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La Rosa M, Fiannaca A, Mendolia I, La Paglia L, Urso A. GL4SDA: Predicting snoRNA-disease associations using GNNs and LLM embeddings. Comput Struct Biotechnol J 2025; 27:1023-1033. [PMID: 40160859 PMCID: PMC11952811 DOI: 10.1016/j.csbj.2025.03.014] [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: 12/23/2024] [Revised: 03/04/2025] [Accepted: 03/08/2025] [Indexed: 04/02/2025] Open
Abstract
Small nucleolar RNAs (snoRNAs) play essential roles in various cellular processes, and their associations with diseases are increasingly recognized. Identifying these snoRNA-disease relationships is critical for advancing our understanding of their functional roles and potential therapeutic implications. This work presents a novel approach, called GL4SDA, to predict snoRNA-disease associations using Graph Neural Networks (GNN) and Large Language Models. Our methodology leverages the unique strengths of heterogeneous graph structures to model complex biological interactions. Differently from existing methods, we define a set of features able to capture deeper information content related to the inner attributes of both snoRNAs and diseases and design a GNN model based on highly performing layers, which can maximize results on this representation. We consider snoRNA secondary structures and disease embeddings derived from large language models to obtain snoRNAs and disease node features, respectively. By combining structural features of snoRNAs with rich semantic embeddings of diseases, we construct a feature-rich graph representation that improves the predictive performance of our model. We evaluate our approach using different architectures that exploit the capabilities of many graph convolutional layers and compare the results with three other state-of-the-art graph-based predictors. GL4SDA demonstrates improved scores in link prediction tasks and demonstrates its potential implication as a tool for exploring snoRNA-disease relationships. We also validate our findings through biological case studies about cancer diseases, highlighting the practical application of our method in real-world scenarios and obtaining the most important snoRNA features using explainable artificial intelligence methods.
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Affiliation(s)
| | | | - Isabella Mendolia
- CNR-ICAR, National Research Council of Italy, via Ugo La Malfa 153, Palermo, 90146, Italy
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Khoshandam M, Sideris N, Ahmadieh-Yazdi A, Sheykhhasan M, Manoochehri H, Tanzadehpanah H, Mahaki H, Ghadam M, Lak S, Kalhor N, Rabiei M, Al-Musawi S, Dama P. The functional role of LncRNA HOXA-AS2 in multiple human cancers. Pathol Res Pract 2025; 266:155795. [PMID: 39756105 DOI: 10.1016/j.prp.2024.155795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 01/07/2025]
Abstract
Humans have more than 270,000 lncRNAs. Among these, lncRNA HOXA-AS2 is considered a transformative gene involved in various cellular processes, including cell proliferation, apoptosis, migration, and invasion. Thus, it can be regarded as a potential tumor marker for both diagnosis and prognosis. Aberrant expression of lncRNAs is associated with many cancers, including hepatocellular carcinoma (HCC), gallbladder carcinoma (GBC), acute promyelocytic leukemia (APL), lung cancer (LC), prostate cancer (PC), osteosarcoma (OS), colorectal cancer (CRC), cervical cancer (CC), and acute myeloid leukemia (AML). Targeting lncRNAs could be a promising strategy to complement or replace current cancer treatments. As a non-coding oncogene, lncRNA HOXA-AS2 is implicated in multiple cancers and could serve as a potential biomarker for various malignancies. The tumor size and disease stage of several cancers are correlated with HOXA-AS2 expression. Silencing HOXA-AS2 effectively suppresses tumor cell proliferation and promotes apoptosis, thereby inhibiting the progression of multiple cancer types. The regulatory mechanisms of HOXA-AS2 include inducing epithelial-mesenchymal transition (EMT), overexpressing B-cell lymphoma-2 (Bcl-2) and MYC proto-oncogene (c-Myc), gene silencing, activating AKT-MMP signaling pathways, EZH2 and LSD1, and functioning within a competing endogenous RNA (ceRNA) regulatory network by competitively binding miRNAs. This review surveys recent research on the structure, biological functions, abnormal expression, regulatory mechanisms, and diagnostic and therapeutic potential of HOXA-AS2 in various cancers.
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Affiliation(s)
- Mohadeseh Khoshandam
- Department of Reproductive Biology, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran
| | - Nikolaos Sideris
- Research Fellow School of Life Sciences, University of Sussex, Brighton, UK.
| | - Amirhossein Ahmadieh-Yazdi
- Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanie Mahaki
- Vascular & Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Ghadam
- National Institute of genetic engineering and biotechnology (NIGEB), Tehran, Iran
| | - Shermin Lak
- National Institute of genetic engineering and biotechnology (NIGEB), Tehran, Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran
| | | | | | - Paola Dama
- Research Fellow School of Life Sciences, University of Sussex, Brighton, UK.
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Ozdemir S, Zadegan SB, Sultana MS, Coffey N, Rice JH, Hewezi T. Regulation and Functions of Long Noncoding RNAs During Meloidogyne incognita Parasitism of Tomato. MOLECULAR PLANT-MICROBE INTERACTIONS : MPMI 2025; 38:72-83. [PMID: 39561195 DOI: 10.1094/mpmi-10-24-0140-r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
Long noncoding RNAs (lncRNAs) are emerging as important regulators of various aspects of immune response and plant-pathogen interactions. However, the regulatory function of lncRNAs during plant-nematode interaction remains largely elusive. In this study, we investigated the differential regulation and function of lncRNAs during two different stages of tomato infection by the root-knot nematode Meloidogyne incognita. At the early stage of infection, 2,218 and 2,827 lncRNAs were regulated locally in the M. incognita-induced galls and systemically in the neighboring root cells, respectively. However, at the later stage of infection, the number of M. incognita-regulated lncRNAs was dramatically reduced, with only 49 lncRNAs being identified as differentially expressed. Differentially expressed lncRNAs were predicted to encode peptides with functionally annotated domains, providing insights into the potential roles of these peptides in regulating gene expression, RNA stability and splicing, and protein-protein-interactions. Among the differentially expressed lncRNAs, 55 were found to contain putative binding sites for 56 microRNAs (miRNAs). Overexpressing five of these lncRNAs significantly increased tomato resistance to M. incognita, supporting the functional importance of lncRNAs for establishing tomato-M. incognita interaction. Functional analysis of the target mimicry of lncRNAs towards miRNAs resulted in the identification of two novel regulatory modules involving miR47 and miR156e-5p and their targeted genes that regulate tomato responses to M. incognita parasitism. Taken together, our data provide novel insights into the transcriptional and posttranscriptional regulatory functions of lncRNA and open a new avenue to engineer crop plants with enhanced nematode resistance by leveraging the regulatory potential of lncRNAs. [Formula: see text] Copyright © 2025 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
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Affiliation(s)
- Selin Ozdemir
- Department of Plant Sciences, University of Tennessee, Knoxville, TN 37996, U.S.A
| | - Sobhan Bahrami Zadegan
- Department of Plant Sciences, University of Tennessee, Knoxville, TN 37996, U.S.A
- UT-ORNL Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996, U.S.A
| | - Mst Shamira Sultana
- Department of Plant Sciences, University of Tennessee, Knoxville, TN 37996, U.S.A
| | - Nicole Coffey
- Department of Plant Sciences, University of Tennessee, Knoxville, TN 37996, U.S.A
| | - J Hollis Rice
- Department of Plant Sciences, University of Tennessee, Knoxville, TN 37996, U.S.A
| | - Tarek Hewezi
- Department of Plant Sciences, University of Tennessee, Knoxville, TN 37996, U.S.A
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Guha P, Chini A, Rishi A, Mandal SS. Long noncoding RNAs in ubiquitination, protein degradation, and human diseases. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2024; 1867:195061. [PMID: 39341591 DOI: 10.1016/j.bbagrm.2024.195061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/07/2024] [Accepted: 09/19/2024] [Indexed: 10/01/2024]
Abstract
Protein stability and turnover is critical in normal cellular and physiological process and their misregulation may contribute to accumulation of unwanted proteins causing cellular malfunction, neurodegeneration, mitochondrial malfunction, and disrupted metabolism. Signaling mechanism associated with protein degradation is complex and is extensively studied. Many protein and enzyme machineries have been implicated in regulation of protein degradation. Despite these insights, our understanding of protein degradation mechanisms remains limited. Emerging studies suggest that long non-coding RNAs (lncRNAs) play critical roles in various cellular and physiological processes including metabolism, cellular homeostasis, and protein turnover. LncRNAs, being large nucleic acids (>200 nt long) can interact with various proteins and other nucleic acids and modulate protein structure and function leading to regulation of cell signaling processes. LncRNAs are widely distributed across cell types and may exhibit tissue specific expression. They are detected in body fluids including blood and urine. Their expressions are also altered in various human diseases including cancer, neurological disorders, immune disorder, and others. LncRNAs are being recognized as novel biomarkers and therapeutic targets. This review article focuses on the emerging role of noncoding RNAs (ncRNAs), particularly long noncoding RNAs (lncRNAs), in the regulation of protein polyubiquitination and proteasomal degradation.
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Affiliation(s)
- Prarthana Guha
- Gene Regulation and Epigenetics Research Laboratory, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States of America
| | - Avisankar Chini
- Gene Regulation and Epigenetics Research Laboratory, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States of America
| | - Ashcharya Rishi
- Gene Regulation and Epigenetics Research Laboratory, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States of America
| | - Subhrangsu S Mandal
- Gene Regulation and Epigenetics Research Laboratory, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States of America.
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Mishra A, Mishra S. Metastasis-Associated Lung Adenocarcinoma Transcript 1 ( MALAT1) lncRNA Conformational Dynamics in Complex with RNA-Binding Protein with Serine-Rich Domain 1 (RNPS1) in the Pan-cancer Splicing and Gene Expression. ACS OMEGA 2024; 9:42212-42226. [PMID: 39431102 PMCID: PMC11483381 DOI: 10.1021/acsomega.4c04467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 09/11/2024] [Accepted: 09/16/2024] [Indexed: 10/22/2024]
Abstract
Alternative splicing events increase the transcriptomic and proteomic complexity in cancers. Overexpression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a highly conserved lncRNA, is widely known to promote cancer development, one mechanism for which may be through the regulation of alternative splicing and, thereby, gene expression. Its regulatory interactions with proteins have been a subject of much interest, yet little research has been carried out on the mechanisms adopted. It has been observed that MALAT1 binds to RNA-binding protein with serine-rich domain 1 (RNPS1), being colocalized in the nuclear speckles, and together, these two binding partners may regulate alternative splicing. Upregulated RNPS1 is predicted to play a key role in the pan-cancer development. Experimental tertiary structure of full-length MALAT1 is currently lacking despite the availability of the 3D structure of 3' expression and nuclear retention element. We hypothesize that the computationally modeled tertiary structures of the specific binding motifs in the M-region, E-region, and full-length structures of MALAT1 may adopt a modular structure and bind to the RNPS1 loop region of RS/P domain involved in exon skipping, interacting in a manner fully consistent with the biochemical experiments. Extensive observations using the powerful molecular dynamics (MD) simulations of MALAT1 regions bound to RNPS1 suggested that all three regions form interactive, yet stable complexes. The ranking of the MM-GBSA- and MM-PBSA-derived binding free energies between these complexes corroborated well in the MD simulations and experiments. Energy decomposition analyses suggested that arginines in the RNPS1 protein are among the major contributors toward the binding free energies as calculated by MM-GBSA present in the Amber package; while among the nucleotides, the major contributors were nucleotides with G and A nucleobases, with more contributory effect in comparison to arginines, across the bound M-region, E-region, and full-length MALAT1. This suggests that specific purines play a greater role in the complex formation, in a loop-specific manner, and the more proactive approach in complexation tilts toward MALAT1. To the best of our knowledge, our studies are the first studies taking a unique approach, utilizing the binding motifs to deduce a tertiary structure of MALAT1, toward our understanding of the lncRNA-protein interactions, stability, and binding on a structural basis. The therapeutic implications of targeting this complex formation to regulate splicing and hence, oncogenesis, is further envisaged.
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Affiliation(s)
- Aanchal Mishra
- Department of Biochemistry, School
of Life Sciences, University of Hyderabad-500046 Hyderabad, India
| | - Seema Mishra
- Department of Biochemistry, School
of Life Sciences, University of Hyderabad-500046 Hyderabad, India
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Hu SL, Chen YL, Zhang LQ, Bai H, Yang JH, Li QZ. LncSTPred: a predictive model of lncRNA subcellular localization and decipherment of the biological determinants influencing localization. Front Mol Biosci 2024; 11:1452142. [PMID: 39301172 PMCID: PMC11411566 DOI: 10.3389/fmolb.2024.1452142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/19/2024] [Indexed: 09/22/2024] Open
Abstract
Introduction Long non-coding RNAs (lncRNAs) play crucial roles in genetic markers, genome rearrangement, chromatin modifications, and other biological processes. Increasing evidence suggests that lncRNA functions are closely related to their subcellular localization. However, the distribution of lncRNAs in different subcellular localizations is imbalanced. The number of lncRNAs located in the nucleus is more than ten times that in the exosome. Methods In this study, we propose a new oversampling method to construct a predictive dataset and develop a predictive model called LncSTPred. This model improves the Adaboost algorithm for subcellular localization prediction using 3-mer, 3-RF sequence, and minimum free energy structure features. Results and Discussion By using our improved Adaboost algorithm, better prediction accuracy for lncRNA subcellular localization was obtained. In addition, we evaluated feature importance by using the F-score and analyzed the influence of highly relevant features on lncRNAs. Our study shows that the ANA features may be a key factor for predicting lncRNA subcellular localization, which correlates with the composition of stems and loops in the secondary structure of lncRNAs.
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Affiliation(s)
- Si-Le Hu
- School of Physical Science and Technology, Inner Mongolia University, Hohhot, China
| | - Ying-Li Chen
- School of Physical Science and Technology, Inner Mongolia University, Hohhot, China
| | - Lu-Qiang Zhang
- School of Physical Science and Technology, Inner Mongolia University, Hohhot, China
| | - Hui Bai
- School of Physical Science and Technology, Inner Mongolia University, Hohhot, China
| | - Jia-Hong Yang
- School of Physical Science and Technology, Inner Mongolia University, Hohhot, China
| | - Qian-Zhong Li
- School of Physical Science and Technology, Inner Mongolia University, Hohhot, China
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, China
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Wei J, Li H, Huang X, Zhao Y, Ouyang L, Wei M, Wang C, Wang J, Lu G. Elucidating the regulatory role of long non-coding RNAs in drought stress response during seed germination in leaf mustard. PeerJ 2024; 12:e17661. [PMID: 38978758 PMCID: PMC11229683 DOI: 10.7717/peerj.17661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/08/2024] [Indexed: 07/10/2024] Open
Abstract
Leaf mustard (Brassica juncea L. Czern & Coss), an important vegetable crop, experiences pronounced adversity due to seasonal drought stress, particularly at the seed germination stage. Although there is partial comprehension of drought-responsive genes, the role of long non-coding RNAs (lncRNAs) in adjusting mustard's drought stress response is largely unexplored. In this study, we showed that the drought-tolerant cultivar 'Weiliang' manifested a markedly lower base water potential (-1.073 MPa vs -0.437 MPa) and higher germination percentage (41.2% vs 0%) than the drought-susceptible cultivar 'Shuidong' under drought conditions. High throughput RNA sequencing techniques revealed a significant repertoire of lncRNAs from both cultivars during germination under drought stress, resulting in the identification of 2,087 differentially expressed lncRNAs (DELs) and their correspondingly linked 12,433 target genes. It was noted that 84 genes targeted by DEL exhibited enrichment in the photosynthesis pathway. Gene network construction showed that MSTRG.150397, a regulatory lncRNA, was inferred to potentially modulate key photosynthetic genes (Psb27, PetC, PetH, and PsbW), whilst MSTRG.107159 was indicated as an inhibitory regulator of six drought-responsive PIP genes. Further, weighted gene co-expression network analysis (WGCNA) corroborated the involvement of light intensity and stress response genes targeted by the identified DELs. The precision and regulatory impact of lncRNA were verified through qPCR. This study extends our knowledge of the regulatory mechanisms governing drought stress responses in mustard, which will help strategies to augment drought tolerance in this crop.
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Affiliation(s)
- Jinxing Wei
- Guangdong University of Petrochemical Technology, Maoming, China
| | - Haibo Li
- Shaoguan University, Shaoguan, China
| | - Xiaoer Huang
- Guangdong University of Petrochemical Technology, Maoming, China
| | - Yongguo Zhao
- Guangdong University of Petrochemical Technology, Maoming, China
| | - Lejun Ouyang
- Guangdong University of Petrochemical Technology, Maoming, China
| | - Mingken Wei
- Guangdong University of Petrochemical Technology, Maoming, China
| | - Chun Wang
- Guangdong University of Petrochemical Technology, Maoming, China
| | - Junxia Wang
- South China Agricultural University, Guangzhou, China
| | - Guangyuan Lu
- Guangdong University of Petrochemical Technology, Maoming, China
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Singh RR, Mondal I, Janjua T, Popat A, Kulshreshtha R. Engineered smart materials for RNA based molecular therapy to treat Glioblastoma. Bioact Mater 2024; 33:396-423. [PMID: 38059120 PMCID: PMC10696434 DOI: 10.1016/j.bioactmat.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 10/19/2023] [Accepted: 11/14/2023] [Indexed: 12/08/2023] Open
Abstract
Glioblastoma (GBM) is an aggressive malignancy of the central nervous system (CNS) that remains incurable despite the multitude of improvements in cancer therapeutics. The conventional chemo and radiotherapy post-surgery have only been able to improve the prognosis slightly; however, the development of resistance and/or tumor recurrence is almost inevitable. There is a pressing need for adjuvant molecular therapies that can successfully and efficiently block tumor progression. During the last few decades, non-coding RNAs (ncRNAs) have emerged as key players in regulating various hallmarks of cancer including that of GBM. The levels of many ncRNAs are dysregulated in cancer, and ectopic modulation of their levels by delivering antagonists or overexpression constructs could serve as an attractive option for cancer therapy. The therapeutic potential of several types of ncRNAs, including miRNAs, lncRNAs, and circRNAs, has been validated in both in vitro and in vivo models of GBM. However, the delivery of these RNA-based therapeutics is highly challenging, especially to the tumors of the brain as the blood-brain barrier (BBB) poses as a major obstacle, among others. Also, since RNA is extremely fragile in nature, careful considerations must be met while designing a delivery agent. In this review we have shed light on how ncRNA therapy can overcome the limitations of its predecessor conventional therapy with an emphasis on smart nanomaterials that can aide in the safe and targeted delivery of nucleic acids to treat GBM. Additionally, critical gaps that currently exist for successful transition from viral to non-viral vector delivery systems have been identified. Finally, we have provided a perspective on the future directions, potential pathways, and target areas for achieving rapid clinical translation of, RNA-based macromolecular therapy to advance the effective treatment of GBM and other related diseases.
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Affiliation(s)
- Ravi Raj Singh
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- University of Queensland –IIT Delhi Academy of Research (UQIDAR)
| | - Indranil Mondal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
| | - Taskeen Janjua
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- Department of Functional Materials and Catalysis, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
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Oh JH, Kim CY, Jeong DS, Kim YC, Kim MH, Cho JY. The homeoprotein HOXB2 limits triple-negative breast carcinogenesis via extracellular matrix remodeling. Int J Biol Sci 2024; 20:1045-1063. [PMID: 38322121 PMCID: PMC10845296 DOI: 10.7150/ijbs.88837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 12/31/2023] [Indexed: 02/08/2024] Open
Abstract
Homeobox genes and their encoded DNA-binding homeoproteins are master regulators of development. Consequently, these homeotic elements may regulate key steps in cancer pathogenesis. Here, using a combination of in silico analyses of large-scale patient datasets, in vitro RNAi phenotyping, and in vivo validation studies, we investigated the role of HOXB2 in different molecular subtypes of human breast cancer (BC). The gene expression signatures of HOXB2 are different across distinct BC subtypes due to various genetic alterations, but HOXB2 was specifically downregulated in the aggressive triple-negative subtype (TNBC). We found that the reduced expression of HOXB2 was correlated with the metastatic abilities (epithelial-to-mesenchymal transition) of TNBC cells. Further, we revealed that HOXB2 restrained TNBC aggressiveness by ECM organization. HOXB2 bound to the promoter regions of MATN3 and ECM2 and regulated their transcription levels. Forced expression of HOXB2 effectively prevented TNBC progression and metastasis in a mouse xenograft model. Reduction of HOXB2 and the HOXB2/MATN3/ECM2 transcriptional axis correlated with poor survival in patients with various cancers. Further, we found the long non-coding RNA HOXB-AS1 in complex with SMYD3, a lysine methyltransferase, as an epigenetic switch controlling HOXB2 expression. Overall, our results indicate a tumor-suppressive role of HOXB2 by maintaining ECM organization and delineate potential clinical utility of HOXB2 as a marker for TNBC patients.
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Affiliation(s)
- Ji Hoon Oh
- Department of Biological Sciences, Keimyung University College of Natural Sciences, Daegu, Republic of Korea
| | - Clara Yuri Kim
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da Som Jeong
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Anatomy, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu Cheon Kim
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Anatomy, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Myoung Hee Kim
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Anatomy, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Je-Yoel Cho
- Department of Biochemistry, Brain Korea 21 Project and Research Institute for Veterinary Science, Seoul National University College of Veterinary Medicine, Seoul, Republic of Korea
- Comparative Medicine Disease Research Center, Seoul National University, Seoul, Republic of Korea
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Huang W, Paul D, Calin GA, Bayraktar R. miR-142: A Master Regulator in Hematological Malignancies and Therapeutic Opportunities. Cells 2023; 13:84. [PMID: 38201290 PMCID: PMC10778542 DOI: 10.3390/cells13010084] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/29/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive exploration of the genetic and molecular landscape of the miR-142 genomic locus, highlighting its mutations and dysregulation within hematological malignancies. Finally, we discuss potential avenues for harnessing the therapeutic potential of miR-142 in the context of hematological malignancies.
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Affiliation(s)
- Wilson Huang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (W.H.); (G.A.C.)
| | - Doru Paul
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (W.H.); (G.A.C.)
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Recep Bayraktar
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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11
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Ma Y, Zhao T, Wu X, Yang Z, Sun Y. Identification cloning and functional analysis of novel natural antisense lncRNA CFL1-AS1 in cattle. Epigenetics 2023; 18:2231707. [PMID: 37406176 DOI: 10.1080/15592294.2023.2231707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/14/2023] [Accepted: 06/26/2023] [Indexed: 07/07/2023] Open
Abstract
Long noncoding RNAs have been identified as important regulators of gene expression and animal development. The expression of natural antisense transcripts (NATs) transcribed in the opposite direction to protein-coding genes is usually positively correlated with the expression of homologous sense genes and is the key factor for expression. Here, we identified a conserved noncoding antisense transcript, CFL1-AS1, that plays an important role in muscle growth and development. CFL1-AS1 overexpression and knockout vectors were constructed and transfected into 293T and C2C12 cells. CFL1-AS1 positively regulated CFL1 gene expression, and the expression of CFL2 was also downregulated when CFL1-AS1 was knocked down. CFL1-AS1 promoted cell proliferation, inhibited apoptosis and participated in autophagy. This study expands the research on NATs in cattle and lays a foundation for the study of the biological function of bovine CFL1 and its natural antisense chain transcript CFL1-AS1 in bovine skeletal muscle development. The discovery of this NAT can provide a reference for subsequent genetic breeding and data on the characteristics and functional mechanisms of NATs.
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Affiliation(s)
- Yaoyao Ma
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Tianqi Zhao
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xinyi Wu
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Zhangping Yang
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Yujia Sun
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
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12
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Barbagallo C, Stella M, Ferrara C, Caponnetto A, Battaglia R, Barbagallo D, Di Pietro C, Ragusa M. RNA-RNA competitive interactions: a molecular civil war ruling cell physiology and diseases. EXPLORATION OF MEDICINE 2023:504-540. [DOI: 10.37349/emed.2023.00159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/02/2023] [Indexed: 09/02/2023] Open
Abstract
The idea that proteins are the main determining factors in the functioning of cells and organisms, and their dysfunctions are the first cause of pathologies, has been predominant in biology and biomedicine until recently. This protein-centered view was too simplistic and failed to explain the physiological and pathological complexity of the cell. About 80% of the human genome is dynamically and pervasively transcribed, mostly as non-protein-coding RNAs (ncRNAs), which competitively interact with each other and with coding RNAs generating a complex RNA network regulating RNA processing, stability, and translation and, accordingly, fine-tuning the gene expression of the cells. Qualitative and quantitative dysregulations of RNA-RNA interaction networks are strongly involved in the onset and progression of many pathologies, including cancers and degenerative diseases. This review will summarize the RNA species involved in the competitive endogenous RNA network, their mechanisms of action, and involvement in pathological phenotypes. Moreover, it will give an overview of the most advanced experimental and computational methods to dissect and rebuild RNA networks.
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Affiliation(s)
- Cristina Barbagallo
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Michele Stella
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | | | - Angela Caponnetto
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Rosalia Battaglia
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Davide Barbagallo
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Cinzia Di Pietro
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Marco Ragusa
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
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13
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Wang QN, Xiao WQ, Yao Y, Kong XD, Sun Y. Response patterns of lncRNAs of the Spodoptera frugiperda (Lepidoptera: Noctuidae) larvae under 23 pesticide treatments. JOURNAL OF INSECT SCIENCE (ONLINE) 2023; 23:8. [PMID: 37471132 DOI: 10.1093/jisesa/iead059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/13/2023] [Accepted: 07/12/2023] [Indexed: 07/21/2023]
Abstract
The response of Spodoptera frugiperda genes toward insecticides is crucial for guiding insecticide use. The regulation of the S. frugiperda genes via long noncoding RNAs (lncRNAs) under insecticide treatment should be investigated. In this study, 452 differentially expressed lncRNAs were identified by analyzing RNA-sequencing data of S. frugiperda under 23 pesticide treatments. We found 59 and 43 differentially expressed lncRNAs that could regulate detoxification-related cytochrome P450 and UDP-glucuronosyltransferase genes, respectively. Furthermore, the target genes of differentially expressed lncRNAs were enriched in Pfam, including chitin bind 4 and gene ontology terms such as structural constituent of the cuticle, revealing their potential mechanism of action on the growth inhibition of S. frugiperda larvae. Insecticide-specific expression of lncRNAs highlights the properties and commonalities of different insecticide-induced lncRNA regulatory mechanisms. To conclude, the results of this study provide new insights and perspectives on the use of 23 insecticides via lncRNA regulation of mRNAs.
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Affiliation(s)
- Qing-Nan Wang
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu 241000, Anhui, China
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Institute of Plant Protection and Agro-products Safety, Anhui Academy of Agricultural Sciences, Hefei 230031, China
| | - Wen-Qing Xiao
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu 241000, Anhui, China
| | - Yu Yao
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu 241000, Anhui, China
| | - Xiang-Dong Kong
- Institute of Bioinformatics, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Yang Sun
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu 241000, Anhui, China
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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14
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Al-Imam MJ, Hussein UAR, Sead FF, Faqri AMA, Mekkey SM, Khazel AJ, Almashhadani HA. The interactions between DNA methylation machinery and long non-coding RNAs in tumor progression and drug resistance. DNA Repair (Amst) 2023; 128:103526. [PMID: 37406581 DOI: 10.1016/j.dnarep.2023.103526] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/07/2023]
Abstract
DNA methylation is one of the main epigenetic mechanisms in cancer development and progression. Aberrant DNA methylation of CpG islands within promoter regions contributes to the dysregulation of various tumor suppressors and oncogenes; this leads to the appearance of malignant features, including rapid proliferation, metastasis, stemness, and drug resistance. The discovery of two important protein families, DNA methyltransferases (DNMTs) and Ten-eleven translocation (TET) dioxygenases, respectively, which are responsible for deregulated transcription of genes that play pivotal roles in tumorigenesis, led to further understanding of DNA methylation-related pathways. But how these enzymes can target specific genes in different malignancies; recent studies have highlighted the considerable role of Long Non-coding RNAs (LncRNAs). LncRNAs recruit these enzymes to promoter regions of genes and mediate their functions, showing great potential as therapeutic agents targeting the epigenetic regulation of various genes. Considering the importance of combining the current treatment methods, especially chemotherapies, with DNA methylation inhibitors in improving patients' outcomes, this review aimed to summarize the recent findings about the interaction between DNA methylation machinery and LncRNAs in regulating genes involved in tumorigenesis and drug resistance. So, these studies could provide insights toward developing novel strategies for cancer-targeted therapy.
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Affiliation(s)
- Mokhtar Jawad Al-Imam
- Department of Experimental Therapy, Iraqi Center for Cancer and Medical Genetics Research, Almustansiriyah University, Baghdad, Iraq
| | | | | | | | - Shereen M Mekkey
- Pharmacy Department, Al-Mustaqbal University College, 51001 Hilla, Babylon, Iraq
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15
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Wang K, Gong M, Zhao S, Lai C, Zhao L, Cheng S, Xia M, Li Y, Wang K, Sun H, Zhu P, Zhou Y, Ao Q, Deng X. A novel lncRNA DFRV plays a dual function in influenza A virus infection. Front Microbiol 2023; 14:1171423. [PMID: 37303776 PMCID: PMC10248499 DOI: 10.3389/fmicb.2023.1171423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/27/2023] [Indexed: 06/13/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been associated with a variety of biological activities, including immune responses. However, the function of lncRNAs in antiviral innate immune responses are not fully understood. Here, we identified a novel lncRNA, termed dual function regulating influenza virus (DFRV), elevating in a dose- and time-dependent manner during influenza A virus (IAV) infection, which was dependent on the NFκB signaling pathway. Meanwhile, DFRV was spliced into two transcripts post IAV infection, in which DFRV long suppress the viral replication while DFRV short plays the opposite role. Moreover, DFRV regulates IL-1β and TNF-α via activating several pro-inflammatory signaling cascades, including NFκB, STAT3, PI3K, AKT, ERK1/2 and p38. Besides, DFRV short can inhibit DFRV long expression in a dose-dependent manner. Collectively, our studies reveal that DFRV may act as a potential dual-regulator to preserve innate immune homeostasis in IAV infection.
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Affiliation(s)
- Keyu Wang
- Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Meiliang Gong
- Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Sumin Zhao
- The PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Chengcai Lai
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Lingna Zhao
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, School of Medicine and Institute for Immunology, Tsinghua University, Beijing, China
| | - Sijie Cheng
- Center for Disease Prevention and Control, Changde, Hunan, China
| | - Min Xia
- Department of Vascular Cell Biology, Max Plank Institute for Molecular Biomedicine, Münster, Germany
| | - Yuru Li
- Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Kun Wang
- Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Heqiang Sun
- Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Pingjun Zhu
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yu Zhou
- Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Qiangguo Ao
- Department of Nephrology, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xinli Deng
- Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
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16
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Ghafouri-Fard S, Hussen BM, Jamali E, Branicki W, Taheri M, Akbari Dilmaghani N. Role of lncRNAs and circRNAs in epilepsy. Ageing Res Rev 2022; 82:101749. [PMID: 36216292 DOI: 10.1016/j.arr.2022.101749] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/02/2022] [Accepted: 10/05/2022] [Indexed: 02/09/2023]
Abstract
Epilepsy is a chronic disorder of with a high prevalence and extensive health burden in almost all age groups of the population. This condition is resulted from disturbance in the balance between excitatory and inhibitory factors in the brain. Genetic elements that affect synaptic connectivity, receptors functions or ion channels have been shown to predispose individuals to the epilepsy. More recently, a body of evidence points to the role of non-coding part of the transcriptome in the pathology of epilepsy. Expression levels of NEAT1, H19, PVT1, ILF3-AS1, GAS5, ZFAS1, UCA1, MALAT1 and SNHG1 have been changed in epileptic patients or animal models of epilepsy. Moreover, circ_ANKMY2, circRNA-0067835 and circHivep2 are among circRNAs which are involved in the pathogenesis of epilepsy. Although the mechanistical impact of these transcripts in the pathogenesis of epilepsy has not been fully explored, disturbances in neuron plasticity, apoptosis or differentiation might be implicated in this process. Expression levels of lncRNAs can be used for discrimination of epileptic patients from normal controls or refractory patients from non-refractory ones. JAK/STAT, Wnt, PI3K/AKT and NF-κB signaling pathways are among the regulated pathways by lncRNAs in the context of epilepsy. In the present review, we summarize the role of lncRNAs and circRNAs in the pathogenesis of epilepsy.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq; Center of Research and Strategic Studies, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Elena Jamali
- Department of Pathology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Wojciech Branicki
- Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Nader Akbari Dilmaghani
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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17
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Khan AQ, Ahmad F, Raza SS, Zarif L, Siveen KS, Sher G, Agha MV, Rashid K, Kulinski M, Buddenkotte J, Uddin S, Steinhoff M. Role of non-coding RNAs in the progression and resistance of cutaneous malignancies and autoimmune diseases. Semin Cancer Biol 2022; 83:208-226. [PMID: 32717336 DOI: 10.1016/j.semcancer.2020.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/28/2020] [Accepted: 07/06/2020] [Indexed: 02/06/2023]
Abstract
Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Fareed Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Syed Shadab Raza
- Department of Stem Cell Biology and Regenerative Medicine, Era University, Lucknow, India
| | - Lubna Zarif
- Department of Biological and Environmental Sciences, Qatar University, Doha 2713, Qatar
| | - Kodappully S Siveen
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Gulab Sher
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Maha Victor Agha
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Khalid Rashid
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Michal Kulinski
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Joerg Buddenkotte
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar
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18
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Mechanisms and functions of long noncoding RNAs in intervertebral disc degeneration. Pathol Res Pract 2022; 235:153959. [DOI: 10.1016/j.prp.2022.153959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/04/2022] [Accepted: 05/25/2022] [Indexed: 01/17/2023]
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19
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D’Souza MH, Mrozowich T, Badmalia MD, Geeraert M, Frederickson A, Henrickson A, Demeler B, Wolfinger M, Patel T. Biophysical characterisation of human LincRNA-p21 sense and antisense Alu inverted repeats. Nucleic Acids Res 2022; 50:5881-5898. [PMID: 35639511 PMCID: PMC9177966 DOI: 10.1093/nar/gkac414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/26/2022] [Accepted: 05/09/2022] [Indexed: 12/05/2022] Open
Abstract
Human Long Intergenic Noncoding RNA-p21 (LincRNA-p21) is a regulatory noncoding RNA that plays an important role in promoting apoptosis. LincRNA-p21 is also critical in down-regulating many p53 target genes through its interaction with a p53 repressive complex. The interaction between LincRNA-p21 and the repressive complex is likely dependent on the RNA tertiary structure. Previous studies have determined the two-dimensional secondary structures of the sense and antisense human LincRNA-p21 AluSx1 IRs using SHAPE. However, there were no insights into its three-dimensional structure. Therefore, we in vitro transcribed the sense and antisense regions of LincRNA-p21 AluSx1 Inverted Repeats (IRs) and performed analytical ultracentrifugation, size exclusion chromatography, light scattering, and small angle X-ray scattering (SAXS) studies. Based on these studies, we determined low-resolution, three-dimensional structures of sense and antisense LincRNA-p21. By adapting previously known two-dimensional information, we calculated their sense and antisense high-resolution models and determined that they agree with the low-resolution structures determined using SAXS. Thus, our integrated approach provides insights into the structure of LincRNA-p21 Alu IRs. Our study also offers a viable pipeline for combining the secondary structure information with biophysical and computational studies to obtain high-resolution atomistic models for long noncoding RNAs.
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Affiliation(s)
- Michael H D’Souza
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
| | - Tyler Mrozowich
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
| | - Maulik D Badmalia
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
| | - Mitchell Geeraert
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
| | - Angela Frederickson
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
| | - Amy Henrickson
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
| | - Borries Demeler
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
- Department of Chemistry and Biochemistry, University of Montana, Missoula, MT 59812, USA
- NorthWest Biophysics Consortium, University of Lethbridge, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
| | - Michael T Wolfinger
- Bioinformatics and Computational Biology, Faculty of Computer Science, Währingerstrasse 29, 1090 Vienna, Austria
- Department of Theoretical Chemistry, University of Vienna, Währingerstrasse 17, 1090 Vienna, Austria
| | - Trushar R Patel
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada
- Department of Microbiology, Immunology and Infectious Disease, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Li Ka Shing Institute of Virology and Discovery Lab, University of Alberta, Edmonton, AB T6G 2E1, Canada
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Wang G, Lin X, Han H, Zhang H, Li X, Feng M, Jiang C. lncRNA H19 promotes glioblastoma multiforme development by activating autophagy by sponging miR-491-5p. Bioengineered 2022; 13:11440-11455. [PMID: 35506168 PMCID: PMC9275997 DOI: 10.1080/21655979.2022.2065947] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma multiforme (GBM) is a malignant cancer with severely poor survival, and the cells continue to thrive during hypoxia and toxic stress through autophagy. To validate the oncogenic role of long noncoding RNA H19 in GBM progression and examine whether autophagy and/or miR-491-5p participate in the process. The expression of H19 and autophagy-related genes in GBM and healthy control tissues was assessed via quantitative polymerase chain reaction. In addition, cell viability, proliferation, apoptosis and autophagy were respectively determined via cell counting kit-8 assay, clone formation assay, flow cytometry, western blotting and green fluorescent protein-microtubule-associated protein 1 light chain 3 alpha fluorescence analysis in vitro. Furthermore, a rescue assay was performed using rapamycin or miR-491-5p antagomir to examine the role of autophagy or miR-491-5p in H19-mediated regulation of proliferation and apoptosis. RNA pull-down and dual-luciferase reporter assays were employed to analyze the interaction between H19 and miR-491-5p. Additionally, tumor growth in a xenograft-bearing mouse model and autophagy in tumor mass were analyzed in vivo. The expression H19 was increased in GBM and was positively correlated with LC3 or Beclin-1. Silencing H19 inhibited growth and promoted apoptosis in GBM cells both in vitro and in vivo, and miR-491-5p was identified as one of the important mediators. H19 regulated the autophagy signaling pathway at least partly via miR-491-5p. Increased H19 expression in GBM exerts oncogenic effects by sponging miR-491-5p and enhancing autophagy. Therefore, H19 may be explored as a target for GBM therapy.
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Affiliation(s)
- Guo Wang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoyan Lin
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Han Han
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Hongxu Zhang
- Department of Ophthalmology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Ophthalmology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoli Li
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Mei Feng
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Chunming Jiang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
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21
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Yuan S, Gong Y, Wang G, Zhang B, Liu Y, Zhang H. MSFF-CDCGAN: A novel method to predict RNA secondary structure based on Generative Adversarial Network. Methods 2022; 204:368-375. [DOI: 10.1016/j.ymeth.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 11/25/2022] Open
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22
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Wang JP, Li C, Ding WC, Peng G, Xiao GL, Chen R, Cheng Q. Research Progress on the Inflammatory Effects of Long Non-coding RNA in Traumatic Brain Injury. Front Mol Neurosci 2022; 15:835012. [PMID: 35359568 PMCID: PMC8961287 DOI: 10.3389/fnmol.2022.835012] [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: 12/14/2021] [Accepted: 02/08/2022] [Indexed: 11/29/2022] Open
Abstract
Globally, traumatic brain injury (TBI) is an acute clinical event and an important cause of death and long-term disability. However, the underlying mechanism of the pathophysiological has not been fully elucidated and the lack of effective treatment a huge burden to individuals, families, and society. Several studies have shown that long non-coding RNAs (lncRNAs) might play a crucial role in TBI; they are abundant in the central nervous system (CNS) and participate in a variety of pathophysiological processes, including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis, and neurogenesis. Some lncRNAs modulate multiple therapeutic targets after TBI, including inflammation, thus, these lncRNAs have tremendous therapeutic potential for TBI, as they are promising biomarkers for TBI diagnosis, treatment, and prognosis prediction. This review discusses the differential expression of different lncRNAs in brain tissue during TBI, which is likely related to the physiological and pathological processes involved in TBI. These findings may provide new targets for further scientific research on the molecular mechanisms of TBI and potential therapeutic interventions.
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Affiliation(s)
- Jian-peng Wang
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Chong Li
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Wen-cong Ding
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Gang Peng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ge-lei Xiao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Rui Chen
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
- *Correspondence: Rui Chen,
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Quan Cheng,
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Forman-Kay JD, Ditlev JA, Nosella ML, Lee HO. What are the distinguishing features and size requirements of biomolecular condensates and their implications for RNA-containing condensates? RNA (NEW YORK, N.Y.) 2022; 28:36-47. [PMID: 34772786 PMCID: PMC8675286 DOI: 10.1261/rna.079026.121] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Exciting recent work has highlighted that numerous cellular compartments lack encapsulating lipid bilayers (often called "membraneless organelles"), and that their structure and function are central to the regulation of key biological processes, including transcription, RNA splicing, translation, and more. These structures have been described as "biomolecular condensates" to underscore that biomolecules can be significantly concentrated in them. Many condensates, including RNA granules and processing bodies, are enriched in proteins and nucleic acids. Biomolecular condensates exhibit a range of material states from liquid- to gel-like, with the physical process of liquid-liquid phase separation implicated in driving or contributing to their formation. To date, in vitro studies of phase separation have provided mechanistic insights into the formation and function of condensates. However, the link between the often micron-sized in vitro condensates with nanometer-sized cellular correlates has not been well established. Consequently, questions have arisen as to whether cellular structures below the optical resolution limit can be considered biomolecular condensates. Similarly, the distinction between condensates and discrete dynamic hub complexes is debated. Here we discuss the key features that define biomolecular condensates to help understand behaviors of structures containing and generating RNA.
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Affiliation(s)
- Julie D Forman-Kay
- Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Jonathon A Ditlev
- Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Michael L Nosella
- Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Hyun O Lee
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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24
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Lawrie RD, Mitchell RD, Deguenon JM, Ponnusamy L, Reisig D, Pozo-Valdivia AD, Kurtz RW, Roe RM. Characterization of Long Non-Coding RNAs in the Bollworm, Helicoverpa zea, and Their Possible Role in Cry1Ac-Resistance. INSECTS 2021; 13:12. [PMID: 35055855 PMCID: PMC8779162 DOI: 10.3390/insects13010012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022]
Abstract
Multiple insect pest species have developed field resistance to Bt-transgenic crops. There has been a significant amount of research on protein-coding genes that contribute to resistance, such as the up-regulation of protease activity or altered receptors. However, our understanding of the role of non-protein-coding mechanisms in Bt-resistance is minimal, as is also the case for resistance to chemical pesticides. To address this problem relative to Bt, RNA-seq was used to examine statistically significant, differential gene expression between a Cry1Ac-resistant (~100-fold resistant) and Cry1Ac-susceptible strain of Helicoverpa zea, a prevalent caterpillar pest in the USA. Significant differential expression of putative long non-coding RNAs (lncRNAs) was found in the Cry1Ac-resistant strain (58 up- and 24 down-regulated gene transcripts with an additional 10 found only in resistant and four only in susceptible caterpillars). These lncRNAs were examined as potential pseudogenes and for their genomic proximity to coding genes, both of which can be indicative of regulatory relationships between a lncRNA and coding gene expression. A possible pseudogenic lncRNA was found with similarities to a cadherin. In addition, putative lncRNAs were found significantly proximal to a serine protease, ABC transporter, and CYP coding genes, potentially involved in the mechanism of Bt and/or chemical insecticide resistance. Characterization of non-coding genetic mechanisms in Helicoverpa zea will improve the understanding of the genomic evolution of insect resistance, improve the identification of specific regulators of coding genes in general (some of which could be important in resistance), and is the first step for potentially targeting these regulators for pest control and resistance management (using molecular approaches, such as RNAi and others).
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Affiliation(s)
- Roger D. Lawrie
- Department of Entomology and Plant Pathology, North Carolina State University, Campus Box 7647, 3230 Ligon Street, Raleigh, NC 27695, USA; (R.D.L.); (R.D.M.III); (J.M.D.); (L.P.)
- Environmental and Molecular Toxicology Program, Department of Biology, College of Sciences, North Carolina State University, 2601 Stinson Drive, Raleigh, NC 27606, USA
| | - Robert D. Mitchell
- Department of Entomology and Plant Pathology, North Carolina State University, Campus Box 7647, 3230 Ligon Street, Raleigh, NC 27695, USA; (R.D.L.); (R.D.M.III); (J.M.D.); (L.P.)
- Office of Pesticide Programs, Invertebrate and Vertebrate Branch 1, Registration Division, U.S. Environmental Protection Agency, 1200 Pennsylvania Avenue, Washington, DC 20460, USA
| | - Jean Marcel Deguenon
- Department of Entomology and Plant Pathology, North Carolina State University, Campus Box 7647, 3230 Ligon Street, Raleigh, NC 27695, USA; (R.D.L.); (R.D.M.III); (J.M.D.); (L.P.)
| | - Loganathan Ponnusamy
- Department of Entomology and Plant Pathology, North Carolina State University, Campus Box 7647, 3230 Ligon Street, Raleigh, NC 27695, USA; (R.D.L.); (R.D.M.III); (J.M.D.); (L.P.)
| | - Dominic Reisig
- Vernon G. James Research & Extension Center, Department of Entomology and Plant Pathology, 207 Research Station Road, Plymouth, NC 27962, USA; (D.R.); (A.D.P.-V.)
| | - Alejandro Del Pozo-Valdivia
- Vernon G. James Research & Extension Center, Department of Entomology and Plant Pathology, 207 Research Station Road, Plymouth, NC 27962, USA; (D.R.); (A.D.P.-V.)
| | - Ryan W. Kurtz
- Cotton Incorporated, 6399 Weston Parkway, Cary, NC 27513, USA;
| | - Richard Michael Roe
- Department of Entomology and Plant Pathology, North Carolina State University, Campus Box 7647, 3230 Ligon Street, Raleigh, NC 27695, USA; (R.D.L.); (R.D.M.III); (J.M.D.); (L.P.)
- Environmental and Molecular Toxicology Program, Department of Biology, College of Sciences, North Carolina State University, 2601 Stinson Drive, Raleigh, NC 27606, USA
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Xiao W, Zheng D, Chen X, Yu B, Deng K, Ma J, Wen X, Hu Y, Hou J. Long non-coding RNA MIAT is involved in the regulation of pyroptosis in diabetic cardiomyopathy via targeting miR-214-3p. iScience 2021; 24:103518. [PMID: 34950859 PMCID: PMC8671938 DOI: 10.1016/j.isci.2021.103518] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 09/14/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is one of the most common complications of diabetes without effective treatment options. Its pathogenesis is complex and remains unclear. Long non-coding RNA (lncRNA) MIAT allele has been reported to be enriched in DCM patients and activate a pyroptosis program in hypoxia-induced H9c2 cells. Thus, whether MIAT played a role in DCM pyroptosis remains to be clarified. In the study, the expression of MIAT was found elevated in the serum of diabetic patients, as well as in high-glucose induced cardiomyocytes and diabetic mice. Further, the expression levels of CASP1 and pyroptosis correlation factors (IL-1 and IL-18) were downregulated after silencing MIAT. Through modeling and validation experiments, we then confirmed that the MIAT-miR-214-3p-CASP1 axis serves as an essential point in pyroptosis of DCM mice. These results suggested that silencing MIAT would be a potential treatment strategy for DCM.
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Affiliation(s)
- Wenjing Xiao
- School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 611756, China
- Department of Pharmacy, The General Hospital of Western Theater Command of PLA, No 270 Rongdu Road, Jinniu District, Chengdu 610083, China
| | - Dezhi Zheng
- Department of Cardiovascular Surgery, The 960th Hospital of the PLA Joint Logistic Support Force, Jinan 250031, China
| | - Xin Chen
- Affiliated Hospital of Southwest Jiaotong University & The Third People's Hospital of Chengdu, Chengdu 610015, China
| | - Botao Yu
- Department of Pharmacy, The General Hospital of Western Theater Command of PLA, No 270 Rongdu Road, Jinniu District, Chengdu 610083, China
| | - Kaiwen Deng
- Department of Pharmacy, The General Hospital of Western Theater Command of PLA, No 270 Rongdu Road, Jinniu District, Chengdu 610083, China
| | - Jie Ma
- Department of Pharmacy, The General Hospital of Western Theater Command of PLA, No 270 Rongdu Road, Jinniu District, Chengdu 610083, China
| | - Xudong Wen
- Department of Gastroenterology and Hepatology, Chengdu First People's Hospital, Chengdu 610016, China
- Corresponding author
| | - Yonghe Hu
- School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 611756, China
- Department of Pharmacy, The General Hospital of Western Theater Command of PLA, No 270 Rongdu Road, Jinniu District, Chengdu 610083, China
- Corresponding author
| | - Jun Hou
- School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 611756, China
- Department of Pharmacy, The General Hospital of Western Theater Command of PLA, No 270 Rongdu Road, Jinniu District, Chengdu 610083, China
- Corresponding author
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Manigrasso J, Marcia M, De Vivo M. Computer-aided design of RNA-targeted small molecules: A growing need in drug discovery. Chem 2021. [DOI: 10.1016/j.chempr.2021.05.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Sabo AA, Dudau M, Constantin GL, Pop TC, Geilfus CM, Naccarati A, Dragomir MP. Two Worlds Colliding: The Interplay Between Natural Compounds and Non-Coding Transcripts in Cancer Therapy. Front Pharmacol 2021; 12:652074. [PMID: 34295245 PMCID: PMC8290364 DOI: 10.3389/fphar.2021.652074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/07/2021] [Indexed: 12/25/2022] Open
Abstract
Cancer is a devastating disease and has recently become the leading cause of death in western countries, representing an immense public health burden. When it comes to cancer treatment, chemotherapy is one of the main pillars, especially for advanced stage tumors. Over the years, natural compounds have emerged as one of the most valuable resources for new chemotherapies. It is estimated that more than half of the currently used chemotherapeutic agents are derived from natural compounds. Usually, natural compounds are discovered empirically and an important limitation of introducing new anti-cancer natural products is lack of knowledge with regard to their mechanism of action. Recent data has proven that several natural compounds may function via modulating the expression and function of non-coding RNAs (ncRNAs). NcRNAs are a heterogenous class of RNA molecules which are usually not translated into proteins but have an important role in gene expression regulation and are involved in multiple tumorigenic processes, including response/resistance to pharmacotherapy. In this review, we will discuss how natural compounds function via ncRNAs while summarizing the available data regarding their effects on over 15 types of cancer. Moreover, we will critically analyze the current advances and limitations in understanding the way natural compounds exert these health-promoting effects by acting on ncRNAs. Finally, we will propose several hypotheses that may open new avenues and perspectives regarding the interaction between natural compounds and ncRNAs, which could lead to improved natural compound-based therapeutic strategies in cancer.
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Affiliation(s)
- Alexandru A. Sabo
- Pediatrics 2 (General and Special Pediatrics), Klinikum Stuttgart, Olgahospital, Zentrum für Kinder, Jugend- und Frauenmedizin, Stuttgart, Germany
| | - Maria Dudau
- Biochemistry-Proteomics Department, Victor Babes National Institute of Pathology, Bucharest, Romania
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - George L. Constantin
- Division of Soil Science and Site Science, Thaer-Institute of Agricultural and Horticultural Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Tudor C. Pop
- Department of Pediatrics, Marie Curie Emergency Clinical Hospital for Children, Bucharest, Romania
| | - Christoph-M. Geilfus
- Division of Controlled Environment Horticulture, Thaer-Institute of Agricultural and Horticultural Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alessio Naccarati
- IIGM Italian Institute for Genomic Medicine, Turin, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Mihnea P. Dragomir
- Department of Surgery, Fundeni Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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28
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Competing Endogenous RNAs in Cervical Carcinogenesis: A New Layer of Complexity. Processes (Basel) 2021. [DOI: 10.3390/pr9060991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) regulate gene expression by binding to complementary sequences within target mRNAs. Apart from working ‘solo’, miRNAs may interact in important molecular networks such as competing endogenous RNA (ceRNA) axes. By competing for a limited pool of miRNAs, transcripts such as long noncoding RNAs (lncRNAs) and mRNAs can regulate each other, fine-tuning gene expression. Several ceRNA networks led by different lncRNAs—described here as lncRNA-mediated ceRNAs—seem to play essential roles in cervical cancer (CC). By conducting an extensive search, we summarized networks involved in CC, highlighting the major impacts of such dynamic molecular changes over multiple cellular processes. Through the sponging of distinct miRNAs, some lncRNAs as HOTAIR, MALAT1, NEAT1, OIP5-AS1, and XIST trigger crucial molecular changes, ultimately increasing cell proliferation, migration, invasion, and inhibiting apoptosis. Likewise, several lncRNAs seem to be a sponge for important tumor-suppressive miRNAs (as miR-140-5p, miR-143-3p, miR-148a-3p, and miR-206), impairing such molecules from exerting a negative post-transcriptional regulation over target mRNAs. Curiously, some of the involved mRNAs code for important proteins such as PTEN, ROCK1, and MAPK1, known to modulate cell growth, proliferation, apoptosis, and adhesion in CC. Overall, we highlight important lncRNA-mediated functional interactions occurring in cervical cells and their closely related impact on cervical carcinogenesis.
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29
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Hou W, Lin Y, Xu W, Chen H, Liu Y, Li C, Zheng Y. Identification and biological analysis of LncSPRY4-IT1-targeted functional proteins in photoaging skin. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2021; 37:530-538. [PMID: 34081809 DOI: 10.1111/phpp.12705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 02/17/2021] [Accepted: 05/30/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND/PURPOSE Skin photoaging, main causes of skin aging, is induced by chronic UV irradiation. LncSPRY4-IT1, a broadly expressed lncRNA, takes part in various biological functions by combining with functional protein molecules. However, the role of LncSPRY4-IT1 in skin photoaging process has not been characterized. This study is to investigate the interacting proteins of LncSPRY4-IT1 by combining RNA pull-down, high-throughput, and bioinformatic analysis. METHODS Human skin fibroblasts (HDFs) were exposed to 10 J/cm2 UVA irradiation, once a day for 14 days. LncSPRY4-IT1 expression was qualified via RT-PCR. In vitro RNA pull-down assays and liquid chromatography-mass spectrometry analysis were used to identify the LncSPRY4-IT1-related proteins. Functional annotation analysis and pathway enrichment were preformed via Gene Ontology and KEGG. RESULTS LncSPRY4-IT1 expression in photoaging fibroblasts was increased 1.66 ± 0.23 folds. 181 LncSPRY4-IT1-interacting proteins in UVA-induced photoaging skin fibroblast irradiation were identified, of which 56 proteins with two or more unique peptides, 73 proteins related to RNA processing, and 5 proteins related to DNA processing. High-throughput and bioinformatic analysis showed that LncSPRY4-IT1-targeting proteins were involved in cellular process, metabolic process, biological regulation, and cell part in skin photoaging process. The KEGG revealed that LncSPRY4-IT1-targeting proteins were mainly enriched in metabolic pathways. CONCLUSION The results of our studies illuminate how LncSPRY4-IT1 formed a LncRNA-protein regulatory network in skin photoaging mechanisms and suggest that LncSPRY4-IT1 may serve as a novel upstream intervention target for the prevention and treatment of photoaging and related skin diseases.
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Affiliation(s)
- Wenyi Hou
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yao Lin
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Weichun Xu
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University -Yuedong Hospital, Meizhou, China
| | - Haiyan Chen
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yufang Liu
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Changxing Li
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yue Zheng
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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30
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Khan S, Masood M, Gaur H, Ahmad S, Syed MA. Long non-coding RNA: An immune cells perspective. Life Sci 2021; 271:119152. [PMID: 33548285 DOI: 10.1016/j.lfs.2021.119152] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/14/2021] [Accepted: 01/24/2021] [Indexed: 02/08/2023]
Abstract
Long non-coding RNAs (lncRNAs) were considered as accumulated genetic waste until they were found to be gene expression regulators by highly sensitive modern genomics platforms. It is a huge class of non-coding transcripts with an arbitrary length of >200 nucleotides, which has gained much attention in the past few years. Increasing evidence from several experimental studies unraveled the expression of lncRNA linked to immune response and disease progression. However, only a small number of lncRNAs have robust evidence of their function. Differential expression of lncRNAs in different immune cells is also evident. In this review, we focused on how lncRNAs expression assist in shaping immune cells (Macrophages, Dendritic cells, NK cells, T cells, B cells, eosinophils, neutrophils, and microglial cells) function and their response to the diseased conditions. Emerging evidence revealed lncRNAs may serve as key regulators in the innate and adaptive immune response system. So, the molecular mechanism insight into the function of lncRNAs in immune response may contribute to the development of potential therapeutic targets for various disease treatments. Therefore, it is imperative to explore the expression of lncRNAs and understand its relevance associated with the immune system.
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Affiliation(s)
- Salman Khan
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Mohammad Masood
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Harshita Gaur
- Department of Life Sciences, University of Glasgow, United Kingdom
| | - Shaniya Ahmad
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.
| | - Mansoor Ali Syed
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.
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31
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Grazioli S, Petris G. Synthetic genomics for curing genetic diseases. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2021; 182:477-520. [PMID: 34175051 DOI: 10.1016/bs.pmbts.2021.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
From the beginning of the genome sequencing era, it has become increasingly evident that genetics plays a role in all diseases, of which only a minority are single-gene disorders, the most common target of current gene therapies. However, the majority of people have some kind of health problems resulting from congenital genetic mutations (over 6000 diseases have been associated to genes, https://www.omim.org/statistics/geneMap) and most genetic disorders are rare and only incompletely understood. The vision and techniques applied to the synthesis of genomes may help to address unmet medical needs from a chromosome and genome-scale perspective. In this chapter, we address the potential therapy of genetic diseases from a different outlook, in which we no longer focus on small gene corrections but on higher-order tools for genome manipulation. These will play a crucial role in the next years, as they prelude to a much deeper understanding of the architecture of the human genome and a more accurate modeling of human diseases, offering new therapeutic opportunities.
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Affiliation(s)
| | - Gianluca Petris
- Medical Research Council Laboratory of Molecular Biology (MRC LMB), Cambridge, United Kingdom.
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32
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Dong M, Xu T, Li H, Li X. LINC00052 promotes breast cancer cell progression and metastasis by sponging miR-145-5p to modulate TGFBR2 expression. Oncol Lett 2021; 21:368. [PMID: 33777194 PMCID: PMC7988718 DOI: 10.3892/ol.2021.12629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 12/17/2020] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) may participate in biological regulatory mechanisms of tumors. The aim of the present study was to uncover the molecular mechanism of the lncRNA LINC00052 in the tumorigenesis of breast cancer (BC). LINC00052 expression in BC tissues and cell lines was detected by reverse transcription-quantitative PCR analysis. The Cell Counting Kit-8, proliferation, Transwell and wound healing assays were employed to confirm the effect of LINC00052 on cell proliferation, migration and invasion. The cell localization of LINC00052 was estimated by cytoplasmic nuclear separation assay. Finally, the potential regulatory mechanism of LINC00052 in BC was detected by western blot analysis. The expression levels of LINC00052 were found to be significantly higher in BC tissues compared with those in the adjacent normal tissues. Downregulation of LINC00052 expression in vitro significantly suppressed the proliferation, migration and invasion of BC cells. LINC00052 was mainly expressed in the cytoplasm and was considered to bind with microRNA (miR)-145-5p based on various databases. Notably, the high expression levels of LINC00052 led to the low expression levels of miR-145-5p and high expression levels of TGF-β receptor II (TGFBR2). In conclusion, the findings of the present study demonstrated that LINC00052 may sponge miR-145-5p to upregulate TGFBR2 expression in order to promote the proliferation and metastasis of BC cells. Therefore, LINC00052 may be an effective potential target for the diagnosis and treatment of BC.
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Affiliation(s)
- Menglu Dong
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Tao Xu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Hanning Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xingrui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Luo X, Jiang Y, Chen F, Wei Z, Qiu Y, Xu H, Tian G, Gong W, Yuan Y, Feng H, Zhong L, Ji N, Xu X, Sun C, Li T, Li J, Feng X, Deng P, Zeng X, Zhou M, Zhou Y, Dan H, Jiang L, Chen Q. ORAOV1-B Promotes OSCC Metastasis via the NF-κB-TNFα Loop. J Dent Res 2021; 100:858-867. [PMID: 33655785 DOI: 10.1177/0022034521996339] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Metastasis, a powerful prognostic indicator of oral squamous cell carcinoma (OSCC), is chiefly responsible for poor cancer outcomes. Despite an increasing number of studies examining the mechanisms underlying poor outcomes, the development of potent strategies is hindered by insufficient characterization of the crucial regulators. Long noncoding RNAs (lncRNAs) have recently been gaining interest as significant modulators of OSCC metastasis; however, the detailed mechanisms underlying lncRNA-mediated OSCC metastasis remain relatively uncharacterized. Here, we identified a novel alternative splice variant of oral cancer overexpressed 1 (ORAOV1), named as ORAOV1-B, which was subsequently validated as an lncRNA and correlated with OSCC lymph node metastasis; significantly increased invasion and migration were observed in ORAOV1-B-overexpressing OSCC cells. RNA pulldown and mass spectrometry identified Hsp90 as a direct target of ORAOV1-B, and cDNA microarrays suggested TNFα as a potential downstream target of ORAOV1-B. ORAOV1-B was shown to directly bind to and stabilize Hsp90, which maintains the function of client proteins, receptor-interaction protein, and IκB kinase beta, thus activating the NF-κB pathway and inducing TNFα. Additionally, TNFα reciprocally enhanced p-NF-κB-p65 and the downstream epithelial-mesenchymal transition. ORAOV1-B effects were reversed by a TNFα inhibitor, demonstrating that TNFα is essential for ORAOV1-B-regulated metastatic ability. Consistent epithelial-mesenchymal transition in the ORAOV1-B group was demonstrated via an orthotopic model. In the metastatic model, ORAOV1-B significantly contributed to OSCC-related lung metastasis. In summary, the novel splice variant ORAOV1-B is an lncRNA, which significantly potentiates OSCC invasion and metastasis by binding to Hsp90 and activating the NF-κB-TNFα loop. These findings demonstrate the versatile role of ORAOV1 family members and the significance of genes located within 11q13 in promoting OSCC. ORAOV1-B might serve as an attractive OSCC metastasis intervention target.
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Affiliation(s)
- X Luo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - F Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- The Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Z Wei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Qiu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - H Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - G Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - W Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - H Feng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- XiangYa Stomatological Hospital, Central South University, Changsha, China
| | - L Zhong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - N Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - X Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - C Sun
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - T Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - J Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - X Feng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - P Deng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - X Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - M Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - H Dan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - L Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Q Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Yuan D, Liu Y, Li M, Zhou H, Cao L, Zhang X, Li Y. Senescence associated long non-coding RNA 1 regulates cigarette smoke-induced senescence of type II alveolar epithelial cells through sirtuin-1 signaling. J Int Med Res 2021; 49:300060520986049. [PMID: 33535826 PMCID: PMC7869169 DOI: 10.1177/0300060520986049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE The primary aim of our study was to explore the mechanisms through which long non-coding RNA (lncRNA)-mediated sirtuin-1 (SIRT1) signaling regulates type II alveolar epithelial cell (AECII) senescence induced by a cigarette smoke-media suspension (CSM). METHODS Pharmacological SIRT1 activation was induced using SRT2104 and senescence-associated lncRNA 1 (SAL-RNA1) was overexpressed. The expression of SIRT1, FOXO3a, p53, p21, MMP-9, and TIMP-1 in different groups was detected by qRT-PCR and Western blotting; the activity of SA-β gal was detected by staining; the binding of SIRT1 to FOXO3a and p53 gene transcription promoters was detected by Chip. RESULTS We found that CSM increased AECII senescence, while SAL-RNA1 overexpression and SIRT1 activation significantly decreased levels of AECII senescence induced by CSM. Using chromatin immunoprecipitation, we found that SIRT1 bound differentially to transcriptional complexes on the FOXO3a and p53 promoters. CONCLUSION Our results suggested that lncRNA-SAL1-mediated SIRT1 signaling reduces senescence of AECIIs induced by CSM. These findings suggest a new therapeutic target to limit the irreversible apoptosis of lung epithelial cells in COPD patients.
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Affiliation(s)
- Dong Yuan
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou, Zhejiang, P.R. China.,Graduate Department, Bengbu Medical College, Bengbu, Anhui, P. R. China
| | - Yuanshun Liu
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou, Zhejiang, P.R. China
| | - Mengyu Li
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou, Zhejiang, P.R. China.,Graduate Department, Bengbu Medical College, Bengbu, Anhui, P. R. China
| | - Hongbin Zhou
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou, Zhejiang, P.R. China
| | - Liming Cao
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou, Zhejiang, P.R. China
| | - Xiaoqin Zhang
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou, Zhejiang, P.R. China
| | - Yaqing Li
- Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou, Zhejiang, P.R. China.,Department of Internal Medicine, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, P. R. China
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Ashrafizadeh M, Gholami MH, Mirzaei S, Zabolian A, Haddadi A, Farahani MV, Kashani SH, Hushmandi K, Najafi M, Zarrabi A, Ahn KS, Khan H. Dual relationship between long non-coding RNAs and STAT3 signaling in different cancers: New insight to proliferation and metastasis. Life Sci 2021; 270:119006. [PMID: 33421521 DOI: 10.1016/j.lfs.2020.119006] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/14/2022]
Abstract
Uncontrolled growth and metastasis of cancer cells is an increasing challenge for overcoming cancer, and improving survival of patients. Complicated signaling networks account for proliferation and invasion of cancer cells that need to be elucidated for providing effective cancer therapy, and minimizing their malignancy. Long non-coding RNAs (lncRNAs) are RNA molecules with a length of more than 200 nucleotides. They participate in cellular events, and their dysregulation in a common phenomenon in different cancers. Noteworthy, lncRNAs can regulate different molecular pathways, and signal transducer and activator of transcription 3 (STAT3) is one of them. STAT3 is a tumor-promoting factors in cancers due to its role in cancer proliferation (cell cycle progression and apoptosis inhibition) and metastasis (EMT induction). LncRNAs can function as upstream mediators of STAT3 pathway, reducing/enhancing its expression. This dual relationship is of importance in affecting proliferation and metastasis of cancer cells. The response of cancer cells to therapy such as chemotherapy and radiotherapy is regulated by lncRNA/STAT3 axis. Tumor-promoting lncRNAs including NEAT1, SNHG3 and H19 induces STAT3 expression, while tumor-suppressing lncRNAs such as MEG3, PTCSC3 and NKILA down-regulate STAT3 expression. Noteworthy, upstream mediators of STAT3 such as microRNAs can be regulated by lncRNAs. These complicated signaling networks are mechanistically described in the current review.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | | | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Haddadi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | | | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran; Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey.
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan.
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Ray SK, Mukherjee S. LncRNAs as Architects in Cancer Biomarkers with Interface of Epitranscriptomics- Incipient Targets in Cancer Therapy. Curr Cancer Drug Targets 2021; 21:416-427. [PMID: 33413062 DOI: 10.2174/1568009620666210106122421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/22/2020] [Accepted: 11/23/2020] [Indexed: 11/22/2022]
Abstract
Long non-coding RNAs (LncRNAs) epitomize a class of non-coding regulatory RNAs with more than 200 nucleotides, which are long and situated in the nucleus or cytoplasm and rarely encode proteins. Accruing evidence signposts that lncRNAs act as molecular switches in different cellular activities like differentiation, apoptosis, as well as reprogramming of cellular states by modifying gene expression patterns. The revelation of immense numbers of lncRNA with their wide variety of expression patterns in different kinds of malignancy, tumor explicitness, and their steadiness in circulating body fluids deliver an innovative groundwork for emerging diagnosis and treatments for cancer. Mechanisms associating lncRNAs in carcinogenesis are conquered by deregulation of cellular signaling pathways and altered epitranscriptome along with their expression. Specified these attributes, it becomes clear that the improvement of new tools to identify lncRNAs with higher affectability will be fundamental to allow the identification of the expression pattern of lncRNAs in various kinds of malignant growth and may likewise be utilized to envisage cancer prognosis in addition to the patients' outcome. Improvement of RNA targeting-based therapeutics is delivering incredible prospects to modulate lncRNAs for anti-cancer initiatives. Henceforth, lncRNAs can be used exclusively as possible cancer biomarkers for early diagnosis and anticipation of malignancy, as well as metastasis. In addition to the basic curative targets and along these, lncRNAs hold resilient assurance towards the revelation of innovative diagnostics and therapeutics for malignant growth with the interface of epitranscriptomics information. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis, regulation, and lncRNA-associated epigenetics of cancer along with targeting lncRNAs with potential approaches for impending diagnosis and therapeutic intervention in malignancies.
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Affiliation(s)
- Suman Kumar Ray
- Independent Researcher, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India
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Wang Y, Liu Y, Wang S, Liu Z, Gao Y, Zhang H, Dong L. ATTfold: RNA Secondary Structure Prediction With Pseudoknots Based on Attention Mechanism. Front Genet 2020; 11:612086. [PMID: 33384721 PMCID: PMC7770172 DOI: 10.3389/fgene.2020.612086] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 11/17/2020] [Indexed: 11/15/2022] Open
Abstract
Accurate RNA secondary structure information is the cornerstone of gene function research and RNA tertiary structure prediction. However, most traditional RNA secondary structure prediction algorithms are based on the dynamic programming (DP) algorithm, according to the minimum free energy theory, with both hard and soft constraints. The accuracy is particularly dependent on the accuracy of soft constraints (from experimental data like chemical and enzyme detection). With the elongation of the RNA sequence, the time complexity of DP-based algorithms will increase geometrically, as a result, they are not good at coping with relatively long sequences. Furthermore, due to the complexity of the pseudoknots structure, the secondary structure prediction method, based on traditional algorithms, has great defects which cannot predict the secondary structure with pseudoknots well. Therefore, few algorithms have been available for pseudoknots prediction in the past. The ATTfold algorithm proposed in this article is a deep learning algorithm based on an attention mechanism. It analyzes the global information of the RNA sequence via the characteristics of the attention mechanism, focuses on the correlation between paired bases, and solves the problem of long sequence prediction. Moreover, this algorithm also extracts the effective multi-dimensional features from a great number of RNA sequences and structure information, by combining the exclusive hard constraints of RNA secondary structure. Hence, it accurately determines the pairing position of each base, and obtains the real and effective RNA secondary structure, including pseudoknots. Finally, after training the ATTfold algorithm model through tens of thousands of RNA sequences and their real secondary structures, this algorithm was compared with four classic RNA secondary structure prediction algorithms. The results show that our algorithm significantly outperforms others and more accurately showed the secondary structure of RNA. As the data in RNA sequence databases increase, our deep learning-based algorithm will have superior performance. In the future, this kind of algorithm will be more indispensable.
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Affiliation(s)
- Yili Wang
- College of Software, Jilin University, Changchun, China
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
| | - Yuanning Liu
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
- College of Computer Science and Technology, Jilin University, Changchun, China
| | - Shuo Wang
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
- College of Computer Science and Technology, Jilin University, Changchun, China
| | - Zhen Liu
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
- College of Computer Science and Technology, Jilin University, Changchun, China
- Graduate School of Engineering, Nagasaki Institute of Applied Science, Nagasaki, Japan
| | - Yubing Gao
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
- College of Computer Science and Technology, Jilin University, Changchun, China
| | - Hao Zhang
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
- College of Computer Science and Technology, Jilin University, Changchun, China
| | - Liyan Dong
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
- College of Computer Science and Technology, Jilin University, Changchun, China
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Sexton RE, Al Hallak MN, Diab M, Azmi AS. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev 2020; 39:1179-1203. [PMID: 32894370 PMCID: PMC7680370 DOI: 10.1007/s10555-020-09925-3] [Citation(s) in RCA: 428] [Impact Index Per Article: 85.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.
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Affiliation(s)
- Rachel E Sexton
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Mohammed Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Maria Diab
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA.
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Chillón I, Marcia M. The molecular structure of long non-coding RNAs: emerging patterns and functional implications. Crit Rev Biochem Mol Biol 2020; 55:662-690. [PMID: 33043695 DOI: 10.1080/10409238.2020.1828259] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Long non-coding RNAs (lncRNAs) are recently-discovered transcripts that regulate vital cellular processes and are crucially connected to diseases. Despite their unprecedented molecular complexity, it is emerging that lncRNAs possess distinct structural motifs. Remarkably, the 3D shape and topology of full-length, native lncRNAs have been visualized for the first time in the last year. These studies reveal that lncRNA structures dictate lncRNA functions. Here, we review experimentally determined lncRNA structures and emphasize that lncRNA structural characterization requires synergistic integration of computational, biochemical and biophysical approaches. Based on these emerging paradigms, we discuss how to overcome the challenges posed by the complex molecular architecture of lncRNAs, with the goal of obtaining a detailed understanding of lncRNA functions and molecular mechanisms in the future.
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Affiliation(s)
- Isabel Chillón
- European Molecular Biology Laboratory (EMBL) Grenoble, Grenoble, France
| | - Marco Marcia
- European Molecular Biology Laboratory (EMBL) Grenoble, Grenoble, France
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40
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Qiu J, Zhou S, Cheng W, Luo C. LINC00294 induced by GRP78 promotes cervical cancer development by promoting cell cycle transition. Oncol Lett 2020; 20:262. [PMID: 32989396 PMCID: PMC7517597 DOI: 10.3892/ol.2020.12125] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 05/27/2020] [Indexed: 12/17/2022] Open
Abstract
Cervical cancer is one of the most common gynecological malignancies, and it has become a crucial public health problem. In the present study, the expression profiles of cervical cancer and normal cervical tissues were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. Subsequently, the dysregulated long non-coding RNAs (lncRNAs) in cervical cancer were identified using R software Differentially expressed lncRNAs in cervical cancer that were associated with glucose-regulated protein 78 (GRP78) were screened out and the results demonstrated that eight lncRNAs were strongly positively correlated with GRP78. In order to confirm the relationship between GRP78 and candidate lncRNAs, GRP78 small interfering RNA (siRNA) was transfected into HeLa cells. The target lncRNAs that were regulated by GRP78 were then identified by reverse transcription-quantitative PCR and it was revealed that LINC00294 was significantly downregulated following GRP78-knockdown. Subsequently, Gene Set Enrichment Analysis demonstrated that LINC00294 was mainly enriched in regulating the cell cycle and the Hedgehog pathway. Following transfection of HeLa and SiHa cells with LINC00294 siRNA, the cell cycle was arrested at the G0/G1 phase. Western blotting suggested that LINC00294-knockdown downregulated the expression of cell cycle-associated factors (cyclin D, cyclin E and cyclin Dependent kinase 4) and upregulated cell cycle inhibitory factors (p16 and p21). The Hedgehog pathway was inhibited following knockdown of LINC00294 in HeLa and SiHa cells. In summary, LINC00294 induced by GRP78 promoted the progression of cervical cancer by regulating the cell cycle via Hedgehog pathway.
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Affiliation(s)
- Jiangnan Qiu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Shulin Zhou
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Wenjun Cheng
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Chengyan Luo
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
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Luo F, Wen Y, Zhou H, Li Z. Roles of long non-coding RNAs in cervical cancer. Life Sci 2020; 256:117981. [DOI: 10.1016/j.lfs.2020.117981] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 06/14/2020] [Accepted: 06/14/2020] [Indexed: 02/07/2023]
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42
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Jones AN, Sattler M. Challenges and perspectives for structural biology of lncRNAs-the example of the Xist lncRNA A-repeats. J Mol Cell Biol 2020; 11:845-859. [PMID: 31336384 PMCID: PMC6917512 DOI: 10.1093/jmcb/mjz086] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 06/30/2019] [Accepted: 07/02/2019] [Indexed: 12/21/2022] Open
Abstract
Following the discovery of numerous long non-coding RNA (lncRNA) transcripts in the human genome, their important roles in biology and human disease are emerging. Recent progress in experimental methods has enabled the identification of structural features of lncRNAs. However, determining high-resolution structures is challenging as lncRNAs are expected to be dynamic and adopt multiple conformations, which may be modulated by interaction with protein binding partners. The X-inactive specific transcript (Xist) is necessary for X inactivation during dosage compensation in female placental mammals and one of the best-studied lncRNAs. Recent progress has provided new insights into the domain organization, molecular features, and RNA binding proteins that interact with distinct regions of Xist. The A-repeats located at the 5′ end of the transcript are of particular interest as they are essential for mediating silencing of the inactive X chromosome. Here, we discuss recent progress with elucidating structural features of the Xist lncRNA, focusing on the A-repeats. We discuss the experimental and computational approaches employed that have led to distinct structural models, likely reflecting the intrinsic dynamics of this RNA. The presence of multiple dynamic conformations may also play an important role in the formation of the associated RNPs, thus influencing the molecular mechanism underlying the biological function of the Xist A-repeats. We propose that integrative approaches that combine biochemical experiments and high-resolution structural biology in vitro with chemical probing and functional studies in vivo are required to unravel the molecular mechanisms of lncRNAs.
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Affiliation(s)
- Alisha N Jones
- Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, 85764, Germany.,Center for Integrated Protein Science Munich and Bavarian NMR Center at Department of Chemistry, Technical University of Munich, Garching, 85747, Germany
| | - Michael Sattler
- Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, 85764, Germany.,Center for Integrated Protein Science Munich and Bavarian NMR Center at Department of Chemistry, Technical University of Munich, Garching, 85747, Germany
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Marcho C, Oluwayiose OA, Pilsner JR. The preconception environment and sperm epigenetics. Andrology 2020; 8:924-942. [PMID: 31901222 PMCID: PMC7346722 DOI: 10.1111/andr.12753] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 11/12/2019] [Accepted: 12/31/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Infertility is a common reproductive disorder, with male factor infertility accounting for approximately half of all cases. Taking a paternal perceptive, recent research has shown that sperm epigenetics, such as changes in DNA methylation, histone modification, chromatin structure, and noncoding RNA expression, can impact reproductive and offspring health. Importantly, environmental conditions during the preconception period has been demonstrated to shape sperm epigenetics. OBJECTIVES To provide an overview on epigenetic modifications that regulate normal gene expression and epigenetic remodeling that occurs during spermatogenesis, and to discuss the epigenetic alterations that may occur to the paternal germline as a consequence of preconception environmental conditions and exposures. MATERIALS AND METHODS We examined published literature available on databases (PubMed, Google Scholar, ScienceDirect) focusing on adult male preconception environmental exposures and sperm epigenetics in epidemiologic studies and animal models. RESULTS The preconception period is a sensitive developmental window in which a variety of exposures such as toxicants, nutrition, drugs, stress, and exercise, affects sperm epigenetics. DISCUSSION AND CONCLUSION Understanding the environmental legacy of the sperm epigenome during spermatogenesis will enhance our understanding of reproductive health and improve reproductive success and offspring well-being.
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Affiliation(s)
| | | | - J. Richard Pilsner
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts
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44
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Singh D, Khan MA, Siddique HR. Emerging role of long non-coding RNAs in cancer chemoresistance: unravelling the multifaceted role and prospective therapeutic targeting. Mol Biol Rep 2020; 47:5569-5585. [PMID: 32601922 DOI: 10.1007/s11033-020-05609-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 06/20/2020] [Indexed: 12/11/2022]
Abstract
Chemotherapy is one of the important treatment modules in early as well as advanced stages of cancer. However, the major limitation of chemotherapy is the development of chemoresistance in the transformed cells of cancer patients, which leads to cancer recurrence. Long non-coding RNAs (lncRNA) are the transcripts longer than 200 nucleotides in length, which are reported to associate with the initiation, progression, recurrence, and metastasis of different cancers. Several lncRNAs have been implicated in the prevalence of chemoresistant phenotypes and also in the restoration of drug sensitivity in chemoresistant cells. LncRNAs such as HOTAIR, H19, and a lot more are involved in the chemoresistance of cancer cells. Therefore, targeting the lncRNAs may serve as a novel strategy for treating chemoresistant cancer. This review throws light on the role of lncRNA in chemoresistance along with the perspective of the therapeutic targets for the treatment of multiple cancers.
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Affiliation(s)
- Deepti Singh
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, 202002, India
| | - Mohammad Afsar Khan
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, 202002, India
| | - Hifzur R Siddique
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, 202002, India.
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45
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Uroda T, Chillón I, Annibale P, Teulon JM, Pessey O, Karuppasamy M, Pellequer JL, Marcia M. Visualizing the functional 3D shape and topography of long noncoding RNAs by single-particle atomic force microscopy and in-solution hydrodynamic techniques. Nat Protoc 2020; 15:2107-2139. [PMID: 32451442 DOI: 10.1038/s41596-020-0323-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/24/2020] [Indexed: 11/09/2022]
Abstract
Long noncoding RNAs (lncRNAs) are recently discovered transcripts that regulate vital cellular processes, such as cellular differentiation and DNA replication, and are crucially connected to diseases. Although the 3D structures of lncRNAs are key determinants of their function, the unprecedented molecular complexity of lncRNAs has so far precluded their 3D structural characterization at high resolution. It is thus paramount to develop novel approaches for biochemical and biophysical characterization of these challenging targets. Here, we present a protocol that integrates non-denaturing lncRNA purification with in-solution hydrodynamic analysis and single-particle atomic force microscopy (AFM) imaging to produce highly homogeneous lncRNA preparations and visualize their 3D topology at ~15-Å resolution. Our protocol is suitable for imaging lncRNAs in biologically active conformations and for measuring structural defects of functionally inactive mutants that have been identified by cell-based functional assays. Once optimized for the specific target lncRNA of choice, our protocol leads from cloning to AFM imaging within 3-4 weeks and can be implemented using state-of-the-art biochemical and biophysical instrumentation by trained researchers familiar with RNA handling and supported by AFM and small-angle X-ray scattering (SAXS) experts.
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Affiliation(s)
- Tina Uroda
- European Molecular Biology Laboratory (EMBL) Grenoble, Grenoble, France.,Department of BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Isabel Chillón
- European Molecular Biology Laboratory (EMBL) Grenoble, Grenoble, France
| | | | - Jean-Marie Teulon
- Université Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS), Grenoble, France
| | - Ombeline Pessey
- European Molecular Biology Laboratory (EMBL) Grenoble, Grenoble, France
| | | | - Jean-Luc Pellequer
- Université Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS), Grenoble, France
| | - Marco Marcia
- European Molecular Biology Laboratory (EMBL) Grenoble, Grenoble, France.
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46
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Wasson CW, Abignano G, Hermes H, Malaab M, Ross RL, Jimenez SA, Chang HY, Feghali-Bostwick CA, Del Galdo F. Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann Rheum Dis 2020; 79:507-517. [PMID: 32041748 PMCID: PMC7147169 DOI: 10.1136/annrheumdis-2019-216542] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3). METHODS Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. RESULTS SSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro. CONCLUSIONS Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.
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Affiliation(s)
- Christopher W Wasson
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
| | - Giuseppina Abignano
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
- Rheumatology Department of Lucania San Carlo Hospital, Potenza, Italy, Rheumatology Institute of Lucania (IReL), Potenza, Italy
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, UK
| | - Heidi Hermes
- Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Maya Malaab
- Rheumatology, Medical University of South Carolina, Charlestown, South Carolina, USA
| | - Rebecca L Ross
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
| | - Sergio A Jimenez
- Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Howard Y Chang
- Center for Personal Dynamic Regulomes, University of Stanford, San Francisco, California, USA
| | | | - Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, UK
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47
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Lin Z, Xiong Y, Xue Y, Mao M, Xiang Y, He Y, Rafique F, Hu H, Liu J, Li X, Sun L, Huang Z, Ma J. Screening and characterization of long noncoding RNAs involved in the albinism of Ananas comosus var. bracteatus leaves. PLoS One 2019; 14:e0225602. [PMID: 31756232 PMCID: PMC6874346 DOI: 10.1371/journal.pone.0225602] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 11/08/2019] [Indexed: 12/19/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) have been reported to play key regulatory roles in plant growth, development, and biotic and abiotic stress physiology. Revealing the mechanism of lncRNA regulation in the albino portions of leaves is important for understanding the development of chimeric leaves in Ananas comosus var. bracteatus. In this study, a total of 3,543 candidate lncRNAs were identified, among which 1,451 were differentially expressed between completely green (CGr) and completely white (CWh) leaves. LncRNAs tend to have shorter transcripts, lower expression levels, and greater expression specificity than protein-coding genes. Predicted lncRNA targets were functionally annotated by the Gene Ontology (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. A lncRNA-mRNA interaction network was constructed, and 36 target mRNAs related to chlorophyll metabolism were predicted to interact with 86 lncRNAs. Among these, 25 significantly differentially expressed lncRNAs putatively interacted with 16 target mRNAs. Based on an expression pattern analysis of the lncRNAs and their target mRNAs, the lncRNAs targeting magnesium chelatase subunit H (ChlH), protochlorophyllide oxidoreductase (POR), and heme o synthase (COX10) were suggested as key regulators of chlorophyll metabolism. This study provides the first lncRNA database for A. comosus var. bracteatus and contributes greatly to understanding the mechanism of epigenetic regulation of leaf albinism.
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Affiliation(s)
- Zhen Lin
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yingyuan Xiong
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yanbin Xue
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Meiqin Mao
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yixuan Xiang
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yehua He
- Horticultural Biotechnology College of South China Agricultural University, Guangzhou, Guangdong, China
| | - Fatima Rafique
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Hao Hu
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Jiawen Liu
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Xi Li
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Lingxia Sun
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Zhuo Huang
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Jun Ma
- College of Landscape Architecture of Sichuan Agricultural University, Chengdu, Sichuan, China
- * E-mail:
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48
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Owens MC, Clark SC, Yankey A, Somarowthu S. Identifying Structural Domains and Conserved Regions in the Long Non-Coding RNA lncTCF7. Int J Mol Sci 2019; 20:ijms20194770. [PMID: 31561429 PMCID: PMC6801803 DOI: 10.3390/ijms20194770] [Citation(s) in RCA: 7] [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: 09/08/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 12/14/2022] Open
Abstract
Long non-coding RNA (lncRNA) biology is a rapidly growing area of study. Thousands of lncRNAs are implicated as key players in cellular pathways and cancer biology. However, the structure–function relationships of these novel biomolecules are not well understood. Recent structural studies suggest that lncRNAs contain modular structural domains, which play a crucial role in their function. Here, we hypothesized that such structural domains exist in lncTCF7, a conserved lncRNA implicated in the development and progression of several cancers. To understand the structure–function relationship of lncTCF7, we characterized its secondary structure using chemical probing methods. Our model revealed structural domains and conserved regions in lncTCF7. One of the modular domains identified here coincides with a known protein-interacting domain. The model reported herein is, to our knowledge, the first structural model of lncTCF7 and thus will serve to direct future studies that will provide fundamental insights into the function of this lncRNA.
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Affiliation(s)
- Michael C Owens
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19101, USA.
| | - Sean C Clark
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19101, USA.
| | - Allison Yankey
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19101, USA.
| | - Srinivas Somarowthu
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19101, USA.
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49
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Dai X, Kaushik AC, Zhang J. The Emerging Role of Major Regulatory RNAs in Cancer Control. Front Oncol 2019; 9:920. [PMID: 31608229 PMCID: PMC6771296 DOI: 10.3389/fonc.2019.00920] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 09/03/2019] [Indexed: 12/12/2022] Open
Abstract
Alterations and personal variations of RNA interactions have been mechanistically coupled with disease etiology and phenotypical variations. RNA biomarkers, RNA mimics, and RNA antagonists have been developed for diagnostic, prognostic, and therapeutic uses. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are two major types of RNA molecules with regulatory roles, deregulation of which has been implicated in the initiation and progression of many human malignancies. Accumulating evidence indicated the clinical roles of regulatory RNAs in cancer control, stimulating a surge in exploring the functionalities of regulatory RNAs for improved understanding on disease pathogenesis and management. In this review, we highlight the critical roles of lncRNAs and miRNAs played in tumorigenesis, scrutinize their potential functionalities as diagnostic/prognostic biomarkers and/or therapeutic targets in clinics, outline opportunities that ncRNAs may bring to complement current clinical practice for improved cancer management and identify challenges faced by translating frontier knowledge on non-coding RNAs (ncRNAs) to bedside clinics as well as possible solutions.
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Affiliation(s)
- Xiaofeng Dai
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Aman Chandra Kaushik
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.,School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Jianying Zhang
- Henan Key Laboratory of Tumor Epidemiology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
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50
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Goustin AS, Thepsuwan P, Kosir MA, Lipovich L. The Growth-Arrest-Specific ( GAS)-5 Long Non-Coding RNA: A Fascinating lncRNA Widely Expressed in Cancers. Noncoding RNA 2019; 5:ncrna5030046. [PMID: 31533355 PMCID: PMC6789762 DOI: 10.3390/ncrna5030046] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 09/08/2019] [Accepted: 09/10/2019] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNA (lncRNA) genes encode non-messenger RNAs that lack open reading frames (ORFs) longer than 300 nucleotides, lack evolutionary conservation in their shorter ORFs, and do not belong to any classical non-coding RNA category. LncRNA genes equal, or exceed in number, protein-coding genes in mammalian genomes. Most mammalian genomes harbor ~20,000 protein-coding genes that give rise to conventional messenger RNA (mRNA) transcripts. These coding genes exhibit sweeping evolutionary conservation in their ORFs. LncRNAs function via different mechanisms, including but not limited to: (1) serving as “enhancer” RNAs regulating nearby coding genes in cis; (2) functioning as scaffolds to create ribonucleoprotein (RNP) complexes; (3) serving as sponges for microRNAs; (4) acting as ribo-mimics of consensus transcription factor binding sites in genomic DNA; (5) hybridizing to other nucleic acids (mRNAs and genomic DNA); and, rarely, (6) as templates encoding small open reading frames (smORFs) that may encode short proteins. Any given lncRNA may have more than one of these functions. This review focuses on one fascinating case—the growth-arrest-specific (GAS)-5 gene, encoding a complicated repertoire of alternatively-spliced lncRNA isoforms. GAS5 is also a host gene of numerous small nucleolar (sno) RNAs, which are processed from its introns. Publications about this lncRNA date back over three decades, covering its role in cell proliferation, cell differentiation, and cancer. The GAS5 story has drawn in contributions from prominent molecular geneticists who attempted to define its tumor suppressor function in mechanistic terms. The evidence suggests that rodent Gas5 and human GAS5 functions may be different, despite the conserved multi-exonic architecture featuring intronic snoRNAs, and positional conservation on syntenic chromosomal regions indicating that the rodent Gas5 gene is the true ortholog of the GAS5 gene in man and other apes. There is no single answer to the molecular mechanism of GAS5 action. Our goal here is to summarize competing, not mutually exclusive, mechanistic explanations of GAS5 function that have compelling experimental support.
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Affiliation(s)
- Anton Scott Goustin
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
| | - Pattaraporn Thepsuwan
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
| | | | - Leonard Lipovich
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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