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Lundrigan E, Uguccioni S, Hum C, Ahmed N, Pezacki JP. SARS-CoV-2 Nsp13 helicase modulates miR-146a-mediated signaling pathways. Virology 2025; 606:110493. [PMID: 40073498 DOI: 10.1016/j.virol.2025.110493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 02/18/2025] [Accepted: 03/06/2025] [Indexed: 03/14/2025]
Abstract
Despite the successful development of vaccines and antiviral therapeutics against SARS-CoV-2, its tendency to mutate rapidly has emphasized the need for continued research to better understand this virus's mechanism of pathogenesis and interactions with host signaling pathways. In this study, we sought to explore how the SARS-CoV-2 non-structural protein 13 (Nsp13) helicase, a highly conserved coronavirus protein that is essential for viral replication, influences host biological and cellular processes. Global transcriptomic analyses of Nsp13-transfected A549 cells identified changes in pathways involved in post-transcriptional gene silencing and translational repression by RNA, such as microRNAs (miRNAs). Upon further bioinformatic analyses, we identified miR-146a-mediated signaling pathways to be of interest as this miRNA has been previously linked to the regulation of host inflammation and innate immune responses. We found that miR-146a was induced in Nsp13-transfected cells and observed a corresponding decrease in the gene expression of two miR-146a targets, TRAF6 and IRAK1, which are important upstream regulators of NF-kB activation and IFN signaling. These results suggest that Nsp13-induced miR-146a signaling cascades, namely NF-kB activation and SMAD4 signaling, may provide valuable insight for the development of novel antiviral therapeutics against COVID-19 variants.
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Affiliation(s)
- Eryn Lundrigan
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - Spencer Uguccioni
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - Christine Hum
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - Nadine Ahmed
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - John Paul Pezacki
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada; University of California Santa Barbara, Santa Barbara, CA, 90117, USA.
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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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Mattera MSDLC, Scaramele NF, Lopes FL, Belardi BE, Tsosura TVS, Sampaio HM, Chiba FY, Pereira RF, Dos Santos RM, Ervolino E, Baliero GF, Nobumoto ACTY, Cachoni AC, Chaves-Neto AH, Matsushita DH. MicroRNA expression profiling in the adult offspring of rats with periodontal disease. Arch Oral Biol 2025; 170:106131. [PMID: 39566203 DOI: 10.1016/j.archoralbio.2024.106131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 11/08/2024] [Accepted: 11/11/2024] [Indexed: 11/22/2024]
Abstract
OBJECTIVE The present study investigated the relationship between maternal periodontal disease, insulin resistance, activation of inflammatory pathways and epigenetic modifications in adult offspring. DESIGN Therefore, female Wistar rats were divided into control and experimental groups. Seven days after the induction of periodontal disease, female rats from both groups were mated with healthy male rats. After weaning, male offspring were divided into control offspring (CN-o) and periodontal disease offspring (PED-o) groups. Body weight was measured at 0-75 days of age. At day 75, the following were measured in the offspring: insulin resistance by the HOMA-IR index; global miRNAs by microtranscriptome array; validation of the selected miRNAs by quantitative real-time PCR expression; interleukin 1 receptor associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) content in the gastrocnemius muscle tissue (GSM) by western blotting. RESULTS Maternal periodontal disease leads to low birth weight (LBW) in the offspring and insulin resistance in adulthood; changes in global miRNA expression (5 miRNAs upregulated and 6 downregulated); and increased protein expression of IRAK1 and TRAF6 in GSM. CONCLUSIONS These findings demonstrate that maternal periodontal disease causes LBW, insulin resistance, activation of inflammatory pathways, and changes in global miRNA expression.
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Affiliation(s)
- Maria Sara de Lima Coutinho Mattera
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil.
| | | | - Flávia Lombardi Lopes
- São Paulo State University (UNESP), School of Veterinary Medicine, Araçatuba, Brazil
| | - Bianca Elvira Belardi
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Thaís Verônica Saori Tsosura
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Heloisa Macedo Sampaio
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Fernando Yamamoto Chiba
- Department of Preventive and Restorative Dentistry, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Renato Felipe Pereira
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Rodrigo Martins Dos Santos
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Edilson Ervolino
- Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Gabriele Fernandes Baliero
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Ana Carla Thalez Ywabuchi Nobumoto
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Anna Clara Cachoni
- Department of Preventive and Restorative Dentistry, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Antonio Hernandes Chaves-Neto
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Doris Hissako Matsushita
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
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Singh RK, Vangala R, Torne AS, Bose D, Robertson ES. Epigenetic and epitranscriptomic regulation during oncogenic γ-herpesvirus infection. Front Microbiol 2025; 15:1484455. [PMID: 39839102 PMCID: PMC11747046 DOI: 10.3389/fmicb.2024.1484455] [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: 08/21/2024] [Accepted: 12/18/2024] [Indexed: 01/23/2025] Open
Abstract
Oncogenic gamma herpesviruses, including Epstein-Barr Virus (EBV) and Kaposi's Sarcoma-associated Herpesvirus (KSHV), are opportunistic cancer-causing viruses and induces oncogenesis through complex mechanisms, which involves manipulation of cellular physiology as well as epigenetic and epitranscriptomic reprogramming. In this review, we describe the intricate processes by which these viruses interact with the epigenetic machinery, leading to alterations in DNA methylation, histone modifications, and the involvement of non-coding RNAs. The key viral proteins such as EBNA1 and LMP1 encoded by EBV; LANA and vGPCR encoded by KSHV; play pivotal roles in these modifications by interacting with host factors, and dysregulating signaling pathways. The resultant reprogramming can lead to activation of oncogenes, silencing of tumor suppressor genes, and evasion of the immune response, which ultimately contributes to the oncogenic potential of these viruses. Furthermore, in this review, we explore current therapeutic strategies targeting these epigenetic alterations and discuss future directions for research and treatment. Through this comprehensive examination of the epigenetic and epitranscriptomic reprogramming mechanisms employed by oncogenic gamma herpesviruses, we aim to provide valuable insights into potential avenues for novel therapeutic interventions.
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Affiliation(s)
| | | | | | | | - Erle S. Robertson
- Departments of Otorhinolaryngology-Head and Neck Surgery and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Salam DSA, Gunasinghe KKJ, Hwang SS, Ginjom IRH, Chee Wezen X, Rahman T. In Silico Modeling and Characterization of Epstein-Barr Virus Latent Membrane Protein 1 Protein. ACS OMEGA 2024; 9:49422-49431. [PMID: 39713625 PMCID: PMC11656244 DOI: 10.1021/acsomega.4c06868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/24/2024]
Abstract
Latent membrane protein 1 (LMP1) plays a crucial role in Epstein-Barr virus (EBV)'s ability to establish latency and is involved in developing and progressing EBV-associated cancers. Additionally, EBV-infected cells affect the immune responses, making it challenging for the immune system to eliminate them. Due to the aforementioned reasons, it is crucial to understand the structural features of LMP1, which are essential for the development of novel cancer therapies that target its signaling pathways. To date, there is yet to be a complete LMP1 protein structure; therefore, in our work, we modeled the full-length LMP1 containing the short cytoplasmic N-terminus, six transmembrane domains (TMDs), and a long-simulated C-terminus. Our model showed good stability and protein compactness evaluated through accelerated-molecular dynamics, where the conformational ensemble exhibited compact folds, particularly in the TMDs. Our results suggest that specific domains or motifs, predominantly in the C-terminal domain of LMP1, show promise as potential drug targets. As a whole, our work provides insights into key structural features of LMP1 that will allow the development of novel LMP1 therapies.
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Affiliation(s)
- Dayang-Sharyati
D. A. Salam
- Faculty
of Engineering, Computing and Science, Swinburne
University of Technology Sarawak, Kuching 93350, Malaysia
| | | | - Siaw San Hwang
- Faculty
of Engineering, Computing and Science, Swinburne
University of Technology Sarawak, Kuching 93350, Malaysia
| | - Irine Runnie Henry Ginjom
- Faculty
of Engineering, Computing and Science, Swinburne
University of Technology Sarawak, Kuching 93350, Malaysia
| | - Xavier Chee Wezen
- Faculty
of Engineering, Computing and Science, Swinburne
University of Technology Sarawak, Kuching 93350, Malaysia
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
| | - Taufiq Rahman
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, U.K.
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Mohammadinasr M, Montazersaheb S, Hosseini V, Kahroba H, Talebi M, Molavi O, Ayromlou H, Hejazi MS. Epstein-Barr virus-encoded BART9 and BART15 miRNAs are elevated in exosomes of cerebrospinal fluid from relapsing-remitting multiple sclerosis patients. Cytokine 2024; 179:156624. [PMID: 38692184 DOI: 10.1016/j.cyto.2024.156624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 04/05/2024] [Accepted: 04/20/2024] [Indexed: 05/03/2024]
Abstract
Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified ebv-miR-BART9-3p and ebv-miR-BART15 in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of ebv-miR-BART9-3p (18.4-fold) and ebv-miR-BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of hsa-miR-21-5p and hsa-miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group compared to those obtained from the HC group. The levels of Interferon-gamma (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF-β), and tumor necrosis factor-alpha (TNF-α) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-β (8.5-fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-β: TNF-α and TGF-β: IFN-γ attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. These findings show EBV activity in RRMS patients is different from that of healthy ones. Elevation of ebv-miR-BART9-3p, ebv-miR-BART15, and inflammatory cytokines expression in CSF exosomes in RRMS patients provides a substantial link between EBV activity and the onset of the disease, as well as the transition from EBV infection to MS.
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Affiliation(s)
- Mina Mohammadinasr
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Vahid Hosseini
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Houman Kahroba
- Department of Toxicogenomics, GROW School of Oncology and Development Biology, Maastricht University, Maastricht, The Netherlands; Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
| | - Mahnaz Talebi
- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ommoleila Molavi
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hormoz Ayromlou
- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Saeid Hejazi
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zadeh-Vakili A, Faam B, Afgar A, Razmpoosh E, Zarkesh M, Amouzegar A. A systematic review of dysregulated microRNAs in Hashimoto's thyroiditis. Endocrine 2024; 84:800-811. [PMID: 38212462 DOI: 10.1007/s12020-023-03673-4] [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: 09/30/2023] [Accepted: 12/19/2023] [Indexed: 01/13/2024]
Abstract
BACKGROUND Plenty of evidence suggests that dysregulated microRNAs are linked to developing autoimmune thyroid diseases. In this study, we aimed to identify commonly linked dysregulated microRNAs in Hashimoto's thyroiditis(HT) and explore microRNA-targeted genes and the involved pathways. METHODS Embase, PubMed, Web of Science, and Scopus databases were searched using the MeSH terms and free text terms, which yielded 11879 articles published up to July 2023. Two-step screening(first for titles and second for abstracts) was completed according to inclusion and exclusion criteria. The search strategy was formulated using the PEO format(Population, Exposure, and Outcome) for observational studies. The corresponding target genes and relevant signaling pathways were also identified using web servers of Diana Tools/its mirPath v.3 software, miRNA Enrichment Analysis, Mirpath DB2, miRPathDB 2.0, and miRmap. RESULTS Review inclusion criteria were met by 16 studies. Thirty-three microRNAs were identified as differentially expressed in HT patients compared to a healthy control after qRT-PCR or RNA sequencing confirmation. Only three miR-146a, miR-142, and miR-301 showed significant results in more than two studies comparing HT cases with healthy controls. CONCLUSION Three key microRNAs in HT were identified by systematic review; the corresponding target genes and signaling pathways involved in the target genes were also identified. These microRNAs regulate the immune response and inflammation and may favor the development and progression of HT. These data may be beneficial to make a step forward to understand the exact etiology of HT and use of these MicroRNAs as possible diagnostic and prognostic biomarkers and as target therapy.
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Affiliation(s)
- Azita Zadeh-Vakili
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bita Faam
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Afgar
- Research Center for Hydatid Disease in Iran, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Razmpoosh
- Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, ON, Canada
| | - Maryam Zarkesh
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Atieh Amouzegar
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Rezaeepoor M, Keramat F, Jourghasemi S, Rahmanpour M, Lipsa A, Hajilooi M, Solgi G. MicroRNA -21 expression as an auxiliary diagnostic biomarker of acute brucellosis. Mol Biol Rep 2024; 51:264. [PMID: 38302783 DOI: 10.1007/s11033-023-09193-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 12/21/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND This study aimed to measure the expression levels of peripheral blood miRNAs in brucellosis and their involvement in the different phases of the brucellosis. METHODS The expression levels of miRNAs including miR-210, miR-155, miR-150, miR-146a, miR-139-3p, miR-125a-5p, miR-29 and miR-21 were quantified in 57 brucellosis patients subgrouped into acute, under treatment & relapse phase and 30 healthy controls (HCs) using real-time polymerase chain reaction (RT-PCR). The receiver operating characteristic (ROC) analysis curve analysis was performed to find a biomarker for discrimination of different phases of brucellosis. RESULTS The expression of miR-155, miR-146a, miR-125a-5p, miR-29, and miR-21 was found to be elevated in the acute brucellosis patients compared to HCs. miR-29 changed in under-treatment patients, while miR-139-3p and miR-125a-5p showed alterations in relapse cases. The ROC curve analysis depicted the potential involvement of miR-21 in the pathogenesis of acute brucellosis. CONCLUSION The expression level of miR-21 is significantly augmented in acute brucellosis and has the potential to be a contributing diagnostic factor for acute infection.
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Affiliation(s)
- Mahsa Rezaeepoor
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
| | - Fariba Keramat
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
- Department of Infectious Diseases, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sanaz Jourghasemi
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
| | - Mina Rahmanpour
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
| | - Anuja Lipsa
- Cancer Genetic Laboratory, Advanced Centre for Treatment Research and Education in Cancer-Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Mehrdad Hajilooi
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran.
| | - Ghasem Solgi
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran.
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Niu M, Wang C, Chen Y, Zou Q, Xu L. Identification, characterization and expression analysis of circRNA encoded by SARS-CoV-1 and SARS-CoV-2. Brief Bioinform 2024; 25:bbad537. [PMID: 38279648 PMCID: PMC10818166 DOI: 10.1093/bib/bbad537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/12/2023] [Accepted: 12/22/2023] [Indexed: 01/28/2024] Open
Abstract
Virus-encoded circular RNA (circRNA) participates in the immune response to viral infection, affects the human immune system, and can be used as a target for precision therapy and tumor biomarker. The coronaviruses SARS-CoV-1 and SARS-CoV-2 (SARS-CoV-1/2) that have emerged in recent years are highly contagious and have high mortality rates. In coronaviruses, little is known about the circRNA encoded by the SARS-CoV-1/2. Therefore, this study explores whether SARS-CoV-1/2 encodes circRNA and characteristics and functions of circRNA. Based on RNA-seq data of SARS-CoV-1 and SARS-CoV-2 infections, we used circRNA identification tools (circRNA_finder, find_circ and CIRI2) to identify circRNAs. The number of circRNAs encoded by SARS-CoV-1 and SARS-CoV-2 was identified as 151 and 470, respectively. It can be found that SARS-CoV-2 shows more prominent circRNA encoding ability than SARS-CoV-1. Expression analysis showed that only a few circRNAs encoded by SARS-CoV-1/2 showed high expression levels, and the positive strand produced more abundant circRNAs. Then, based on the identified SARS-CoV-1/2-encoded circRNAs, we performed circRNA identification and characterization using the previously developed CirRNAPL. Finally, target gene prediction and functional enrichment analysis were performed. It was found that viral circRNA is closely related to cancer and has a potential role in regulating host cell functions. This study studied the characteristics and functions of viral circRNA encoded by coronavirus SARS-CoV-1/2, providing a valuable resource for further research on the function and molecular mechanism of coronavirus circRNA.
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Affiliation(s)
- Mengting Niu
- School of Electronic and Communication Engineering, Shenzhen Polytechnic University, Shenzhen 518055, China
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Chunyu Wang
- Faculty of Computing, Harbin Institute of Technology, Harbin, Heilongjiang 150000, China
| | - Yaojia Chen
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, No.4 Block 2 North Jianshe Road, Chengdu 610054, China
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou, China
| | - Quan Zou
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, No.4 Block 2 North Jianshe Road, Chengdu 610054, China
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou, China
| | - Lei Xu
- School of Electronic and Communication Engineering, Shenzhen Polytechnic University, Shenzhen 518055, China
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Chen X, Li Y, Li M, Xie Y, Wang K, Zhang L, Zou Z, Xiong L. Exosomal miRNAs assist in the crosstalk between tumor cells and immune cells and its potential therapeutics. Life Sci 2023; 329:121934. [PMID: 37460057 DOI: 10.1016/j.lfs.2023.121934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023]
Abstract
Exosomes are small extracellular vesicles that carry active substances (including proteins, lipids, and nucleic acids) and are essential for homeostasis and signal transmission. Recent studies have focused on the function of exosomal miRNAs in tumor progression. Researchers have expanded the use of exosomes and miRNAs as potential therapeutic tools and biomarkers to detect tumor progression. Immune cells, as an important part of the tumor microenvironment (TME), secrete a majority of exosome-derived miRNAs involved in the biological processes of malignancies. However, the underlying mechanisms remain unclear. Currently, there is no literature that systematically summarizes the communication of exosome-derived miRNAs between tumor cells and immune cells. Based on the cell specificity of exosome-derived miRNAs, this review provides the first comprehensive summary of the significant miRNAs from the standpoint of exosome sources, which are tumor cells and immune cells. Furthermore, we elaborated on the potential clinical applications of these miRNAs, attempting to propose existing difficulties and future possibilities in tumor diagnostics and therapy.
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Affiliation(s)
- Xinyue Chen
- Department of Pathophysiology, Medical College, Nanchang University, Nanchang 330006, China; Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Yuqiu Li
- Queen Mary College of Nanchang University, Nanchang 330006, China
| | - Miao Li
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Yujie Xie
- College of Pharmacy, Nanchang University, Nanchang 330006, China
| | - Keqin Wang
- First Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Lifang Zhang
- Department of Pathophysiology, Medical College, Nanchang University, Nanchang 330006, China
| | - Zhuoling Zou
- Queen Mary College of Nanchang University, Nanchang 330006, China
| | - Lixia Xiong
- Department of Pathophysiology, Medical College, Nanchang University, Nanchang 330006, China.
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11
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Pandita S, Verma A, Kumar N. Role of miRNAs in regulating virus replication. ANIMAL GENE 2023; 30:200162. [DOI: 10.1016/j.angen.2023.200162] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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12
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Kim KU, Han K, Kim J, Kwon DH, Ji YW, Yi DY, Min H. The Protective Role of Exosome-Derived MicroRNAs and Proteins from Human Breast Milk against Infectious Agents. Metabolites 2023; 13:metabo13050635. [PMID: 37233676 DOI: 10.3390/metabo13050635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/28/2023] [Accepted: 05/06/2023] [Indexed: 05/27/2023] Open
Abstract
Human breast milk (HBM)-derived exosomes contain various biological and immunological components. However, comprehensive immune-related and antimicrobial factor analysis requires transcriptomic, proteomic, and multiple databases for functional analyses, and has yet to be conducted. Therefore, we isolated and confirmed HBM-derived exosomes by detecting specific markers and examining their morphology using western blot and transmission electron microscopy. Moreover, we implemented small RNA sequencing and liquid chromatography-mass spectrometry to investigate substances within the HBM-derived exosomes and their roles in combating pathogenic effects, identifying 208 miRNAs and 377 proteins associated with immunological pathways and diseases. Integrated omics analyses identified a connection between the exosomal substances and microbial infections. In addition, gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses demonstrated that HBM-derived exosomal miRNA and proteins influence immune-related functions and pathogenic infections. Finally, protein-protein interaction analysis identified three primary proteins (ICAM1, TLR2, and FN1) associated with microbial infections mediating pro-inflammation, controlling infection, and facilitating microbial elimination. Our findings determine that HBM-derived exosomes modulate the immune system and could offer therapeutic strategies for regulating pathogenic microbial infection.
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Affiliation(s)
- Ki-Uk Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Kyusun Han
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jisu Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Da Hyeon Kwon
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Yong Woo Ji
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Department of Ophthalmology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin 16995, Republic of Korea
| | - Dae Yong Yi
- Department of Pediatrics, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea
| | - Hyeyoung Min
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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13
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Ziętara KJ, Lejman J, Wojciechowska K, Lejman M. The Importance of Selected Dysregulated microRNAs in Diagnosis and Prognosis of Childhood B-Cell Precursor Acute Lymphoblastic Leukemia. Cancers (Basel) 2023; 15:428. [PMID: 36672378 PMCID: PMC9856444 DOI: 10.3390/cancers15020428] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/30/2022] [Accepted: 01/06/2023] [Indexed: 01/12/2023] Open
Abstract
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a frequent type of childhood hematological malignancy. The disease is classified into several subtypes according to genetic abnormalities. MicroRNAs (miRNAs) are involved in pathological processes (e.g., proliferation, apoptosis, differentiation). A miRNA is a group of short non-coding RNAs with relevant regulatory effects on gene expression achieved by suppression of the translation or degradation of messenger RNA (mRNA). These molecules act as tumor suppressors and/or oncogenes in the pathogenesis of pediatric leukemias. The characteristic features of miRNAs are their stable form and the possibility of secretion to the circulatory system. The role of miRNA in BCP-ALL pathogenesis is still emerging, but several studies have suggested using miRNA expression profiles as biomarkers for diagnosis, prognosis, and response to therapy in leukemia. The dysregulation of some miRNAs involved in childhood acute lymphoid leukemia, such as miR-155, miR-200c, miR-100, miR-181a, miR125b, and miR146a is discussed, showing their possible employment as therapeutic targets. In the current review, the capabilities of miRNAs in non-invasive diagnostics and their prognostic potential as biomarkers are presented.
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Affiliation(s)
- Karolina Joanna Ziętara
- Student Scientific Society, Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
| | - Jan Lejman
- Independent Public Health Care Facility of The Ministry of Internal Affairs and Administration in Lublin, 20-331 Lublin, Poland
| | - Katarzyna Wojciechowska
- Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-059 Lublin, Poland
| | - Monika Lejman
- Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-059 Lublin, Poland
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14
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Farr RJ, Dahal S, Tribolet L, Bean AGD, Cowled C, Stewart CR. Profiling Host MicroRNA Responses to Henipavirus Infection. Methods Mol Biol 2023; 2682:261-279. [PMID: 37610588 DOI: 10.1007/978-1-0716-3283-3_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Diseases caused by henipaviruses feature incubation periods of up to 16 days, during which infected animals may show no apparent signs of disease yet be capable of transmitting the virus to humans. This risk has prompted research into host-derived biomarkers for early disease detection. Here, we describe a methodology for the assaying of host microRNAs (miRs), small non-coding RNAs that show promise as biomarkers for several human diseases and are responsive during early-stage henipavirus infection. In addition to their potential as disease biomarkers, miRNA profiling of henipavirus infections provides insight into cellular and immune pathways associated with disease pathogenesis.
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Affiliation(s)
- Ryan J Farr
- CSIRO Australian Animal Health Laboratory, Health & Biosecurity, Geelong, VIC, Australia
| | - Sudeep Dahal
- CSIRO Australian Animal Health Laboratory, Health & Biosecurity, Geelong, VIC, Australia
| | - Leon Tribolet
- CSIRO Australian Animal Health Laboratory, Health & Biosecurity, Geelong, VIC, Australia
| | - Andrew G D Bean
- CSIRO Australian Animal Health Laboratory, Health & Biosecurity, Geelong, VIC, Australia
| | - Christopher Cowled
- CSIRO Australian Animal Health Laboratory, Health & Biosecurity, Geelong, VIC, Australia
| | - Cameron R Stewart
- CSIRO Australian Animal Health Laboratory, Health & Biosecurity, Geelong, VIC, Australia.
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15
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Zhang S, Meng Y, Zhou L, Qiu L, Wang H, Su D, Zhang B, Chan K, Han J. Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy. MedComm (Beijing) 2022; 3:e173. [PMID: 36176733 PMCID: PMC9477794 DOI: 10.1002/mco2.173] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 11/11/2022] Open
Abstract
Emerging evidence indicates that resolution of inflammation is a critical and dynamic endogenous process for host tissues defending against external invasive pathogens or internal tissue injury. It has long been known that autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses, leading to excessive and uncontrol tissue inflammation. The dysregulation of epigenetic alterations including DNA methylation, posttranslational modifications to histone proteins, and noncoding RNA expression has been implicated in a host of inflammatory disorders and the immune system. The inflammatory response is considered as a critical trigger of epigenetic alterations that in turn intercede inflammatory actions. Thus, understanding the molecular mechanism that dictates the outcome of targeting epigenetic regulators for inflammatory disease is required for inflammation resolution. In this article, we elucidate the critical role of the nuclear factor-κB signaling pathway, JAK/STAT signaling pathway, and the NLRP3 inflammasome in chronic inflammatory diseases. And we formulate the relationship between inflammation, coronavirus disease 2019, and human cancers. Additionally, we review the mechanism of epigenetic modifications involved in inflammation and innate immune cells. All that matters is that we propose and discuss the rejuvenation potential of interventions that target epigenetic regulators and regulatory mechanisms for chronic inflammation-associated diseases to improve therapeutic outcomes.
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Affiliation(s)
- Su Zhang
- Laboratory of Cancer Epigenetics and GenomicsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Yang Meng
- Laboratory of Cancer Epigenetics and GenomicsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Lian Zhou
- Laboratory of Cancer Epigenetics and GenomicsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Lei Qiu
- Laboratory of Cancer Epigenetics and GenomicsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Heping Wang
- Department of NeurosurgeryTongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Dan Su
- Laboratory of Cancer Epigenetics and GenomicsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Bo Zhang
- Laboratory of Cancer Epigenetics and GenomicsDepartment of Gastrointestinal SurgeryFrontiers Science Center for Disease‐Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina
| | - Kui‐Ming Chan
- Department of Biomedical SciencesCity University of Hong KongHong KongChina
| | - Junhong Han
- Laboratory of Cancer Epigenetics and GenomicsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
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16
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Pinacchio C, Scordio M, Santinelli L, Frasca F, Sorrentino L, Bitossi C, Oliveto G, Viscido A, Ceci FM, Celani L, Ceccarelli G, Antonelli G, Mastroianni CM, d’Ettorre G, Scagnolari C. Analysis of serum microRNAs and rs2910164 GC single-nucleotide polymorphism of miRNA-146a in COVID-19 patients. J Immunoassay Immunochem 2022; 43:347-364. [DOI: 10.1080/15321819.2022.2035394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Claudia Pinacchio
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Mirko Scordio
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
| | - Letizia Santinelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Federica Frasca
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
| | - Leonardo Sorrentino
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
| | - Camilla Bitossi
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
| | - Giuseppe Oliveto
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
| | - Agnese Viscido
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
| | - Flavio Maria Ceci
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Luigi Celani
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Guido Antonelli
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
- Microbiology and Virology Unit, Sapienza University, Hospital Policlinico Umberto I, Rome, Italy
- Department of Molecular Medicine, Pasteur Institute Italy, Cenci Bolognetti Foundation, Rome, Italy
| | | | - Gabriella d’Ettorre
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Carolina Scagnolari
- Department of Molecular Medicine, Laboratory of Virology, Sapienza University, Rome, Italy
- Department of Molecular Medicine, Pasteur Institute Italy, Cenci Bolognetti Foundation, Rome, Italy
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17
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Cong X, Zhang J, Sun R, Pu Y. Short-term ambient particulate air pollution exposure, microRNAs, blood pressure and lung function. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 292:118387. [PMID: 34673158 DOI: 10.1016/j.envpol.2021.118387] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 10/15/2021] [Accepted: 10/17/2021] [Indexed: 06/13/2023]
Abstract
Ambient particulate air pollution is a risk factor for cardiovascular and respiratory disease, yet the biological mechanisms underlying this association are not well understood. The current study aimed to investigate the mediation role of microRNAs on the association between personal PM2.5 exposure and blood pressure and lung function. One hundred and twenty adults (60 truck drivers and 60 office workers) aged 18-46 years were assessed on the June 15, 2008 and at follow-up (1- to 2-weeks later). MicroRNAs were extracted from the peripheral blood samples. Compared to truck drivers, there is a significant increase in FEF25-75, FEV1, and FEV1/FVC and a decrease in PM2.5 in office workers (all p < 0.05). According to the Bonferroni corrected threshold p-value < 6.81 × 10-5 (0.05/734) used, personal PM2.5 data showed a significant positive association with miR-644 after the adjustment for age, BMI, smoking status, and habitual alcohol use. The mediation effect of miR-644 on the association between personal PM2.5 exposure and FEF25-75 [B (95%CI) = -1.342 (-2.810, -0.113)], PEF [B (95%CI) = -1.793 (-3.926, -0.195)], and FEV1/FVC [B (95%CI) = -0.119‰ (-0.224‰, -0.026‰)] was significant only for truck drivers after the adjustment for covariates. There were no similar associations with blood pressure. These results demonstrate microRNAs to potentially mediate association of PM2.5 with lung function. Subsequent studies are needed to further elucidate the potential mechanisms of action by which the mediation effect of microRNAs is achieved with this process.
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Affiliation(s)
- Xiaowei Cong
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Juan Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China.
| | - Rongli Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yuepu Pu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
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18
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Wang C, Xue M, Wu P, Wang H, Liu Z, Wu G, Liu P, Wang K, Xu W, Feng L. Coronavirus transmissible gastroenteritis virus antagonizes the antiviral effect of the microRNA miR-27b via the IRE1 pathway. SCIENCE CHINA. LIFE SCIENCES 2021; 65:1413-1429. [PMID: 34826094 PMCID: PMC8617553 DOI: 10.1007/s11427-021-1967-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/18/2021] [Indexed: 12/16/2022]
Abstract
Although the functional parameters of microRNAs (miRNAs) have been explored to some extent, the roles of these molecules in coronavirus infection and the regulatory mechanism of miRNAs in virus infection are still unclear. Transmissible gastroenteritis virus (TGEV) is an enteropathgenic coronavirus and causes high morbidity and mortality in suckling piglets. Here, we demonstrated that microRNA-27b-3p (miR-27b-3p) suppressed TGEV replication by directly targeting porcine suppressor of cytokine signaling 6 (SOCS6), while TGEV infection downregulated miR-27b-3p expression in swine testicular (ST) cells and in piglets. Mechanistically, the decrease of miR-27b-3p expression during TGEV infection was mediated by the activated inositol-requiring enzyme 1 (IRE1) pathway of the endoplasmic reticulum (ER) stress. Further studies showed that when ER stress was induced by TGEV, IRE1 acted as an RNase activated by autophosphorylation and unconventionally spliced mRNA encoding a potent transcription factor, X-box-binding protein 1 (Xbp1s). Xbp1s inhibited the transcription of miR-27 and ultimately reduced the production of miR-27b-3p. Therefore, our findings indicate that TGEV inhibits the expression of an anti-coronavirus microRNA through the IRE1 pathway and suggest a novel way in which coronavirus regulates the host cell response to infection.
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Affiliation(s)
- Changlin Wang
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Mei Xue
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Peng Wu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Honglei Wang
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Zhongqing Liu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Guangzheng Wu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Pinghuang Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Keliang Wang
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. .,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China.
| | - Wanhai Xu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. .,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China.
| | - Li Feng
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China.
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19
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Host miRNA and immune cell interactions: relevance in nano-therapeutics for human health. Immunol Res 2021; 70:1-18. [PMID: 34716546 DOI: 10.1007/s12026-021-09247-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Around 2200 miRNA (microRNA) genes were found in the human genome. miRNAs are arranged in clusters within the genome and share the same transcriptional regulatory units. It has been revealed that approximately 50% of miRNAs elucidated in the genome are transcribed from non-protein-coding genes, and the leftover miRNAs are present in the introns of coding sequences. We are now approaching a stage in which miRNA diagnostics and therapies can be established confidently, and several commercial efforts are underway to carry these innovations from the bench to the clinic. MiRNAs control many of the significant cellular activities such as production, differentiation, growth, and metabolism. Particularly in the immune system, miRNAs have emerged as a crucial biological component during diseased state and homeostasis. miRNAs have been found to regulate inflammatory responses and autoimmune disorders. Moreover, each miRNA targets multiple genes simultaneously, making miRNAs promising tools as diagnostic biomarkers and as remedial targets. Still, one of the major obstacles in miRNA-based approaches is the achievement of specific and efficient systemic delivery of miRNAs. To overcome these challenges, nanoformulations have been synthesized to protect miRNAs from degradation and enhance cellular uptake. The current review deals with the miRNA-mediated regulation of the recruitment and activation of immune cells, especially in the tumor microenvironment, viral infection, inflammation, and autoimmunity. The nano-based miRNA delivery modes are also discussed here, especially in the context of immune modulation.
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20
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Afshari A, Yaghobi R, Rezaei G. Inter-regulatory role of microRNAs in interaction between viruses and stem cells. World J Stem Cells 2021; 13:985-1004. [PMID: 34567421 PMCID: PMC8422934 DOI: 10.4252/wjsc.v13.i8.985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are well known for post-transcriptional regulatory ability over specific mRNA targets. miRNAs exhibit temporal or tissue-specific expression patterns and regulate the cell and tissue developmental pathways. They also have determinative roles in production and differentiation of multiple lineages of stem cells and might have therapeutic advantages. miRNAs are a part of some viruses' regulatory machinery, not a byproduct. The trace of miRNAs was detected in the genomes of viruses and regulation of cell reprograming and viral pathogenesis. Combination of inter-regulatory systems has been detected for miRNAs during viral infections in stem cells. Contraction between viruses and stem cells may be helpful in therapeutic tactics, pathogenesis, controlling viral infections and defining stem cell developmental strategies that is programmed by miRNAs as a tool. Therefore, in this review we intended to study the inter-regulatory role of miRNAs in the interaction between viruses and stem cells and tried to explain the advantages of miRNA regulatory potentials, which make a new landscape for future studies.
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Affiliation(s)
- Afsoon Afshari
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
| | - Ramin Yaghobi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran.
| | - Ghazal Rezaei
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
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21
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Ten Bosch GJA, Bolk J, 't Hart BA, Laman JD. Multiple sclerosis is linked to MAPK ERK overactivity in microglia. J Mol Med (Berl) 2021; 99:1033-1042. [PMID: 33948692 PMCID: PMC8313465 DOI: 10.1007/s00109-021-02080-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/31/2021] [Accepted: 04/19/2021] [Indexed: 12/18/2022]
Abstract
Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPKERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPKERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPKERK negative feedback phosphatases that normally regulate MAPKERK activity. Consequently, these factors may contribute to inappropriate MAPKERK overactivity, and thereby to neurodegeneration. Also, MAPKERK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPKERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.
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Affiliation(s)
- George J A Ten Bosch
- Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
| | - Jolande Bolk
- Department of Anesthesiology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Bert A 't Hart
- Department Anatomy and Neuroscience, Amsterdam University Medical Center (VUmc), Amsterdam, The Netherlands.,Department Biomedical Sciences of Cells & Systems, University Medical Center Groningen, Groningen, The Netherlands
| | - Jon D Laman
- Department Biomedical Sciences of Cells & Systems, University Medical Center Groningen, Groningen, The Netherlands
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22
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Abstract
Antigen recognition by the B cell receptor (BCR) is a physiological trigger for reactivation of Epstein-Barr virus (EBV) and can be recapitulated in vitro by cross-linking of surface immunoglobulins. Previously, we identified a subset of EBV microRNAs (miRNAs) that attenuate BCR signal transduction and subsequently dampen lytic reactivation in B cells. The roles of host miRNAs in the EBV lytic cycle are not completely understood. Here, we profiled the small RNAs in reactivated Burkitt lymphoma cells and identified several miRNAs, such as miR-141, that are induced upon BCR cross-linking. Notably, EBV encodes a viral miRNA, miR-BART9, with sequence homology to miR-141. To better understand the functions of these two miRNAs, we examined their molecular targets and experimentally validated multiple candidates commonly regulated by both miRNAs. Targets included B cell transcription factors and known regulators of EBV immediate-early genes, leading us to hypothesize that these miRNAs modulate kinetics of the lytic cascade in B cells. Through functional assays, we identified roles for miR-141 and EBV miR-BART9 and one specific target, FOXO3, in progression of the lytic cycle. Our data support a model whereby EBV exploits BCR-responsive miR-141 and further mimics activity of this miRNA family via a viral miRNA to promote productive lytic replication. IMPORTANCE EBV is a human pathogen associated with several malignancies. A key aspect of lifelong virus persistence is the ability to switch between latent and lytic replication modes. The mechanisms governing latency, reactivation, and progression of the lytic cycle are only partly understood. This study reveals that specific miRNAs can act to support the EBV lytic phase following BCR-mediated reactivation triggers. Furthermore, this study identifies a role for FOXO3, commonly suppressed by both host and viral miRNAs, in modulating progression of the EBV lytic cycle.
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23
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Avenoso A, D'Ascola A, Scuruchi M, Mandraffino G, Campo S, Campo GM. miR146a up-regulation is involved in small HA oligosaccharides-induced pro-inflammatory response in human chondrocytes. Biochim Biophys Acta Gen Subj 2021; 1865:129731. [PMID: 32931869 DOI: 10.1016/j.bbagen.2020.129731] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/05/2020] [Accepted: 09/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Small HA fragments are produced during cartilage degradation and their role seems to be preponderant during pathologies in which cartilage injury contribute to trigger and perpetuate the inflammatory mechanism. Several reports have increasingly shown that MicroRNAs (miRs), a small non-coding mRNAs are involved in the regulation of multiple biological processes, including cell proliferation and inflammation response in different pathologies, among them miR146a seems to be involved in inflammatory processes. METHODS Starting by these evidences we investigated the levels of miR146a and its correlation with inflammatory mediators in an experimental model of 6-mer HA-induced inflammatory response in human cultured chondrocytes. RESULTS Treatment of chondrocytes with 6-mer HA showed up-regulation in inflammation parameters such as TLR-4, and CD44 receptors activation, IL-6, IL-1β and MMP-13 mRNA expression and proteins production, as well as NF-kB activation. We also revealed an up-regulation of miR146a. Transfection with a miR146a mimic or miR146a inhibitor produced the following effects: chondrocytes receiving miR146a mimic and then 6-mer HA significantly reduced inflammatory cytokines and MMP-13, while exposition of chondrocytes with miR146a inhibitor and then the 6-mer HA incremented the activity of damaging cytokines and MMP13. Expression of CD44 receptor was not affected by miR-146a treatments, while TLR-4 expression and NF-kB activation were modified. CONCLUSIONS We concluded that up-regulation of miR146a occurred in 6-mer HA-induced inflammation response may reduce the inflammatory cascade by modulating TLR-4 and NF-kB activation. GENERAL SIGNIFICANCE These results could be useful in develop new therapeutic strategies with the aim to reduce OA and RA incidence.
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Affiliation(s)
- Angela Avenoso
- Department of Biomedical and Dental Sciences and Morphofunctional Images, Policlinico Universitario, University of Messina, 98125 - Messina, Italy
| | - Angela D'Ascola
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, 98125 Messina, Italy
| | - Michele Scuruchi
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, 98125 Messina, Italy
| | - Giuseppe Mandraffino
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, 98125 Messina, Italy
| | - Salvatore Campo
- Department of Biomedical and Dental Sciences and Morphofunctional Images, Policlinico Universitario, University of Messina, 98125 - Messina, Italy
| | - Giuseppe M Campo
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, 98125 Messina, Italy.
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24
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Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes. Metabolites 2020; 10:metabo10110452. [PMID: 33182622 PMCID: PMC7697558 DOI: 10.3390/metabo10110452] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/02/2020] [Accepted: 10/10/2020] [Indexed: 02/07/2023] Open
Abstract
Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove misfolded proteins thereby limiting their accumulation. Beta cells function optimally when they sense glucose and, in response, biosynthesize and secrete sufficient insulin. Overnutrition drives the pathogenesis of obesity and diabetes, with adverse effects on beta cells. The interleukin signaling system maintains beta cell physiology and plays a role in beta cell inflammation. In pre-diabetes and compromised metabolic states such as obesity, insulin resistance, and glucose intolerance, beta cells biosynthesize and secrete more insulin, i.e., hyperfunction. Obesity is entwined with inflammation, characterized by compensatory hyperinsulinemia, for a defined period, to normalize glycemia. However, with chronic hyperglycemia and diabetes, there is a perpetual high demand for insulin, and beta cells become exhausted resulting in insufficient insulin biosynthesis and secretion, i.e., they hypofunction in response to elevated glycemia. Therefore, beta cell hyperfunction progresses to hypofunction, and may progressively worsen towards failure. Preserving beta cell physiology, through healthy nutrition and lifestyles, and therapies that are aligned with beta cell functional transitions, is key for diabetes prevention and management.
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25
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Ahmad I, Valverde A, Siddiqui H, Schaller S, Naqvi AR. Viral MicroRNAs: Interfering the Interferon Signaling. Curr Pharm Des 2020; 26:446-454. [PMID: 31924149 DOI: 10.2174/1381612826666200109181238] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/22/2019] [Indexed: 12/23/2022]
Abstract
Interferons are secreted cytokines with potent antiviral, antitumor and immunomodulatory functions. As the first line of defense against viruses, this pathway restricts virus infection and spread. On the contrary, viruses have evolved ingenious strategies to evade host immune responses including the interferon pathway. Multiple families of viruses, in particular, DNA viruses, encode microRNA (miR) that are small, non-protein coding, regulatory RNAs. Virus-derived miRNAs (v-miR) function by targeting host and virus-encoded transcripts and are critical in shaping host-pathogen interaction. The role of v-miRs in viral pathogenesis is emerging as demonstrated by their function in subverting host defense mechanisms and regulating fundamental biological processes such as cell survival, proliferation, modulation of viral life-cycle phase. In this review, we will discuss the role of v-miRs in the suppression of host genes involved in the viral nucleic acid detection, JAK-STAT pathway, and cytokine-mediated antiviral gene activation to favor viral replication and persistence. This information has yielded new insights into our understanding of how v-miRs promote viral evasion of host immunity and likely provide novel antiviral therapeutic targets.
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Affiliation(s)
- Imran Ahmad
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, IL 60612, United States
| | - Araceli Valverde
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, IL 60612, United States
| | - Hasan Siddiqui
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, IL 60612, United States
| | - Samantha Schaller
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, IL 60612, United States
| | - Afsar R Naqvi
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, IL 60612, United States
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26
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Li J, Zou J, Wan X, Sun C, Peng F, Chu Z, Hu Y. The Role of Noncoding RNAs in B-Cell Lymphoma. Front Oncol 2020; 10:577890. [PMID: 33194698 PMCID: PMC7645065 DOI: 10.3389/fonc.2020.577890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022] Open
Abstract
In recent years, emerging evidence has suggested that noncoding RNAs (ncRNAs) participate in nearly every aspect of biological processes and play a crucial role in the genesis and progression of numerous tumors, including B-cell lymphoma. The exploration of ncRNA dysregulations and their functions in B-cell lymphoma provides new insights into lymphoma pathogenesis and is essential for indicating future clinical trials and optimizing the diagnostic and therapeutic strategies. In this review, we summarize the role of ncRNAs in B-cell lymphoma and discuss their potential in clinical applications.
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Affiliation(s)
- Jingwen Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Zou
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyue Wan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Peng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangbo Chu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China
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27
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The interplay between EBV and KSHV viral products and NF-κB pathway in oncogenesis. Infect Agent Cancer 2020; 15:62. [PMID: 33072180 PMCID: PMC7559203 DOI: 10.1186/s13027-020-00317-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/29/2020] [Indexed: 02/08/2023] Open
Abstract
Among the DNA tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV), account for a considerable percentage of virus-associated cancers. Deregulation of transcription factors signaling pathways is one of the most significant oncogenic characteristics of EBV and KSHV. NF-κB is a transcription factor that play a remarkable role in oncogenesis because of its function as a master regulator of a spectrum of genes involved in physiological and pathophysiological process. Constitutive activation of NF-κB is a frequent and well-described event in many human malignancies. Compelling evidence represent EBV and KSHV are capable of targeting different components of NF-κB cascade. Here, we summarized recent findings to clarify the precise relationship between dysregulation of NF-κB and EBV and KSHV-related malignancies. This essay also emphasizes on contribution of various viral products in developing cancer through alteration of NF-κB signaling pathway.
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28
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Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Suppresses Type I Interferon Signaling To Promote EBV Reactivation. J Virol 2020; 94:JVI.00258-20. [PMID: 32213613 DOI: 10.1128/jvi.00258-20] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 03/14/2020] [Indexed: 12/27/2022] Open
Abstract
Interferon alpha (IFN-α) and IFN-β are type I IFNs that are induced by virus infection and are important in the host's innate antiviral response. EBV infection activates multiple cell signaling pathways, resulting in the production of type I IFN which inhibits EBV infection and virus-induced B-cell transformation. We reported previously that EBV tegument protein BGLF2 activates p38 and enhances EBV reactivation. To further understand the role of BGLF2 in EBV infection, we used mass spectrometry to identify cellular proteins that interact with BGLF2. We found that BGLF2 binds to Tyk2 and confirmed this interaction by coimmunoprecipitation. BGLF2 blocked type I IFN-induced Tyk2, STAT1, and STAT3 phosphorylation and the expression of IFN-stimulated genes (ISGs) IRF1, IRF7, and MxA. In contrast, BGLF2 did not inhibit STAT1 phosphorylation induced by IFN-γ. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of the protein to repress type I IFN signaling. Treatment of gastric carcinoma and Raji cells with IFN-α blocked BZLF1 expression and EBV reactivation; however, expression of BGLF2 reduced the ability of IFN-α to inhibit BZLF1 expression and enhanced EBV reactivation. In summary, EBV BGLF2 interacts with Tyk2, inhibiting Tyk2, STAT1, and STAT3 phosphorylation and impairs type I IFN signaling; BGLF2 also counteracts the ability of IFN-α to suppress EBV reactivation.IMPORTANCE Type I interferons are important for controlling virus infection. We have found that the Epstein-Barr virus (EBV) BGLF2 tegument protein binds to a protein in the type I interferon signaling pathway Tyk2 and inhibits the expression of genes induced by type I interferons. Treatment of EBV-infected cells with type I interferon inhibits reactivation of the virus, while expression of EBV BGLF2 reduces the ability of type I interferon to inhibit virus reactivation. Thus, a tegument protein delivered to cells during virus infection inhibits the host's antiviral response and promotes virus reactivation of latently infected cells. Therefore, EBV BGLF2 might protect virus-infected cells from the type I interferon response in cells undergoing lytic virus replication.
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29
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Khan N, Cheemadan S, Saxena H, Bammidi S, Jayandharan GR. MicroRNA-based recombinant AAV vector assembly improves efficiency of suicide gene transfer in a murine model of lymphoma. Cancer Med 2020; 9:3188-3201. [PMID: 32108448 PMCID: PMC7196056 DOI: 10.1002/cam4.2935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 02/01/2020] [Accepted: 02/04/2020] [Indexed: 12/12/2022] Open
Abstract
Recent success in clinical trials with recombinant Adeno-associated virus (AAV)-based gene therapy has redirected efforts in optimizing AAV assembly and production, to improve its potency. We reasoned that inclusion of a small RNA during vector assembly, which specifically alters the phosphorylation status of the packaging cells may be beneficial. We thus employed microRNAs (miR-431, miR-636) identified by their ability to bind AAV genome and also dysregulate Mitogen-activated protein kinase (MAPK) signaling during vector production, by a global transcriptome study in producer cells. A modified vector assembly protocol incorporating a plasmid encoding these microRNAs was developed. AAV2 vectors packaged in the presence of microRNA demonstrated an improved gene transfer potency by 3.7-fold, in vitro. Furthermore, AAV6 serotype vectors encoding an inducible caspase 9 suicide gene, packaged in the presence of miR-636, showed a significant tumor regression (~2.2-fold, P < .01) in a syngeneic murine model of T-cell lymphoma. Taken together, we have demonstrated a simple but effective microRNA-based approach to improve the assembly and potency of suicide gene therapy with AAV vectors.
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Affiliation(s)
- Nusrat Khan
- Department of Biological Sciences and BioengineeringIndian Institute of TechnologyKanpurUPIndia
| | - Sabna Cheemadan
- Centre for Stem Cell ResearchChristian Medical CollegeVelloreTNIndia
| | - Himanshi Saxena
- Department of Biological Sciences and BioengineeringIndian Institute of TechnologyKanpurUPIndia
| | - Sridhar Bammidi
- Department of Biological Sciences and BioengineeringIndian Institute of TechnologyKanpurUPIndia
| | - Giridhara R. Jayandharan
- Department of Biological Sciences and BioengineeringIndian Institute of TechnologyKanpurUPIndia
- Centre for Stem Cell ResearchChristian Medical CollegeVelloreTNIndia
- Department of HematologyChristian Medical CollegeVelloreTNIndia
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30
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Moss LI, Tompkins VS, Moss WN. Differential expression analysis comparing EBV uninfected to infected human cell lines identifies induced non-micro small non-coding RNAs. Noncoding RNA Res 2020; 5:32-36. [PMID: 32154466 PMCID: PMC7052066 DOI: 10.1016/j.ncrna.2020.02.002] [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: 10/24/2019] [Revised: 02/11/2020] [Accepted: 02/12/2020] [Indexed: 11/29/2022] Open
Abstract
Epstein–Barr virus (EBV) is a ubiquitous human herpes virus, which is implicated in cancer and various autoimmune diseases. This study profiles non-micro small non-coding RNA expression changes induced by latent EBV infection. Using small RNA-Seq, 346 non-micro small RNAs were identified as being significantly differentially expressed between EBV(+) BJAB-B1 and EBV(−) BJAB cell lines. Select small RNA expression changes were experimentally validated in the BJAB-B1 cell line as well as the EBV-infected Raji and Jijoye cell lines. This latter analysis recapitulated the previously identified induction of vault RNA1, while also finding novel evidence for the deregulation of several tRNAs and a snoRNA.
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Affiliation(s)
- Lumbini I Moss
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, 50011, USA
| | - Van S Tompkins
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, 50011, USA
| | - Walter N Moss
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, 50011, USA
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31
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Nahand JS, Karimzadeh MR, Nezamnia M, Fatemipour M, Khatami A, Jamshidi S, Moghoofei M, Taghizadieh M, Hajighadimi S, Shafiee A, Sadeghian M, Bokharaei-Salim F, Mirzaei H. The role of miR-146a in viral infection. IUBMB Life 2019; 72:343-360. [PMID: 31889417 DOI: 10.1002/iub.2222] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022]
Abstract
Cellular microRNAs (miRNAs) were identified as a key player in the posttranscriptional regulation of cellular-genes regulatory pathways. They also emerged as a significant regulator of the immune response. In particular, miR-146a acts as an importance modulator of function and differentiation cells of the innate and adaptive immunity. It has been associated with disorder including cancer and viral infections. Given its significance in the regulation of key cellular processes, it is not surprising which virus infection have found ways to dysregulation of miRNAs. miR-146a has been identified in exosomes (exosomal miR-146a). After the exosomes release from donor cells, they are taken up by the recipient cell and probably the exosomal miR-146a is able to modulate the antiviral response in the recipient cell and result in making them more susceptible to virus infection. In this review, we discuss recent reports regarding miR-146a expression levels, target genes, function, and contributing role in the pathogenesis of the viral infection and provide a clue to develop the new therapeutic and preventive strategies for viral disease in the future.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Karimzadeh
- Department of Medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Maria Nezamnia
- Department of Obstetrics and Gynecology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Maryam Fatemipour
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Khatami
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sogol Jamshidi
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarah Hajighadimi
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Alimohammad Shafiee
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Mohammad Sadeghian
- Orthopedic Surgeon Fellowship of Spine Surgery, Sasan General Hospital, Tehran, Iran
| | - Farah Bokharaei-Salim
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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Pakshir K, Badali H, Nami S, Mirzaei H, Ebrahimzadeh V, Morovati H. Interactions between immune response to fungal infection and microRNAs: The pioneer tuners. Mycoses 2019; 63:4-20. [PMID: 31597205 DOI: 10.1111/myc.13017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 10/03/2019] [Accepted: 10/04/2019] [Indexed: 12/12/2022]
Abstract
Due to their physiological and biological characteristics, numerous fungi are potentially emerging pathogens. Active dynamicity of fungal pathogens causes life-threatening infections annually impose high costs to the health systems. Although immune responses play crucial roles in controlling the fate of fungal infections, immunocompromised patients are at high risk with high mortality. Tuning the immune response against fungal infections might be an effective strategy for controlling and reducing the pathological damages. MicroRNAs (miRNAs) are known as the master regulators of immune response. These single-stranded tuners (18-23 bp non-coding RNAs) are endogenously expressed by all metazoan eukaryotes and have emerged as the master gene expression controllers of at least 30% human genes. In this review article, following the review of biology and physiology (biogenesis and mechanism of actions) of miRNAs and immune response against fungal infections, the interactions between them were scrutinised. In conclusion, miRNAs might be considered as one of the potential goals in immunotherapy for fungal infections. Undoubtedly, advanced studies in this field, further identifying of miRNA roles in governing the immune response, pave the way for inclusion of miRNA-related immunotherapeutic in the treatment of life-threatening fungal infections.
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Affiliation(s)
- Keyvan Pakshir
- Department of Parasitology and Mycology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamid Badali
- Invasive Fungi Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Sanam Nami
- Department of Medical Mycology and Parasitology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Veghar Ebrahimzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Morovati
- Department of Medical Mycology and Parasitology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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33
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Mai S, Xiao R, Shi L, Zhou X, Yang T, Zhang M, Weng N, Zhao X, Wang R, Liu J, Sun R, Qin H, Wang H. MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma. Cell Death Dis 2019; 10:819. [PMID: 31659158 PMCID: PMC6817863 DOI: 10.1038/s41419-019-2060-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 09/17/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.
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Affiliation(s)
- ShiJuan Mai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - RuoWen Xiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Lu Shi
- Department of thoracic oncology, the cancer center of the fifth affiliated hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - XiaoMin Zhou
- ZhouKou Hospital of Traditional Chinese Medicine, Zhoukou, 466000, China
| | - Te Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - MeiYin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - NuoQing Weng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - XinGe Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - RuiQi Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ji Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Rui Sun
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - HaiDe Qin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - HuiYun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Wang H, Li X, Li T, Wang L, Wu X, Liu J, Xu Y, Wei W. Multiple roles of microRNA-146a in immune responses and hepatocellular carcinoma. Oncol Lett 2019; 18:5033-5042. [PMID: 31612014 PMCID: PMC6781720 DOI: 10.3892/ol.2019.10862] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 08/06/2019] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs/miRs), consisting of ~22 nucleotides of single-stranded RNA, participate in post-transcriptional gene regulation by binding to the 3′-untranslated region (UTR) of mRNAs, repressing their translation and promoting their degradation. Studies have shown that certain miRNAs play a key role in the control of various cellular activities, such as inhibiting inflammation, modulating cell differentiation and suppressing cancer growth. The role of miR-146a in the immune response and in the pathogenesis of hepatocellular carcinoma (HCC) has also been investigated. Although some studies have shown that increased miR-146a levels are associated with HCC, others have revealed that miR-146a suppresses cancer cell proliferation, invasion and metastasis. Toll-like receptor 4 (TLR4) signaling has an important role in regulating innate and adaptive immune responses. In addition, TLR4 is functionally expressed in HCC cells and promotes HCC cell proliferation, which can be regulated by miR-146a. The present review focuses on the recent progress in analyzing the multiple roles of miR-146a in mediating the TLR4 pathway and adaptive immune response. Finally, the function of miR-146a in the pathogenesis of HCC is also discussed.
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Affiliation(s)
- Huihui Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xuemei Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Tao Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Lianzi Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xian Wu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Jiaqing Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yuanhong Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Wei Wei
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Chen X, Xie D, Zhao Q, You ZH. MicroRNAs and complex diseases: from experimental results to computational models. Brief Bioinform 2019; 20:515-539. [PMID: 29045685 DOI: 10.1093/bib/bbx130] [Citation(s) in RCA: 423] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/13/2017] [Indexed: 12/22/2022] Open
Abstract
Plenty of microRNAs (miRNAs) were discovered at a rapid pace in plants, green algae, viruses and animals. As one of the most important components in the cell, miRNAs play a growing important role in various essential and important biological processes. For the recent few decades, amounts of experimental methods and computational models have been designed and implemented to identify novel miRNA-disease associations. In this review, the functions of miRNAs, miRNA-target interactions, miRNA-disease associations and some important publicly available miRNA-related databases were discussed in detail. Specially, considering the important fact that an increasing number of miRNA-disease associations have been experimentally confirmed, we selected five important miRNA-related human diseases and five crucial disease-related miRNAs and provided corresponding introductions. Identifying disease-related miRNAs has become an important goal of biomedical research, which will accelerate the understanding of disease pathogenesis at the molecular level and molecular tools design for disease diagnosis, treatment and prevention. Computational models have become an important means for novel miRNA-disease association identification, which could select the most promising miRNA-disease pairs for experimental validation and significantly reduce the time and cost of the biological experiments. Here, we reviewed 20 state-of-the-art computational models of predicting miRNA-disease associations from different perspectives. Finally, we summarized four important factors for the difficulties of predicting potential disease-related miRNAs, the framework of constructing powerful computational models to predict potential miRNA-disease associations including five feasible and important research schemas, and future directions for further development of computational models.
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Affiliation(s)
- Xing Chen
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Di Xie
- School of Mathematics, Liaoning University
| | - Qi Zhao
- School of Mathematics, Liaoning University
| | - Zhu-Hong You
- Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Science
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LMP1–miR-146a–CXCR4 axis regulates cell proliferation, apoptosis and metastasis. Virus Res 2019; 270:197654. [DOI: 10.1016/j.virusres.2019.197654] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/07/2019] [Accepted: 07/08/2019] [Indexed: 11/23/2022]
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Kumar S, Espinosa EC, Leandro AC, Curran JE, Blangero J. microRNA and mRNA interactions in induced pluripotent stem cell reprogramming of lymphoblastoid cell lines. AMERICAN JOURNAL OF STEM CELLS 2019; 8:28-37. [PMID: 31523484 PMCID: PMC6737382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 07/23/2019] [Indexed: 06/10/2023]
Abstract
A large number of Epstein Barr virus (EBV) immortalized lymphoblastoid cell lines (LCLs) have been generated and maintained in genetic/epidemiological studies as a perpetual source of DNA and as a surrogate in vitro cell model. Recent successes in reprograming LCLs into induced pluripotent stem cells (iPSCs) has paved the way to generate more relevant in vitro disease models using this existing bioresource. However, the latent EBV infection in the LCLs make them a unique cell type by altering expression of many cellular genes and miRNAs. These EBV induced changes in the LCL miRNome and transcriptome are reversed upon reprogramming into iPSCs, which allows a unique opportunity to better understand the miRNA and mRNA interactions that are EBV induced in LCLs and the changes that takes place during iPSC reprogramming. To identify the potential miRNA-mRNA interactions and better understand their role in regulating the cellular transitions in LCLs and their reprogrammed iPSCs, we performed a parallel genome-wide miRNA and mRNA expression analysis in six LCLs and their reprogrammed iPSCs. A total of 85 miRNAs and 5,228 mRNAs were significantly differentially expressed (DE). The target prediction of the DE miRNAs using TargetScan-Human, TarBase and miRecords databases identified 1,842 mRNA targets that were DE between LCLs and their reprogrammed iPSCs. The functional annotation, upstream regulator and gene expression analysis of the predicted DE mRNA targets suggest the role of DE miRNAs in regulating EBV induced changes in LCLs and self-renewal, pluripotency and differentiation in iPSCs.
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Affiliation(s)
- Satish Kumar
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine Edinburg and Brownsville, TX, USA
| | - Erika C Espinosa
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine Edinburg and Brownsville, TX, USA
| | - Ana C Leandro
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine Edinburg and Brownsville, TX, USA
| | - Joanne E Curran
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine Edinburg and Brownsville, TX, USA
| | - John Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine Edinburg and Brownsville, TX, USA
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Curtale G, Rubino M, Locati M. MicroRNAs as Molecular Switches in Macrophage Activation. Front Immunol 2019; 10:799. [PMID: 31057539 PMCID: PMC6478758 DOI: 10.3389/fimmu.2019.00799] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 03/26/2019] [Indexed: 12/25/2022] Open
Abstract
The efficacy of macrophage- mediated inflammatory response relies on the coordinated expression of key factors, which expression is finely regulated at both transcriptional and post-transcriptional level. Several studies have provided compelling evidence that microRNAs play pivotal roles in modulating macrophage activation, polarization, tissue infiltration, and resolution of inflammation. In this review, we highlight the essential molecular mechanisms underlying the different phases of inflammation that are targeted by microRNAs to inhibit or accelerate restoration to tissue integrity and homeostasis. We further review the impact of microRNA-dependent regulation of tumor-associated macrophages and the relative implication for tumor biology.
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Affiliation(s)
- Graziella Curtale
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.,Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - Marcello Rubino
- Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - Massimo Locati
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.,Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
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Mjelle R, Sjursen W, Thommesen L, Sætrom P, Hofsli E. Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location. BMC Cancer 2019; 19:161. [PMID: 30786859 PMCID: PMC6381638 DOI: 10.1186/s12885-019-5330-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 01/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNA) and other small RNAs are frequently dysregulated in cancer and are promising biomarkers for colon cancer. Here we profile human, virus and bacteria small RNAs in normal and tumor tissue from early stage colon cancer and correlate the expression with clinical parameters. METHODS Small RNAs from colon cancer tissue and adjacent normal mucosa of 48 patients were sequenced using Illumina high-throughput sequencing. Clinical parameters were correlated with the small RNA expression data using linear models. We performed a meta-analysis by comparing publicly available small RNA sequencing datasets with our original sequencing data to confirm the main findings. RESULTS We identified 331 differentially expressed miRNAs between tumor and normal samples. We found that the major changes in miRNA expression between left and right colon are due to miRNAs located within the Hox-developmental genes, including miR-10b, miR-196b and miR-615. Further, we identified new miRNAs associated with microsatellite instability (MSI), including miR-335, miR-26 and miR-625. We performed a meta-analysis on all publicly available miRNA-seq datasets and identified 117 common miRNAs that were differentially expressed between tumor and normal tissue. The miRNAs miR-135b and miR-31 were the most significant upregulated miRNA in tumor across all datasets. The miRNA miR-133a was the most strongly downregulated miRNA in our dataset and also showed consistent downregulation in the other datasets. The miRNAs associated with MSI and tumor location in our data showed similar changes in the other datasets. Finally, we show that small RNAs from Epstein-Barr virus and Fusobacterium nucleatum are differentially expressed between tumor and normal adjacent tissue. CONCLUSIONS Small RNA profiling in colon cancer tissue revealed novel RNAs associated with MSI and tumor location. We show that Fusobacterium nucleatum are detectable at the RNA-level in colon tissue, and that both Fusobacterium nucleatum and Epstein-Barr virus separate tumor and normal tissue.
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Affiliation(s)
- Robin Mjelle
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.
| | - Wenche Sjursen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Department of Medical Genetics, St Olavs Hospital, Trondheim Norway, Erling Skjalgssons gt 1, 7030, Trondheim, Norway
| | - Liv Thommesen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Department of Biomedical Laboratory Science, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway
| | - Pål Sætrom
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Department of Computer and Information Science, Norwegian University of Science and Technology, NTNU, Sem Sælandsvei 9, 7491, Trondheim, Norway.,Bioinformatics core facility-BioCore, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway.,K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway
| | - Eva Hofsli
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,The Cancer Clinic, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
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40
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Zheng G, Li Z, Xiang W, Huang Y, Pan M. Differentiation expression of toll‐like receptor4 (TLR4) caused by the dysregulation of microRNA‐140‐5p is responsible for the development of postoperation infection. J Cell Biochem 2018; 120:3479-3490. [PMID: 30321456 DOI: 10.1002/jcb.27623] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 08/15/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Ge Zheng
- Department of Pediatrics Ruian People's Hospital Ruian Zhejiang China
| | - Zhishu Li
- Department of Pediatrics Ruian People's Hospital Ruian Zhejiang China
| | - Wenna Xiang
- Department of Pediatrics Ruian People's Hospital Ruian Zhejiang China
| | - Yumao Huang
- Department of Pediatrics Ruian People's Hospital Ruian Zhejiang China
| | - Minli Pan
- Department of Pediatrics Ruian People's Hospital Ruian Zhejiang China
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41
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Shinde P, Bharat V, Rodriguez-Oquendo A, Zhou B, Vella AT. Understanding how combinatorial targeting of TLRs and TNFR family costimulatory members promote enhanced T cell responses. Expert Opin Biol Ther 2018; 18:1073-1083. [PMID: 30169979 DOI: 10.1080/14712598.2018.1518422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/28/2018] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Due to the ability of pathogen-associated molecular patters and tumor necrosis factor receptor (TNFR) family costimulatory agonists to boost T cell responses, studies have combined Toll-like receptor (TLR) ligands with TNFR family costimulatory receptor agonists to induce impressive and long-lasting T cell responses. Although some studies have determined how these combinatorial vaccines promote enhanced T cell responses, much remains unknown about the mechanism used by these combinations to promote synergistic T cell responses - especially in settings of infectious diseases or cancer. AREAS COVERED In this review, we look in detail at the signaling pathways induced by combinatorial targeting of TLR and TNFR family costimulatory members that help them promote synergistic T cell responses. Understanding this can greatly aid the development of novel vaccine regimens that promote cellular immune responses, which is essential for treating certain infectious diseases and cancer. EXPERT OPINION Vaccines against some infectious diseases as well as therapeutic cancer vaccines require cellular immunity. Therefore, we evaluate here how signaling pathways induced by TLR ligand and costimulatory agonist combinations promote enhanced T cell responses during immunization with model antigens, viral pathogens, or tumor antigens. Once pathways that drive these combinatorial vaccines to boost T cell activation are identified, they can be incorporated in vaccines designed to target pathogens or cancer.
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Affiliation(s)
- Paurvi Shinde
- a Bloodworks Northwest Research Institute , Seattle , WA , USA
| | - Vinita Bharat
- b Department of Neurosurgery , Stanford University School of Medicine , Stanford , CA , USA
| | | | - Beiyan Zhou
- d Department of Immunology, UConn School of Medicine , UConn Health , Farmington , CT , USA
| | - Anthony T Vella
- d Department of Immunology, UConn School of Medicine , UConn Health , Farmington , CT , USA
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MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage. PLoS One 2018; 13:e0203713. [PMID: 30260972 PMCID: PMC6160007 DOI: 10.1371/journal.pone.0203713] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/24/2018] [Indexed: 01/22/2023] Open
Abstract
Inflammatory β-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Pro-inflammatory cytokines cause β-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent β-cell failure in vitro and in vivo, in part by reducing NF-κB transcriptional activity. We investigated the hypothesis that the protective effect of KDACi involves transcriptional regulation of microRNAs (miRs), potential new targets in diabetes treatment. Insulin-producing INS1 cells were cultured with or without the broad-spectrum KDACi Givinostat, prior to exposure to the pro-inflammatory cytokines IL-1β and IFN-γ for 6 h or 24 h, and miR expression was profiled with miR array. Thirteen miRs (miR-7a-2-3p, miR-29c-3p, miR-96-5p, miR-101a-3p, miR-140-5p, miR-146a-5p, miR-146b-5p, miR-340-5p, miR-384-5p, miR-455-5p, miR-466b-2-3p, miR-652-5p, and miR-3584-5p) were regulated by both cytokines and Givinostat, and nine were examined by qRT-PCR. miR-146a-5p was strongly regulated by cytokines and KDACi and was analyzed further. miR-146a-5p expression was induced by cytokines in rat and human islets. Cytokine-induced miR-146a-5p expression was specific for INS1 and β-TC3 cells, whereas α-TC1 cells exhibited a higher basal expression. Transfection of INS1 cells with miR-146a-5p reduced cytokine signaling, including the activity of NF-κB and iNOS promoters, as well as NO production and protein levels of iNOS and its own direct targets TNF receptor associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1). miR-146a-5p was elevated in the pancreas of diabetes-prone BB-DP rats at diabetes onset, suggesting that miR-146a-5p could play a role in type 1 diabetes development. The miR array of cytokine-exposed INS1 cells rescued by KDACi revealed several other miRs potentially involved in cytokine-induced β-cell apoptosis, demonstrating the strength of this approach.
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Carvalho de Oliveira J, Molinari Roberto G, Baroni M, Bezerra Salomão K, Alejandra Pezuk J, Sol Brassesco M. MiRNA Dysregulation in Childhood Hematological Cancer. Int J Mol Sci 2018; 19:ijms19092688. [PMID: 30201877 PMCID: PMC6165337 DOI: 10.3390/ijms19092688] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/03/2018] [Accepted: 09/08/2018] [Indexed: 12/14/2022] Open
Abstract
For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors.
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Affiliation(s)
| | - Gabriela Molinari Roberto
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Mirella Baroni
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Karina Bezerra Salomão
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Julia Alejandra Pezuk
- Programa de Pós-graduação em Farmácia, Anhanguera University of São Paulo, UNIAN/SP, 05145-200 São Paulo, Brazil.
| | - María Sol Brassesco
- Departamento de Biologia, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, 14040-901 Ribeirão Preto, Brazil.
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Vrzalikova K, Sunmonu T, Reynolds G, Murray P. Contribution of Epstein⁻Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma. Pathogens 2018; 7:pathogens7030059. [PMID: 29954084 PMCID: PMC6161176 DOI: 10.3390/pathogens7030059] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 06/19/2018] [Accepted: 06/20/2018] [Indexed: 02/07/2023] Open
Abstract
Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein–Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma.
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Affiliation(s)
- Katerina Vrzalikova
- Institute for Cancer and Genomic Medicine, University of Birmingham, Birmingham B15 2TT, UK.
| | - Taofik Sunmonu
- Institute for Cancer and Genomic Medicine, University of Birmingham, Birmingham B15 2TT, UK.
| | - Gary Reynolds
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
| | - Paul Murray
- Institute for Cancer and Genomic Medicine, University of Birmingham, Birmingham B15 2TT, UK.
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 775 15 Olomouc, Czech Republic.
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Tahamtan A, Teymoori-Rad M, Nakstad B, Salimi V. Anti-Inflammatory MicroRNAs and Their Potential for Inflammatory Diseases Treatment. Front Immunol 2018; 9:1377. [PMID: 29988529 PMCID: PMC6026627 DOI: 10.3389/fimmu.2018.01377] [Citation(s) in RCA: 259] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 06/04/2018] [Indexed: 12/27/2022] Open
Abstract
Inflammation is a complicated biological and pathophysiological cascade of responses to infections and injuries, and inflammatory mechanisms are closely related to many diseases. The magnitude, the complicated network of pro- and anti-inflammatory factors, and the direction of the inflammatory response can impact on the development and progression of various disorders. The currently available treatment strategies often target the symptoms and not the causes of inflammatory disease and may often be ineffective. Since the onset and termination of inflammation are crucial to prevent tissue damage, a range of mechanisms has evolved in nature to regulate the process including negative and positive feedback loops. In this regard, microRNAs (miRNAs) have emerged as key gene regulators to control inflammation, and it is speculated that they are fine-tune signaling regulators to allow for proper resolution and prevent uncontrolled progress of inflammatory reactions. In this review, we discuss recent findings related to significant roles of miRNAs in immune regulation, especially the potential utility of these molecules as novel anti-inflammatory agents to treat inflammatory diseases. Furthermore, we discuss the possibilities of using miRNAs as drugs in the form of miRNA mimics or miRNA antagonists.
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Affiliation(s)
- Alireza Tahamtan
- Infectious Diseases Research Centre, Golestan University of Medical Sciences, Gorgan, Iran.,Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Teymoori-Rad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Britt Nakstad
- Department of Pediatric and Adolescent Medicine, Akershus University Hospital, Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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46
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Wu W, Li Y. Lung injury caused by paraquat poisoning results in increased interleukin-6 and decreased microRNA-146a levels. Exp Ther Med 2018; 16:406-412. [PMID: 29896267 DOI: 10.3892/etm.2018.6153] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Accepted: 01/03/2018] [Indexed: 12/29/2022] Open
Abstract
The aim of the present study was to investigate the expression of microRNA (miR)-146a in the pulmonary macrophages, peripheral blood mononuclear cells and serum of patients with lung injury caused by paraquat poisoning, as well as the underlying mechanism of its regulation in the disease. A total of 26 patients with lung injury caused by paraquat poisoning were included in the present study. In addition, 33 healthy subjects were included as the control group. The expression levels of interleukin (IL)-6 mRNA and miR-146a was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting was used to measure IL-6 protein expression, while enzyme-linked immunosorbent assay was also performed to determine the secretion of IL-6 protein. A dual-luciferase reporter assay was conducted to examine whether IL-6 mRNA is a direct target of miR-146a. Patients with lung injury caused by paraquat poisoning exhibited higher IL-6 mRNA and protein levels as compared with those in healthy subjects. In addition, miR-146a expression in patients with paraquat poisoning-induced lung injury was significantly reduced in comparison with that in healthy subjects. Notably, the overexpression of miR-146a by mimic transfection downregulated the expression of IL-6 in pulmonary macrophages. The results of dual-luciferase reporter assay demonstrated that IL-6 mRNA was a direct target of miR-146a. Therefore, the present study demonstrated that increased expression of IL-6 in patients with lung injury caused by paraquat poisoning is associated with decreased expression of miR-146a. Furthermore, miR-146a may regulate the occurrence and immune response of lung injury caused by paraquat poisoning and this process is possibly achieved via IL-6, an important cytokine that mediates inflammation.
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Affiliation(s)
- Wei Wu
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Yong Li
- Emergency Department, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
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47
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Nejad C, Stunden HJ, Gantier MP. A guide to miRNAs in inflammation and innate immune responses. FEBS J 2018; 285:3695-3716. [DOI: 10.1111/febs.14482] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/08/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Charlotte Nejad
- Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research Clayton Australia
- Department of Molecular and Translational Science Monash University Clayton Australia
| | - H. James Stunden
- Institute of Innate Immunity Biomedical Center University Hospitals Bonn Bonn Germany
| | - Michael P. Gantier
- Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research Clayton Australia
- Department of Molecular and Translational Science Monash University Clayton Australia
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Eilam-Frenkel B, Naaman H, Brkic G, Veksler-Lublinsky I, Rall G, Shemer-Avni Y, Gopas J. MicroRNA 146-5p, miR-let-7c-5p, miR-221 and miR-345-5p are differentially expressed in Respiratory Syncytial Virus (RSV) persistently infected HEp-2 cells. Virus Res 2018; 251:34-39. [PMID: 29733865 DOI: 10.1016/j.virusres.2018.05.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 04/17/2018] [Accepted: 05/03/2018] [Indexed: 11/15/2022]
Abstract
Many viruses can establish non-cytolytic, chronic infections in host cells. Beyond the intrinsically interesting questions of how this long-term parasitism is achieved, persistently infected cells can be useful to study virus-host interactions. MicroRNAs (miRNAs) are a class of noncoding RNAs transcribed from the genomes of all multicellular organisms and some viruses. Individual miRNAs may regulate several hundred genes. In this research we have studied the expression of a selective group of host-cell encoded miRNAs, as expressed in a Respiratory Syncytial Virus (RSV) persistently infected HEp-2 cell line (HEp-2 + RSV-GFP). The RSV is a virus that does not encode miRNAs in its genome. Our study shows that Dicer is down regulated, miRNA's 146a-5p is strongly up-regulated and miRNAs 345-5p, let-7c-5p and miRNA's-221 are down-regulated in HEp-2 + RSV-GFP cells. Correspondingly, changes in the miRNA 146a-5p and he sequences of the reference genes are miRNA 345-5p respective miRNAs target proteins: HSP-70 and p21, were observed. Thus, RSV persistent viral infection induces unique patterns of miRNA's expression with relevance to how the virus regulates the host cell response to infection.
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Affiliation(s)
- B Eilam-Frenkel
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - H Naaman
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - G Brkic
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - I Veksler-Lublinsky
- Department of Computer Science, Faculty of Engineering Sciences Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - G Rall
- Fox Chase Cancer Center, Dept. of Blood Cell Development and Function, Philadelphia, Pennsylvania, United States
| | - Y Shemer-Avni
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Department of Clinical Virology Soroka University Medical Center, Beer Sheva, Israel
| | - J Gopas
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Department of Oncology, Soroka University Medical Center, Beer Sheva, Israel.
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Soltanzadeh-Yamchi M, Shahbazi M, Aslani S, Mohammadnia-Afrouzi M. MicroRNA signature of regulatory T cells in health and autoimmunity. Biomed Pharmacother 2018; 100:316-323. [DOI: 10.1016/j.biopha.2018.02.030] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 02/03/2018] [Accepted: 02/09/2018] [Indexed: 02/07/2023] Open
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50
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Peta E, Sinigaglia A, Masi G, Di Camillo B, Grassi A, Trevisan M, Messa L, Loregian A, Manfrin E, Brunelli M, Martignoni G, Palù G, Barzon L. HPV16 E6 and E7 upregulate the histone lysine demethylase KDM2B through the c-MYC/miR-146a-5p axys. Oncogene 2018; 37:1654-1668. [PMID: 29335520 DOI: 10.1038/s41388-017-0083-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 11/24/2017] [Accepted: 11/24/2017] [Indexed: 12/13/2022]
Abstract
Persistent infection by high-risk human papillomaviruses (HPVs) is associated with the development of cervical cancer and a subset of anogenital and head and neck squamous cell carcinomas. Abnormal expression of cellular microRNAs (miRNAs) plays an important role in the development of cancer, including HPV-related tumors. In this study, we demonstrated that miR-146a-5p was down-regulated by E6 and, less efficiently, by E7 of high-risk HPV16 in keratinocytes and the presence of low levels of this miRNA in cervical carcinoma cell lines and in high-risk HPV-positive cervical specimens. Down-regulation of miR-146a-5p was mediated at least in part by the transcription repressor c-MYC, through binding sites in the miR-146a promoter. Overexpression of miR-146a-5p significantly inhibited proliferation and migration of keratinocytes and cervical cancer cells. The histone demethylase KDM2B was validated as a new direct target of miR-146a-5p and two putative binding sites for miR-146a-5p were identified in its 3'UTR sequence. Western blot analysis and immunohistochemistry showed that KDM2B was overexpressed in HPV16 E6/E7-positive keratinocytes, in cervical cancer cell lines, and in a subset of invasive cervical carcinomas and HPV-positive laryngeal squamous cell carcinomas. In these tumors, KDM2B overexpression was associated with c-MYC copy number gain. In vitro, silencing of KDM2B inhibited proliferation of cervical cancer cells. In conclusion, this study identified a novel player, the hystone demethylase KDM2B, in HPV-mediated tumorigenesis. E6 and, less efficiently, E7 of high-risk HPV16 up-regulated KDM2B expression in human keratinocytes through a pathway involving overexpression of c-MYC, which in turn downregulated miR-146a-5p.
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Affiliation(s)
- Elektra Peta
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | | | - Giulia Masi
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Barbara Di Camillo
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Angela Grassi
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Marta Trevisan
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Lorenzo Messa
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Arianna Loregian
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Erminia Manfrin
- Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Verona, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Verona, Italy
| | - Guido Martignoni
- Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Verona, Italy
| | - Giorgio Palù
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Luisa Barzon
- Department of Molecular Medicine, University of Padova, Padova, Italy.
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