulating miR-424/ROCK2 axis. Mol Immunol 2020; 126:111-119. [PMID: 32818819 DOI: 10.1016/j.molimm.2020.07.021] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/27/2020] [Accepted: 07/30/2020] [Indexed: 01/04/2023]
Abstract
Here, we aimed to investigate the role of long noncoding RNA (lncRNA) THRIL in septic-induced acute lung injury. C57BL/6 mice were injected with Adenoviruses (Ad)-shTHRIL or negative control (NC) before caecal ligation and puncture (CLP) operation. MPVECs were transfected with Ad-shTHRIL or NC, followed by lipopolysaccharide (LPS) treatment. MiR-424 and Rho-associated kinase 2 (ROCK2) were predicted and verified as direct targets of THRIL and miR-424, respectively, by using dual-luciferase reporter assay. ROCK2 overexpression vector and shTHRIL were co-transfected into mouse pulmonary microvascular endothelial cells for 24 h before LPS treatment. Our results showed that THRIL was highly expressed in the lung of sepsis mice. CLP triggered severe lung injury and apoptosis in mice, which was abolished by THRIL knockdown. Moreover, CLP treatment visibly increased protein concentration, the number of total cell of neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF). Besides, elevated protein levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were observed in both lung and BALF. However, inhibition of THRIL reduced the number of inflammatory cells and the production of pro-inflammatory cytokines in sepsis mouse model. The effect of THRIL on inflammatory response and apoptosis in the lung was confirmed in sepsis cell model. Moreover, mechanistic studies have shown that THRIL up-regulated ROCK2 level through sponging miR-424. Furthermore, ROCK2 overexpression reversed the inhibitory effects of THRIL knockdown on LPS-induced inflammatory response and apoptosis. Overall, in vivo and in vitro results suggested that THRIL accelerates sepsis-induced lung injury by sponging miR-424 and further restoring ROCK2.
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Affiliation(s)
- Huibin Chen
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Xuemei Hu
- Department of Nephrology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Ruiting Li
- Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei Province, 430022, China
| | - Boyi Liu
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Xiang Zheng
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Zhicheng Fang
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Li Chen
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Wei Chen
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Li Min
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China
| | - Shengli Hu
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, 442000, China.
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23
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Rzeszutek I, Singh A. Small RNAs, Big Diseases. Int J Mol Sci 2020; 21:E5699. [PMID: 32784829 PMCID: PMC7460979 DOI: 10.3390/ijms21165699] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/06/2020] [Accepted: 08/08/2020] [Indexed: 02/06/2023] Open
Abstract
The past two decades have seen extensive research done to pinpoint the role of microRNAs (miRNAs) that have led to discovering thousands of miRNAs in humans. It is not, therefore, surprising to see many of them implicated in a number of common as well as rare human diseases. In this review article, we summarize the progress in our understanding of miRNA-related research in conjunction with different types of cancers and neurodegenerative diseases, as well as their potential in generating more reliable diagnostic and therapeutic approaches.
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Affiliation(s)
- Iwona Rzeszutek
- Institute of Biology and Biotechnology, Department of Biotechnology, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, Poland
| | - Aditi Singh
- Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, 72076 Tübingen, Germany
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24
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Qu Y, Tan HY, Chan YT, Jiang H, Wang N, Wang D. The functional role of long noncoding RNA in resistance to anticancer treatment. Ther Adv Med Oncol 2020; 12:1758835920927850. [PMID: 32536982 PMCID: PMC7268113 DOI: 10.1177/1758835920927850] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 04/28/2020] [Indexed: 12/12/2022] Open
Abstract
Chemotherapy is one of the fundamental methods of cancer treatment. However, drug resistance remains the main cause of clinical treatment failure. We comprehensively review the newly identified roles of long noncoding RNAs (lncRNAs) in oncobiology that are associated with drug resistance. The expression of lncRNAs is tissue-specific and often dysregulated in human cancers. Accumulating evidence suggests that lncRNAs are involved in chemoresistance of cancer cells. The main lncRNA-driven mechanisms of chemoresistance include regulation of drug efflux, DNA damage repair, cell cycle, apoptosis, epithelial-mesenchymal transition (EMT), induction of signaling pathways, and angiogenesis. LncRNA-driven mechanisms of resistance to various antineoplastic agents have been studied extensively. There are unique mechanisms of resistance against different types of drugs, and each mechanism may have more than one contributing factor. We summarize the emerging strategies that can be used to overcome the technical challenges in studying and addressing lncRNA-mediated drug resistance.
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Affiliation(s)
- Yidi Qu
- School of Life Sciences, Jilin University, Changchun, China
| | - Hor-Yue Tan
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R., P.R. China
| | - Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R., P.R. China
| | - Hongbo Jiang
- School of Life Sciences, Jilin University, Changchun, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R., P.R. China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun, 130012, China
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25
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Yin RH, Wang YR, Zhao SJ, Yin RL, Bai M, Wang ZY, Zhu YB, Cong YY, Liu HY, Bai WL. LncRNA-599554 sponges miR-15a-5p to contribute inductive ability of dermal papilla cells through positive regulation of the expression of Wnt3a in cashmere goat. ELECTRON J BIOTECHN 2020. [DOI: 10.1016/j.ejbt.2020.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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26
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Genome-Wide Detection of Key Genes and Epigenetic Markers for Chicken Fatty Liver. Int J Mol Sci 2020; 21:ijms21051800. [PMID: 32151087 PMCID: PMC7084419 DOI: 10.3390/ijms21051800] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/13/2020] [Accepted: 02/19/2020] [Indexed: 12/21/2022] Open
Abstract
Chickens are one of the most important sources of meat worldwide, and the occurrence of fatty liver syndrome (FLS) is closely related to production efficiency. However, the potential mechanism of FLS remains poorly understood. An integrated analysis of data from whole-genome bisulfite sequencing and long noncoding RNA (lncRNA) sequencing was conducted. A total of 1177 differentially expressed genes (DEGs) and 1442 differentially methylated genes (DMGs) were found. There were 72% of 83 lipid- and glucose-related genes upregulated; 81% of 150 immune-related genes were downregulated in fatty livers. Part of those genes was within differentially methylated regions (DMRs). Besides, sixty-seven lncRNAs were identified differentially expressed and divided into 13 clusters based on their expression pattern. Some lipid- and glucose-related lncRNAs (e.g., LNC_006756, LNC_012355, and LNC_005024) and immune-related lncRNAs (e.g., LNC_010111, LNC_010862, and LNC_001272) were found through a co-expression network and functional annotation. From the expression and epigenetic profiles, 23 target genes (e.g., HAO1, ABCD3, and BLMH) were found to be hub genes that were regulated by both methylation and lncRNAs. We have provided comprehensive epigenetic and transcriptomic profiles on FLS in chicken, and the identification of key genes and epigenetic markers will expand our understanding of the molecular mechanism of chicken FLS.
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27
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Qiu N, Xu X, He Y. LncRNA TUG1 alleviates sepsis-induced acute lung injury by targeting miR-34b-5p/GAB1. BMC Pulm Med 2020; 20:49. [PMID: 32087725 PMCID: PMC7036216 DOI: 10.1186/s12890-020-1084-3] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background Sepsis-induced acute lung injury (ALI) is a clinical syndrome characterized by the injury of alveolar epithelium and pulmonary endothelial cells. This study aimed to investigate the regulation of long noncoding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) in a murine ALI model and in primary murine pulmonary microvascular endothelial cells (PMVECs) stimulated with lipopolysaccharide (LPS). Methods Adult C57BL/6 mice were intravenously injected with or without TUG1-expressiong adenoviral vector or control vector 1 week before the establishment of ALI model. PMVECs were transfected with TUG1-expressiong or control vectors followed by LPS stimulation. MiR-34b-5p was confirmed as a target of TUG1 using dual-luciferase reporter assay. GRB2 associated binding protein 1 (GAB1) was confirmed as a downstream target of miR-34b-5p using the same method. In the rescue experiment, PMVECs were co-transfected with TUG1-expressing vector and miR-34b-5p mimics (or control mimics) 24 h before LPS treatment. Results ALI mice showed reduced levels of TUG1, pulmonary injury, and induced apoptosis and inflammation compared to the control group. The overexpression of TUG1 in ALI mice ameliorated sepsis-induced pulmonary injury, apoptosis and inflammation. TUG1 also showed protective effect in LPS-treated PMVECs. The expression of MiR-34b-5p was negatively correlated with the level of TUG1. TUG1-supressed apoptosis and inflammation in LPS-stimulated PMVECs were restored by miR-34b-5p overexpression. GAB1 was inversely regulated by miR-34b-5p but was positively correlated with TUG1 expression. Conclusion TUG1 alleviated sepsis-induced inflammation and apoptosis via targeting miR-34b-5p and GAB1. These findings suggested that TUG1 might be served as a therapeutic potential for the treatment of sepsis-induced ALI.
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Affiliation(s)
- Nan Qiu
- Department of Emergency Internal Medicine, Guizhou Provincial People's Hospital, Guiyang City, No. 1 Baoshan South Road, Guiyang City, Guizhou Province, China.
| | - Xinmei Xu
- Department of Emergency Internal Medicine, Guizhou Provincial People's Hospital, Guiyang City, No. 1 Baoshan South Road, Guiyang City, Guizhou Province, China
| | - Yingying He
- Department of Emergency Internal Medicine, Guizhou Provincial People's Hospital, Guiyang City, No. 1 Baoshan South Road, Guiyang City, Guizhou Province, China
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28
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Bao Q, Liao X, Li R, Ding N. KCNQ1OT1 promotes migration and inhibits apoptosis by modulating miR-185-5p/Rab14 axis in oral squamous cell carcinoma. Dev Growth Differ 2019; 61:466-474. [PMID: 31755091 DOI: 10.1111/dgd.12638] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/23/2019] [Accepted: 10/23/2019] [Indexed: 12/20/2022]
Abstract
Long non-coding RNAs (lncRNAs) play essential roles in the regulation of gene transcription in carcinogenesis and metastasis via interacting with microRNA. In this study, we explored the expressions and functions of lncRNA KCNQ1OT1 and miR-185-5p in oral squamous cell carcinoma (OSCC) cells. KCNQ1OT1 expression in OSCC tissues and cells was examined by qRT-PCR. Small interfering RNAs against KCNQ1OT1 (si- KCNQ1OT1) were used to knockdown KCNQ1OT1 in OSCC cells. Cell function was assessed by wound healing assay, transwell assay, and apoptosis detection. The binding region between KCNQ1OT1 and miR-185-5p was confirmed by luciferase assays. MiR-185-5p expression was measured by qRT-PCR. Rab14 was confirmed as a downstream target gene of miR-185-5p by measuring luciferase activities. The protein level of Rab14 in OSCC cells transfected with miR-185-5p or si-KCNQ1OT1 was determined by Western blot. The OSCC cell function and Rab14 expression after co-transfection of si-KCNQ1OT1 and miR-185-5p inhibitor were also examined. KCNQ1OT1 was upregulated in OSCC tissues and cells. KCNQ1OT1 silencing suppressed OSCC cell malignancy and downregulated miR-185-5p level, which showed upregulated expression in OSCC samples. Rab14 as a target gene of miR-185-5p was highly expressed in OSCC. KCNQ1OT1 knockdown impaired the invasion capability of OSCC cells, promoted apoptosis, and suppressed Rab14 expression. The inhibition of miR-185-5p in KCNQ1OT1 silencing cells reversed the suppression of Rab14 and restored the cancerous growth of OSCC cells. These results indicated that KCNQ1OT1 promoted OSCC tumorigenesis via the modulation of miR-185-5p/Rab14 axis, which may serve as a therapeutic target for the treatment of OSCC.
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Affiliation(s)
- Qiyan Bao
- Department of Stomatology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Xiangling Liao
- Department of Stomatology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Rongyin Li
- Department of Stomatology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Nan Ding
- Department of Stomatology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
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29
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Zhang S, Wang Y, Jia L, Wen X, Du Z, Wang C, Hao Y, Yu D, Zhou L, Chen N, Chen J, Chen H, Zhang H, Celik I, Gülsoy G, Luo J, Qin B, Cui X, Liu Z, Zhang S, Esteban MA, Ay F, Xu W, Chen R, Li W, Hoffman AR, Hu JF, Cui J. Profiling the long noncoding RNA interaction network in the regulatory elements of target genes by chromatin in situ reverse transcription sequencing. Genome Res 2019; 29:1521-1532. [PMID: 31315906 PMCID: PMC6724666 DOI: 10.1101/gr.244996.118] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 07/10/2019] [Indexed: 12/27/2022]
Abstract
Long noncoding RNAs (lncRNAs) can regulate the activity of target genes by participating in the organization of chromatin architecture. We have devised a “chromatin-RNA in situ reverse transcription sequencing” (CRIST-seq) approach to profile the lncRNA interaction network in gene regulatory elements by combining the simplicity of RNA biotin labeling with the specificity of the CRISPR/Cas9 system. Using gene-specific gRNAs, we describe a pluripotency-specific lncRNA interacting network in the promoters of Sox2 and Pou5f1, two critical stem cell factors that are required for the maintenance of pluripotency. The promoter-interacting lncRNAs were specifically activated during reprogramming into pluripotency. Knockdown of these lncRNAs caused the stem cells to exit from pluripotency. In contrast, overexpression of the pluripotency-associated lncRNA activated the promoters of core stem cell factor genes and enhanced fibroblast reprogramming into pluripotency. These CRIST-seq data suggest that the Sox2 and Pou5f1 promoters are organized within a unique lncRNA interaction network that determines the fate of pluripotency during reprogramming. This CRIST approach may be broadly used to map lncRNA interaction networks at target loci across the genome.
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Affiliation(s)
- Shilin Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Yichen Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Lin Jia
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Xue Wen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Zhonghua Du
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Cong Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China.,Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
| | - Yajing Hao
- CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
| | - Dehai Yu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Lei Zhou
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Naifei Chen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Jingcheng Chen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China.,Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
| | - Huiling Chen
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hui Zhang
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, P.R. China
| | - Ilkay Celik
- Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
| | - Günhan Gülsoy
- Google Incorporated, Mountain View, California 94043, USA
| | - Jianjun Luo
- CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
| | - Baoming Qin
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, P.R. China
| | - Xueling Cui
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Zhonghui Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Songling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Miguel A Esteban
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, P.R. China
| | - Ferhat Ay
- La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA
| | - Wei Xu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Runsheng Chen
- CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
| | - Wei Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Andrew R Hoffman
- Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
| | - Ji-Fan Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China.,Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
| | - Jiuwei Cui
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
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30
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Wang J, Zhang Y, Li Q, Zhao J, Yi D, Ding J, Zhao F, Hu S, Zhou J, Deng T, Li X, Guo F, Liang C, Cen S. Influenza Virus Exploits an Interferon-Independent lncRNA to Preserve Viral RNA Synthesis through Stabilizing Viral RNA Polymerase PB1. Cell Rep 2019; 27:3295-3304.e4. [PMID: 31189112 DOI: 10.1016/j.celrep.2019.05.036] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 12/08/2018] [Accepted: 05/09/2019] [Indexed: 12/14/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) participate in host antiviral defense by modulating immune responses. However, it remains largely unexplored how viruses exploit interferon (IFN)-independent host lncRNAs to facilitate viral replication. Here, we have identified a group of human lncRNAs that modulate influenza A virus (IAV) replication in a loss-of-function screen and found that an IFN-independent lncRNA, called IPAN, is hijacked by IAV to assist IAV replication. IPAN is specifically induced by IAV infection independently of IFN and associates with and stabilizes viral RNA-dependent RNA polymerase PB1, enabling efficient viral RNA synthesis. Silencing IPAN results in PB1 degradation and severely impairs viral infection. Therefore, our data unveil an important role of host lncRNAs in promoting viral replication by modulating viral protein stability. Our findings may open avenues to the development of antiviral therapeutics.
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Affiliation(s)
- Jing Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China
| | - Yongxin Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China
| | - Quanjie Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China
| | - Jianyuan Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China
| | - Dongrong Yi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China
| | - Jiwei Ding
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China
| | - Fei Zhao
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100730, PR China
| | - Siqi Hu
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100730, PR China
| | - Jinming Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China
| | - Tao Deng
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100730, PR China
| | - Xiaoyu Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China.
| | - Fei Guo
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100730, PR China
| | - Chen Liang
- Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
| | - Shan Cen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, PR China.
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31
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Liu Y, Cheng Z, Pang Y, Cui L, Qian T, Quan L, Zhao H, Shi J, Ke X, Fu L. Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia. J Hematol Oncol 2019; 12:51. [PMID: 31126316 PMCID: PMC6534901 DOI: 10.1186/s13045-019-0734-5] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 04/16/2019] [Indexed: 12/16/2022] Open
Abstract
Acute myeloid leukemia (AML) is a malignant tumor of the immature myeloid hematopoietic cells in the bone marrow (BM). It is a highly heterogeneous disease, with rising morbidity and mortality in older patients. Although researches over the past decades have improved our understanding of AML, its pathogenesis has not yet been fully elucidated. Long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) are three noncoding RNA (ncRNA) molecules that regulate DNA transcription and translation. With the development of RNA-Seq technology, more and more ncRNAs that are closely related to AML leukemogenesis have been discovered. Numerous studies have found that these ncRNAs play an important role in leukemia cell proliferation, differentiation, and apoptosis. Some may potentially be used as prognostic biomarkers. In this systematic review, we briefly described the characteristics and molecular functions of three groups of ncRNAs, including lncRNAs, miRNAs, and circRNAs, and discussed their relationships with AML in detail.
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Affiliation(s)
- Yan Liu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.,Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, 475000, China.,Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Zhiheng Cheng
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Yifan Pang
- Department of Medicine, William Beaumont Hospital, Royal Oak, MI, 48073, USA
| | - Longzhen Cui
- Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Tingting Qian
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.,Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Liang Quan
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.,Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Hongyou Zhao
- Department of Laser Medicine, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jinlong Shi
- Department of Biomedical Engineering, Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiaoyan Ke
- Department of Hematology and Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China
| | - Lin Fu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China. .,Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China. .,Department of Hematology, Huaihe Hospital of Henan University, Kaifeng, 475000, China.
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Su W, Tang J, Wang Y, Sun S, Shen Y, Yang H. Long non-coding RNA highly up-regulated in liver cancer promotes epithelial-to-mesenchymal transition process in oral squamous cell carcinoma. J Cell Mol Med 2019; 23:2645-2655. [PMID: 30677230 PMCID: PMC6433680 DOI: 10.1111/jcmm.14160] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 12/24/2018] [Accepted: 12/27/2018] [Indexed: 12/17/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is an oral and maxillofacial malignancy that exhibits high incidence worldwide. In diverse human cancers, the long non-coding RNA (lncRNA) highly up-regulated in liver cancer (HULC) is aberrantly expressed, but how HULC affects OSCC development and progression has remained mostly unknown. We report that HULC was abnormally up-regulated in oral cancer tissues and OSCC cell lines, and that suppression of HULC expression in OSCC cells not only inhibited the proliferation, drug tolerance, migration and invasion of the cancer cells, but also increased their apoptosis rate. Notably, in a mouse xenograft model, HULC depletion reduced tumorigenicity and inhibited the epithelial-to-mesenchymal transition process. Collectively, our findings reveal a crucial role of the lncRNA HULC in regulating oral cancer carcinogenesis and tumour progression, and thus suggest that HULC could serve as a novel therapeutic target for OSCC.
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Affiliation(s)
- Wen Su
- Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.,Peking University Shenzhen Hospital Clinical College, Anhui Medical University, Hefei, Anhui, China
| | - Jing Tang
- Jingzhou Central Hospital, Jingzhou, Hubei
| | - Yufan Wang
- Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Shuai Sun
- Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yuehong Shen
- Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Hongyu Yang
- Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
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Chen L, Liu J, Tang T, Zhang YC, Liu MZ, Xu LY, Zhang J. lncRNA differentiation antagonizing nonprotein coding RNA overexpression accelerates progression and indicates poor prognosis in pancreatic ductal adenocarcinoma. Onco Targets Ther 2018; 11:7955-7965. [PMID: 30519037 PMCID: PMC6235324 DOI: 10.2147/ott.s167065] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background lncRNA differentiation antagonizing nonprotein coding RNA (lncRNA DANCR) has been suggested to play an oncogenic role in multiple cancers. However, to the best of our knowledge, the clinical significance and role of DANCR in pancreatic ductal adenocarcinoma (PDAC) has not been illuminated till now. The present study aims to identify the functional role of DANCR in PDAC. Methods The expression of DANCR was detected in PDAC cells and tissues. The correlation of DANCR expression and PDAC clinicopahological features was analysed. Kaplan-Meier method was used to depict the overall survival (OS) rate and shorter progression-free survival (PFS) of PDAC patients, and Log-rank test was performed to analyse the difference. Univariate and multivariate COX regression model were utilized to analyse the risk factors for prognosis. Transwell assay and Matrigel assay were conducted to detect the effect of DANCR on the migration and invasion of PDAC cells, respectively. Colony formation assay and Cell Counting Kit-8 (CCK-8) assay were performed to evaluate the function of DANCR on proliferation. The mechanisms of DANCR exerting its function were also explored. Results DANCR was revealed to promote PDAC progression, with relatively higher expression levels in PDAC cell lines and tissues. Correlation analysis of the clinicopathological features and DANCR expression found that high DANCR expression was statistically correlated with vascular invasion (P=0.013), advanced T stage (P=0.005), lymph node metastasis (P<0.001) and advanced TNM stage (P<0.001). Notably, survival analysis discovered that high DANCR expression predicted lower OS rate and shorter PFS period. In addition, high DANCR expression was identified as an independent risk factor for poor OS (HR=1.199, 95% CI=1.113–1.290, P<0.001) and PFS (HR=1.199, 95% CI=1.114–1.290, P<0.001) of PDAC. Moreover, in vitro assays detected that the migration and invasion of Panc1 cells with DANCR deficiency were significantly suppressed in the Transwell assay and the Matrigel assay. However, the motility of BxPC3 cells with DANCR overexpression was obviously increased. In addition, the loss of DANCR suppressed the proliferation of Panc1 cells in the CCK-8 assay and the colony formation assay, while ectopic expression of DANCR in BxPC3 cells promoted the proliferation. Besides, microRNA-33a-5p/AXL signaling pathway may be involved in mediating the function of DANCR. Conclusion Overexpression of lncRNA DANCR in PDAC is associated with cancer progression and predicts poor OS and PFS. DANCR could promote the proliferation and metastasis of PDAC cells. DANCR may serve as a potential prognostic marker and therapeutic target in PDAC.
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Affiliation(s)
- Lei Chen
- General Surgery Department, Dazhou Central Hospital, Dazhou 635000, Sichuan, China,
| | - Jie Liu
- General Surgery Department, Dazhou Central Hospital, Dazhou 635000, Sichuan, China,
| | - Tong Tang
- General Surgery Department, Dazhou Central Hospital, Dazhou 635000, Sichuan, China,
| | - Yong-Chuan Zhang
- General Surgery Department, Dazhou Central Hospital, Dazhou 635000, Sichuan, China,
| | - Ming-Zhong Liu
- General Surgery Department, Dazhou Central Hospital, Dazhou 635000, Sichuan, China,
| | - Li-Ya Xu
- General Surgery Department, Dazhou Central Hospital, Dazhou 635000, Sichuan, China,
| | - Jun Zhang
- General Surgery Department, Dazhou Central Hospital, Dazhou 635000, Sichuan, China,
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Huang H, Sun J, Sun Y, Wang C, Gao S, Li W, Hu JF. Long noncoding RNAs and their epigenetic function in hematological diseases. Hematol Oncol 2018; 37:15-21. [PMID: 30052285 DOI: 10.1002/hon.2534] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/08/2018] [Accepted: 06/11/2018] [Indexed: 12/14/2022]
Abstract
Recent discoveries demonstrate the importance of long noncoding RNA (lncRNA) in the regulation of multiple major processes impacting development, differentiation, and metastasis of hematological diseases through epigenetic mechanisms. In contrast to genetic changes, epigenetic modification does not modify genes but is frequently reversible, thus providing opportunities for targeted treatment using specific inhibitors. In this review, we will summarize the function and epigenetic mechanism of lncRNA in malignant hematologic diseases.
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Affiliation(s)
- Hanying Huang
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jingnan Sun
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China.,Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, California
| | - Yunpeng Sun
- Cardiovascular Surgery Department, First Hospital of Jilin University, Changchun, Jilin, China
| | - Cong Wang
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China.,Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, California
| | - Sujun Gao
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Li
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ji-Fan Hu
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China.,Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, California
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lncRNA TNXA-PS1 Modulates Schwann Cells by Functioning As a Competing Endogenous RNA Following Nerve Injury. J Neurosci 2018; 38:6574-6585. [PMID: 29915133 DOI: 10.1523/jneurosci.3790-16.2018] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 06/09/2018] [Accepted: 06/11/2018] [Indexed: 11/21/2022] Open
Abstract
As the major glia in PNS, Schwann cells play a critical role in peripheral nerve injury repair. Finding an efficient approach to promote Schwann cell activation might facilitate peripheral nerve repair. Long noncoding RNAs (lncRNAs) have been shown to regulate gene expression and take part in many biological processes. However, the role of lncRNAs in peripheral nerve regeneration is not fully understood. In this study, we obtained a global lncRNA portrayal following sciatic nerve injury in male rats using microarray and further investigated one of these dys-regulated lncRNAs, TNXA-PS1, confirming its vital role in regulating Schwann cells. Silencing TNAX-PS1 could promote Schwann cell migration and mechanism analyses showed that TNXA-PS1 might exert its regulatory role by sponging miR-24-3p/miR-152-3p and affecting dual specificity phosphatase 1 (Dusp1) expression. Systematic lncRNA expression profiling of sciatic nerve segments following nerve injury in rats suggested lncRNA TNXA-PS1 as a key regulator of Schwann cell migration, providing a potential therapeutic target for nerve injury repair.SIGNIFICANCE STATEMENT The PNS has an intrinsic regeneration capacity after injury in which Schwann cells play a crucial role. Therefore, further exploration of functional molecules in the Schwann cell phenotype modulation is of great importance. We have identified a set of dys-regulated long noncoding RNAs (lncRNAs) in rats following sciatic nerve injury and found that the expression of TNXA-PS1 was significantly downregulated. Mechanically analyses showed that TNXA-PS1 might act as a competing endogenous RNA to affect dual specificity phosphatase 1 (Dusp1) expression, regulating migration of Schwann cells. This study provides for the first time a global landscape of lncRNAs following sciatic nerve injury in rats and broadens the known functions of lncRNA during nerve injury. The investigation of TNXA-PS1 might facilitate the development of novel targets for nerve injury therapy.
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Wang J, Wang Y, Zhou R, Zhao J, Zhang Y, Yi D, Li Q, Zhou J, Guo F, Liang C, Li X, Cen S. Host Long Noncoding RNA lncRNA-PAAN Regulates the Replication of Influenza A Virus. Viruses 2018; 10:v10060330. [PMID: 29914164 PMCID: PMC6024364 DOI: 10.3390/v10060330] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/13/2018] [Accepted: 06/14/2018] [Indexed: 12/24/2022] Open
Abstract
The productive infection of influenza A virus (IAV) depends on host factors. However, the involvement of long non-coding RNAs (lncRNAs) in IAV infection remains largely uninvestigated. In this work, we have discovered a human lncRNA, named lncRNA-PAAN (PA-associated noncoding RNA) that enhances IAV replication. The level of lncRNA-PAAN increases upon infection of IAV, but not other viruses, nor interferon treatment, suggesting specific up-regulation of lncRNA-PAAN expression by IAV. Silencing lncRNA-PAAN significantly decreases IAV replication through impairing the activity of viral RNA-dependent RNA polymerase (RdRp). This function of lncRNA-PAAN is a result of its association with viral PA protein, a key component of IAV RNA polymerase complex. Consequently, depletion of lncRNA-PAAN prevents the formation of functional RdRp. Together, these results suggest that lncRNA-PAAN promotes the assembly of viral RNA polymerase, thus warranting efficient viral RNA synthesis. Elucidating the functions of lncRNAs in IAV infection is expected to advance our understanding of IAV pathogenesis and open new avenues to the development of novel anti-IAV therapeutics.
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Affiliation(s)
- Jing Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Yujia Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Rui Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Jianyuan Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Yongxin Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Dongrong Yi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Quanjie Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Jinming Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Fei Guo
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100730, China.
| | - Chen Liang
- Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
| | - Xiaoyu Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
| | - Shan Cen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
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Wang Y, Lu Z, Wang N, Feng J, Zhang J, Luan L, Zhao W, Zeng X. Long noncoding RNA DANCR promotes colorectal cancer proliferation and metastasis via miR-577 sponging. Exp Mol Med 2018; 50:1-17. [PMID: 29717105 PMCID: PMC5938019 DOI: 10.1038/s12276-018-0082-5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/23/2018] [Accepted: 02/14/2018] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) play key roles in various malignant tumors, including colorectal cancer (CRC). Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is overexpressed in CRC patients, but whether it affects CRC proliferation and metastasis via regulation of heat shock protein 27 (HSP27) remains unclear. In the present study, we found that DANCR was highly expressed and correlated with proliferation and metastasis in CRC. In addition, we demonstrated that DANCR and HSP27 were both targets of microRNA-577 (miR-577) and shared the same binding site. Furthermore, we revealed that DANCR promoted HSP27 expression and its mediation of proliferation/metastasis via miR-577 sponging. Finally, using an in vivo study, we confirmed that overexpression of DANCR promoted CRC tumor growth and liver metastasis. The present study demonstrated the function of DANCR in CRC and might provide a new target in the treatment of CRC.
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Affiliation(s)
- Yong Wang
- The 4th Department of Orthopedic Surgery, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, China
| | - Zhi Lu
- Department of Nuclear Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Ningnin Wang
- The 2nd Department of Cardiology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, China
| | - Jianzhou Feng
- The 4th Department of Orthopedic Surgery, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, China
| | - Junjie Zhang
- Department of Pathology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, China
| | - Lan Luan
- Department of Pathology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, China
| | - Wei Zhao
- The 4th Department of Orthopedic Surgery, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, China
| | - Xiandong Zeng
- Department of Surgical Oncology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, China.
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Xu S, Wang P, You Z, Meng H, Mu G, Bai X, Zhang G, Zhang J, Pang D. The long non-coding RNA EPB41L4A-AS2 inhibits tumor proliferation and is associated with favorable prognoses in breast cancer and other solid tumors. Oncotarget 2018; 7:20704-17. [PMID: 26980733 PMCID: PMC4991486 DOI: 10.18632/oncotarget.8007] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 02/18/2016] [Indexed: 02/01/2023] Open
Abstract
EPB41L4A-AS2 is a novel long non-coding RNA of unknown function. In this study, we investigated the expression of EPB41L4A-AS2 in breast cancer tissues and evaluated its relationship with the clinicopathological features and prognosis of patients with breast cancer. This entailed conducting a meta-analysis and prognosis validation study using two cohorts from the Gene Expression Omnibus (GEO). In addition, we assessed EPB41L4A-AS2 expression and its relationship with the clinicopathological features of renal and lung cancers using the Cancer Genome Atlas cohort and a GEO dataset. We also clarified the role of EPB41L4A-AS2 expression in mediating cancer cell proliferation in breast, renal, and lung cancer cell lines transfected with an EPB41L4A-AS2 expression vector. We found that high EPB41L4A-AS2 expression is associated with favorable disease outcomes. Gene ontology enrichment analysis revealed that EPB41L4A-AS2 may be involved in processes associated with tumor biology. Finally, overexpression of EPB41L4A-AS2 inhibited tumor cell proliferation in breast, renal, and lung cancer cell lines. Our clinical and in vitro results suggest that EPB41L4A-AS2 inhibits solid tumor formation and that evaluation of this long non-coding RNA may have prognostic value in the clinical management of such malignancies.
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Affiliation(s)
- Shouping Xu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Peiyuan Wang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zilong You
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hongxue Meng
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guannan Mu
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xianan Bai
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guangwen Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jinfeng Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
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Latgé G, Poulet C, Bours V, Josse C, Jerusalem G. Natural Antisense Transcripts: Molecular Mechanisms and Implications in Breast Cancers. Int J Mol Sci 2018; 19:ijms19010123. [PMID: 29301303 PMCID: PMC5796072 DOI: 10.3390/ijms19010123] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 12/07/2017] [Accepted: 12/29/2017] [Indexed: 12/13/2022] Open
Abstract
Natural antisense transcripts are RNA sequences that can be transcribed from both DNA strands at the same locus but in the opposite direction from the gene transcript. Because strand-specific high-throughput sequencing of the antisense transcriptome has only been available for less than a decade, many natural antisense transcripts were first described as long non-coding RNAs. Although the precise biological roles of natural antisense transcripts are not known yet, an increasing number of studies report their implication in gene expression regulation. Their expression levels are altered in many physiological and pathological conditions, including breast cancers. Among the potential clinical utilities of the natural antisense transcripts, the non-coding|coding transcript pairs are of high interest for treatment. Indeed, these pairs can be targeted by antisense oligonucleotides to specifically tune the expression of the coding-gene. Here, we describe the current knowledge about natural antisense transcripts, their varying molecular mechanisms as gene expression regulators, and their potential as prognostic or predictive biomarkers in breast cancers.
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Affiliation(s)
- Guillaume Latgé
- Laboratory of Human Genetics, GIGA-Institute, University of Liège, 4500 Liège, Belgium.
| | - Christophe Poulet
- Laboratory of Human Genetics, GIGA-Institute, University of Liège, 4500 Liège, Belgium.
| | - Vincent Bours
- Laboratory of Human Genetics, GIGA-Institute, University of Liège, 4500 Liège, Belgium.
- Center of Genetics, University Hospital (CHU), 4500 Liège, Belgium.
| | - Claire Josse
- Laboratory of Human Genetics, GIGA-Institute, University of Liège, 4500 Liège, Belgium.
- Department of Medical Oncology, University Hospital (CHU), 4500 Liège, Belgium.
- Laboratory of Medical Oncology, GIGA-Institute, University of Liège, 4500 Liège, Belgium.
| | - Guy Jerusalem
- Department of Medical Oncology, University Hospital (CHU), 4500 Liège, Belgium.
- Laboratory of Medical Oncology, GIGA-Institute, University of Liège, 4500 Liège, Belgium.
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40
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Abstract
Comparative analysis of the gestural communication of our nearest animal relatives, the great apes, implies that humans should have the biological potential to produce and understand 60-70 gestures, by virtue of shared common descent. These gestures are used intentionally in apes to convey separate requests, rather than as referential items in syntactically structured signals. At present, no such legacy of shared gesture has been described in humans. We suggest that the fate of "ape gestures" in modern human communication is relevant to the debate regarding the evolution of language through a possible intermediate stage of gestural protolanguage.
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41
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Han D, Gao X, Wang M, Qiao Y, Xu Y, Yang J, Dong N, He J, Sun Q, Lv G, Xu C, Tao J, Ma N. Long noncoding RNA H19 indicates a poor prognosis of colorectal cancer and promotes tumor growth by recruiting and binding to eIF4A3. Oncotarget 2017; 7:22159-73. [PMID: 26989025 PMCID: PMC5008352 DOI: 10.18632/oncotarget.8063] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/23/2016] [Indexed: 02/06/2023] Open
Abstract
The overall biological role and clinical significance of long non-coding RNA H19 in colorectal cancer (CRC) remain largely unknown. Here, we firstly report that the lncRNA H19 recruits eIF4A3 and promotes the CRC cell proliferation. We observed higher expression of H19 was significantly correlated with tumor differentiation and advanced TNM stage in a cohort of 83 CRC patients. Multivariate analyses revealed that expression of H19 served as an independent predictor for overall survival and disease-free survival. Further experiments revealed that overexpression of H19 promoted the proliferation of CRC cells, while depletion of H19 inhibited cell viability and induced growth arrest. Moreover, expression profile data showed that H19 upregulated a series of cell-cycle genes. Using bioinformatics prediction and RNA immunoprecipitation assays, we identified eIF4A3 as an RNA-binding protein that binds to H19. We confirmed that combining eIF4A3 with H19 obstructed the recruitment of eIF4A3 to the cell-cycle gene mRNA. Our results suggest that H19, as a growth regulator, could serve as a candidate prognostic biomarker and target for new therapies in human CRC.
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Affiliation(s)
- Dong Han
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Meng Wang
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yu Qiao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Ya Xu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Jing Yang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Nazhen Dong
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Jun He
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Qian Sun
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Guixiang Lv
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Changqing Xu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Ji Tao
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Ning Ma
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
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Jacob R, Zander S, Gutschner T. The Dark Side of the Epitranscriptome: Chemical Modifications in Long Non-Coding RNAs. Int J Mol Sci 2017; 18:ijms18112387. [PMID: 29125541 PMCID: PMC5713356 DOI: 10.3390/ijms18112387] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 11/05/2017] [Accepted: 11/06/2017] [Indexed: 12/20/2022] Open
Abstract
The broad application of next-generation sequencing technologies in conjunction with improved bioinformatics has helped to illuminate the complexity of the transcriptome, both in terms of quantity and variety. In humans, 70–90% of the genome is transcribed, but only ~2% carries the blueprint for proteins. Hence, there is a huge class of non-translated transcripts, called long non-coding RNAs (lncRNAs), which have received much attention in the past decade. Several studies have shown that lncRNAs are involved in a plethora of cellular signaling pathways and actively regulate gene expression via a broad selection of molecular mechanisms. Only recently, sequencing-based, transcriptome-wide studies have characterized different types of post-transcriptional chemical modifications of RNAs. These modifications have been shown to affect the fate of RNA and further expand the variety of the transcriptome. However, our understanding of their biological function, especially in the context of lncRNAs, is still in its infancy. In this review, we will focus on three epitranscriptomic marks, namely pseudouridine (Ψ), N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We will introduce writers, readers, and erasers of these modifications, and we will present methods for their detection. Finally, we will provide insights into the distribution and function of these chemical modifications in selected, cancer-related lncRNAs.
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Affiliation(s)
- Roland Jacob
- Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
| | - Sindy Zander
- Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
| | - Tony Gutschner
- Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
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Imai-Sumida M, Chiyomaru T, Majid S, Saini S, Nip H, Dahiya R, Tanaka Y, Yamamura S. Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways. Oncotarget 2017; 8:92032-92042. [PMID: 29190895 PMCID: PMC5696161 DOI: 10.18632/oncotarget.20734] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 08/07/2017] [Indexed: 01/17/2023] Open
Abstract
Silibinin is the major active constituent of silymarin, an extract of milk thistle seeds. Silibinin has been shown to have significant anti-cancer effects in a variety of malignancies. However, the molecular mechanisms of silibinin action in bladder cancer have not been studied extensively. In the present study, we found that silibinin (10 μM) significantly suppressed proliferation, migration, invasion and induced apoptosis of T24 and UM-UC-3 human bladder cancer cells. Silibinin down-regulated the actin cytoskeleton and phosphatidylinositide 3-kinase (PI3K)/Akt signaling pathways in these cancer cell lines. These pathways were found to crosstalk through RAS cascades. We found that silibinin suppressed levels of trimethylated histone H3 lysine 4 and acetylated H3 at the KRAS promoter. Furthermore, silibinin targets long non-coding RNA: HOTAIR and ZFAS1, which are known to play roles as oncogenic factors in various cancers. This study shows that silibinin exerts anti-cancer effects through down-regulation of actin cytoskeleton and PI3K/Akt pathways and thus suppresses bladder cancer growth and progression.
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Affiliation(s)
- Mitsuho Imai-Sumida
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
| | - Takeshi Chiyomaru
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
- Current address: Department of Urology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan
| | - Shahana Majid
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
| | - Sharanjot Saini
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
| | - Hannah Nip
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
| | - Rajvir Dahiya
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
| | - Yuichiro Tanaka
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
| | - Soichiro Yamamura
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA, USA
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Kong D, Wang Y. Knockdown of lncRNA HULC inhibits proliferation, migration, invasion, and promotes apoptosis by sponging miR-122 in osteosarcoma. J Cell Biochem 2017; 119:1050-1061. [PMID: 28688193 DOI: 10.1002/jcb.26273] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 07/07/2017] [Indexed: 02/06/2023]
Abstract
Osteosarcoma is a rare malignant bone tumor with high degree of malignancy. HULC (highly upregulated in liver cancer), a long noncoding RNA (lncRNA) was involved in hepatocellular carcinoma development and progression, but its underlying mechanism in osteosarcoma is unknown. The aim of this study was to explore the functional role of HULC in osteosarcoma. The study was conducted in human osteosarcoma cell lines and the expression of HULC in the cell lines was detected by qRT-PCR. Furthermore, the effects of HULC on tumorigenicity of osteosarcoma cells were evaluated by in vitro assays. Results revealed that HULC was highly expressed in osteosarcoma MG63 and OS-732 cells compared to osteoblast hFOB1.19 cells. Suppression of HULC in osteosarcoma cells inhibited cell viability, migration, invasion, and promoted apoptosis. HULC functioned as an endogenous sponge for miR-122, and its silence functioned through upregulating miR-122. HNF4G was a target of miR-122, and the effect of HNF4G on OS-732 cells was the same as HULC. Furthermore, overexpression of miR-122 inactivated PI3K/AKT, JAK/STAT, and Notch pathways by downregulation of HNF4G. These findings suggest that knockdown of HULC inhibited proliferation, migration, and invasion by sponging miR-122 in osteosarcoma cells. HULC may act as a novel therapeutic target for management of osteosarcoma.
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Affiliation(s)
- Daliang Kong
- Department of Orthopaedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Wang
- Department of Orthopaedics, China-Japan Union Hospital of Jilin University, Changchun, China
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Wu D, Zhao B, Cao X, Wan J. Long non-coding RNA LINK-A promotes glioma cell growth and invasion via lactate dehydrogenase A. Oncol Rep 2017; 38:1525-1532. [DOI: 10.3892/or.2017.5806] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 06/06/2017] [Indexed: 11/06/2022] Open
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Li J, Wang J, Zhong Y, Guo R, Chu D, Qiu H, Yuan Z. HOTAIR: a key regulator in gynecologic cancers. Cancer Cell Int 2017; 17:65. [PMID: 28649178 PMCID: PMC5480152 DOI: 10.1186/s12935-017-0434-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 05/27/2017] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) play critical roles in the initiation and progression of human cancers. HOX transcript antisense RNA (HOTAIR) is an lncRNA localized to the mammalian HOXC gene cluster; it can interact with polycomb repressive complex 2 and the lysine-specific histone demethylase/CoREST/REST complex, and it manipulates the expression of various genes. HOTAIR promotes tumor invasion and metastasis by silencing tumor suppressors, and activating oncogenes and signaling pathways. HOTAIR is deregulated in many human cancers; despite its critical roles in health and disease, the underlying mechanisms governing HOTAIR function are unknown. In this review, we summarize the recent findings on the roles of HOTAIR in gynecologic cancers.
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Affiliation(s)
- Jing Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Jing Wang
- Department of Obstetrics and Gynecology, Yantai Yuhuangding Hospital Affiliated to the Medical College of Qingdao University, Yantai, 264000 China
| | - Yan Zhong
- Department of Gynecological Oncology, Linyi Tumor Hospital, Linyi, 276001 China
| | - Ruixia Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Danxia Chu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Haifeng Qiu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Zhongfu Yuan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
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Rotini A, Martínez-Sarrà E, Pozzo E, Sampaolesi M. Interactions between microRNAs and long non-coding RNAs in cardiac development and repair. Pharmacol Res 2017. [PMID: 28629929 DOI: 10.1016/j.phrs.2017.05.029] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Non-coding RNAs (ncRNAs) are emerging players in muscle regulation. Based on their length and differences in molecular structure, ncRNAs are subdivided into several categories including small interfering RNAs, stable non-coding RNAs, microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs. miRs and lncRNAs are able to post-transcriptionally regulate many genes and bring into play several traits simultaneously due to a myriad of different targets. Recent studies have emphasized their importance in cardiac regeneration and repair. As their altered expression affects cardiac function, miRs and lncRNAs could be potential targets for therapeutic intervention. In this context, miR- and lncRNA-based gene therapies are an interesting field for harnessing the complexity of ncRNA-based therapeutic approaches in cardiac diseases. In this review we will focus on lncRNA- and miR-driven regulations of cardiac development and repair. Finally, we will summarize miRs and lncRNAs as promising candidates for the treatment of heart diseases.
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Affiliation(s)
- Alessio Rotini
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium; Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy; Interuniversity Institute of Myology, Italy
| | - Ester Martínez-Sarrà
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium; Regenerative Medicine Research Institute, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Enrico Pozzo
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium
| | - Maurilio Sampaolesi
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium; Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Via Forlanini 8, 27100 Pavia, Italy.
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Richtig G, Ehall B, Richtig E, Aigelsreiter A, Gutschner T, Pichler M. Function and Clinical Implications of Long Non-Coding RNAs in Melanoma. Int J Mol Sci 2017; 18:E715. [PMID: 28350340 PMCID: PMC5412301 DOI: 10.3390/ijms18040715] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 03/16/2017] [Accepted: 03/17/2017] [Indexed: 02/06/2023] Open
Abstract
Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein coding RNAs involved in (epigenetic) regulation of cell growth, invasion, and other important cellular functions. Consequently, recent research activities focused on the discovery of these lncRNAs in a broad spectrum of human diseases, especially cancer. Additional efforts have been undertaken to dissect the underlying molecular mechanisms employed by lncRNAs. In this review, we will summarize the growing evidence of deregulated lncRNA expression in melanoma, which is linked to tumor growth and progression. Moreover, we will highlight specific molecular pathways and modes of action for some well-studied lncRNAs and discuss their potential clinical implications.
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Affiliation(s)
- Georg Richtig
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz 8010, Austria.
- Department of Dermatology, Medical University of Graz, Graz 8036, Austria.
| | - Barbara Ehall
- Institute for Pathology, Medical University of Graz, Graz 8036, Austria.
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz 8036, Austria.
| | - Erika Richtig
- Department of Dermatology, Medical University of Graz, Graz 8036, Austria.
| | | | - Tony Gutschner
- Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06120, Germany.
| | - Martin Pichler
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz 8036, Austria.
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Han Y, Zhou L, Wu T, Huang Y, Cheng Z, Li X, Sun T, Zhou Y, Du Z. Downregulation of lncRNA-MALAT1 Affects Proliferation and the Expression of Stemness Markers in Glioma Stem Cell Line SHG139S. Cell Mol Neurobiol 2016; 36:1097-107. [PMID: 26649728 PMCID: PMC11482515 DOI: 10.1007/s10571-015-0303-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 11/07/2015] [Indexed: 10/22/2022]
Abstract
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is among the most abundant and highly conserved lncRNAs, which has been detected in a wide variety of human tumors, including gastric cancer, gallbladder cancer, and so on. Previous research has showed that MALAT1 can activate LTBP3 gene in mesenchymal stem cells. However, the specific roles of MALAT1 in glioma stem cells (GSCs) remain unclear. In this study, we aimed to identify the effects of MALAT1 on proliferation and the expression of stemness markers on glioma stem cell line SHG139S. Our results showed that downregulation of MALAT1 suppressed the expression of Sox2 and Nestin which are related to stemness, while downregulation of MALAT1 promoted the proliferation in SHG139S. Further research on the underlying mechanism showed that the effects of MALAT1 downregulation on SHG139S were through regulating ERK/MAPk signaling activity. And we also found that downregulation of MALAT1 could activate ERK/MAPK signaling and promoted proliferation in SHG139 cells. These findings show that MALAT1 plays an important role in regulating the expression of stemness markers and proliferation of SHG139S, and provide a new research direction to target the progression of GSCs.
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Affiliation(s)
- Yong Han
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
| | - Liang Zhou
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
| | - Tingfeng Wu
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
| | - Yulun Huang
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
| | - Zhe Cheng
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
| | - Xuetao Li
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
| | - Ting Sun
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
| | - Youxin Zhou
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China.
| | - Ziwei Du
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, People's Republic of China
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Cao D, Ding Q, Yu W, Gao M, Wang Y. Long noncoding RNA SPRY4-IT1 promotes malignant development of colorectal cancer by targeting epithelial-mesenchymal transition. Onco Targets Ther 2016; 9:5417-25. [PMID: 27621655 PMCID: PMC5012848 DOI: 10.2147/ott.s111794] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The clinical significance and biological functions of long noncoding RNA SPRY4 intronic transcript 1 (SPRY4-IT1) in colorectal cancer (CRC) remain largely unclear. Herein, we are the first to report that the SPRY4-IT1 was significantly upregulated in CRC tissues, serum, and cells. Higher SPRY4-IT1 expression was markedly associated with advanced Tumor Node Metastasis (TNM) stage in a cohort of 84 CRC patients. Multivariate analyses indicated that SPRY4-IT1 expression could be useful as an independent predictor for overall survival. Further in vitro experiments revealed that knockdown of SPRY4-IT1 inhibited the proliferation, migration, and invasion of CRC cells and induced cell cycle arrestment. Moreover, we confirmed that the expression of epithelial–mesenchymal transition-related genes was modulated through alteration of SPRY4-IT1 expression. These results suggest that SPRY4-IT1, as an oncogenic regulator, may serve as a candidate prognostic marker and potential target for CRC therapies.
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Affiliation(s)
- Dong Cao
- Department of General Surgery, The People's Hospital of Putuo, Zhoushan
| | - Qiong Ding
- Department of General Surgery, The People's Hospital of Putuo, Zhoushan
| | - Wubin Yu
- Department of General Surgery, The People's Hospital of Putuo, Zhoushan
| | - Ming Gao
- Department of General Surgery, The People's Hospital of Putuo, Zhoushan
| | - Yilian Wang
- Department of Cardiology, The Second People's Hospital of Lianyungang, Xinpu, People's Republic of China
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