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1
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Stewart J, Damania B. Innate Immune Recognition of EBV. Curr Top Microbiol Immunol 2025. [PMID: 40399572 DOI: 10.1007/82_2025_297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
Epstein-Barr virus (EBV) is a very successful human pathogen, with ~95% seroprevalence worldwide (Mentzer et al, Nat Commun 13:1818, 2022). If contracted in early childhood, EBV infection is typically asymptomatic; however, infections in adolescence and adulthood can manifest as infectious mononucleosis (IM). The innate immune response is the first line of defense, and its function is critical for controlling EBV infection. During EBV infection, components of the virus, known as pathogen-associated molecular patterns (PAMPs), are recognized by germline-encoded pattern recognition receptors (PRRs). PRRs are found on both non-immune and immune cells including antigen-presenting cells, such as macrophages, monocytes, dendritic cells, natural killer (NK), and mast cells. PRRs are also found on B cells and epithelial cells, the primary targets of EBV infection. Without immune surveillance, EBV can transform cells inducing various malignancies. Conversely, a prolonged innate immune response can lead to chronic inflammation which increases the likelihood of cancer. This review discusses innate immune recognition of EBV and its associated diseases.
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Affiliation(s)
- Jessica Stewart
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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2
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Zhan Y, Zheng F, Liao S, Lu X, Cao F, Huang T, Yang X, Han Y, Zeng L, Li L, Huang W. Epstein-Barr virus-positive small cell neuroendocrine carcinoma of the nasopharynx: A clinicopathologic study of 7 cases and literature review. Hum Pathol 2025; 158:105787. [PMID: 40354885 DOI: 10.1016/j.humpath.2025.105787] [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: 02/26/2025] [Revised: 05/03/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025]
Abstract
Epstein-Barr virus (EBV)-positive small cell neuroendocrine carcinoma (NEC) of the nasopharynx is a rare entity with poorly characterized clinicopathological and prognostic features. In this study, seven cases of EBV-positive nasopharyngeal small cell NEC will be compared to 6 EBV-negative cases of nasopharyngeal small cell NEC. The overall EBV-positive rate, defined by EBV-encoded small RNAs (EBERs) in situ hybridization of nasopharyngeal small cell NEC, was 53.8 % (7/13). The patients' age ranged from 38 to 73 years, with a median age of 56 years. There was a large preponderance of males, with a male-to-female ratio of 6:1. In the present study, EBV-positive nasopharyngeal small cell NEC had a significantly higher expression of POU2F3 (85.7 %, 6/7) than EBV-negative nasopharyngeal small cell NEC (16.7 %, 1/6). RNA sequencing revealed that EBV-positive nasopharyngeal small cell NEC was distinct from EBV-negative nasopharyngeal small cell NEC in the control group. There was no statistically significant difference in overall survival between patients with EBV-positive and EBV-negative nasopharyngeal small cell NEC in the present cohort. These findings suggest that EBV-positive nasopharyngeal small cell NEC may be closely associated with POU2F3. In addition, POU2F3 and ASCL1 may play important roles in the tumorigenesis of EBV-positive nasopharyngeal small cell NEC.
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Aged
- Carcinoma, Neuroendocrine/virology
- Carcinoma, Neuroendocrine/pathology
- Carcinoma, Neuroendocrine/mortality
- Carcinoma, Neuroendocrine/chemistry
- Nasopharyngeal Neoplasms/virology
- Nasopharyngeal Neoplasms/pathology
- Nasopharyngeal Neoplasms/mortality
- Epstein-Barr Virus Infections/virology
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/pathology
- Adult
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/isolation & purification
- Carcinoma, Small Cell/virology
- Carcinoma, Small Cell/pathology
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- RNA, Viral/genetics
- In Situ Hybridization
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Affiliation(s)
- Yuan Zhan
- Department of Pathology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Fei Zheng
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Shousheng Liao
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Xiangtong Lu
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Fang Cao
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Tao Huang
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Xuan Yang
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Yue Han
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Lei Zeng
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Lixiang Li
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
| | - Wenyong Huang
- Department of Pathology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China.
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3
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Hsu CL, Chang YS, Li HP. Molecular diagnosis of nasopharyngeal carcinoma: Past and future. Biomed J 2025; 48:100748. [PMID: 38796105 PMCID: PMC11772973 DOI: 10.1016/j.bj.2024.100748] [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: 03/24/2024] [Revised: 05/01/2024] [Accepted: 05/12/2024] [Indexed: 05/28/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from the nasopharynx epithelial cells and has been linked with Epstein-Barr virus (EBV) infection, dietary habits, environmental and genetic factors. It is a common malignancy in Southeast Asia, especially with gender preference among men. Due to its non-specific symptoms, NPC is often diagnosed at a late stage. Thus, the molecular diagnosis of NPC plays a crucial role in early detection, treatment selection, disease monitoring, and prognosis prediction. This review aims to provide a summary of the current state and the latest emerging molecular diagnostic techniques for NPC, including EBV-related biomarkers, gene mutations, liquid biopsy, and DNA methylation. Challenges and potential future directions of NPC molecular diagnosis will be discussed.
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Affiliation(s)
- Cheng-Lung Hsu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Sun Chang
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-Pai Li
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
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4
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Ma L, Guo H, Zhao Y, Liu Z, Wang C, Bu J, Sun T, Wei J. Liquid biopsy in cancer current: status, challenges and future prospects. Signal Transduct Target Ther 2024; 9:336. [PMID: 39617822 PMCID: PMC11609310 DOI: 10.1038/s41392-024-02021-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/10/2024] [Accepted: 10/14/2024] [Indexed: 12/06/2024] Open
Abstract
Cancer has a high mortality rate across the globe, and tissue biopsy remains the gold standard for tumor diagnosis due to its high level of laboratory standardization, good consistency of results, relatively stable samples, and high accuracy of results. However, there are still many limitations and drawbacks in the application of tissue biopsy in tumor. The emergence of liquid biopsy provides new ideas for early diagnosis and prognosis of tumor. Compared with tissue biopsy, liquid biopsy has many advantages in the diagnosis and treatment of various types of cancer, including non-invasive, quickly and so on. Currently, the application of liquid biopsy in tumor detection has received widely attention. It is now undergoing rapid progress, and it holds significant potential for future applications. Around now, liquid biopsies encompass several components such as circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. In addition, advances in the identification of liquid biopsy indicators have significantly enhanced the possibility of utilizing liquid biopsies in clinical settings. In this review, we will discuss the application, advantages and challenges of liquid biopsy in some common tumors from the perspective of diverse systems of tumors, and look forward to its future development prospects in the field of cancer diagnosis and treatment.
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Affiliation(s)
- Liwei Ma
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China.
| | - Huiling Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Yunxiang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhibo Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Chenran Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Jiahao Bu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ting Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China.
| | - Jianwei Wei
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Chakraborty C, Bhattacharya M, Lee SS. Regulatory role of miRNAs in the human immune and inflammatory response during the infection of SARS-CoV-2 and other respiratory viruses: A comprehensive review. Rev Med Virol 2024; 34:e2526. [PMID: 38446531 DOI: 10.1002/rmv.2526] [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: 01/16/2024] [Revised: 02/11/2024] [Accepted: 02/22/2024] [Indexed: 03/07/2024]
Abstract
miRNAs are single-stranded ncRNAs that act as regulators of different human body processes. Several miRNAs have been noted to control the human immune and inflammatory response during severe acute respiratory infection syndrome (SARS-CoV-2) infection. Similarly, many miRNAs were upregulated and downregulated during different respiratory virus infections. Here, an attempt has been made to capture the regulatory role of miRNAs in the human immune and inflammatory response during the infection of SARS-CoV-2 and other respiratory viruses. Firstly, the role of miRNAs has been depicted in the human immune and inflammatory response during the infection of SARS-CoV-2. In this direction, several significant points have been discussed about SARS-CoV-2 infection, such as the role of miRNAs in human innate immune response; miRNAs and its regulation of granulocytes; the role of miRNAs in macrophage activation and polarisation; miRNAs and neutrophil extracellular trap formation; miRNA-related inflammatory response; and miRNAs association in adaptive immunity. Secondly, the miRNAs landscape has been depicted during human respiratory virus infections such as human coronavirus, respiratory syncytial virus, influenza virus, rhinovirus, and human metapneumovirus. The article will provide more understanding of the miRNA-controlled mechanism of the immune and inflammatory response during COVID-19, which will help more therapeutics discoveries to fight against the future pandemic.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal, India
| | | | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopaedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Gangwon-do, Republic of Korea
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6
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Abdoli Shadbad M, Hemmat N, Abdoli Shadbad M, Brunetti O, Silvestris N, Baradaran B. HSV1 microRNAs in glioblastoma development: an in silico study. Sci Rep 2024; 14:27. [PMID: 38167429 PMCID: PMC10761845 DOI: 10.1038/s41598-023-45249-2] [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: 04/16/2023] [Accepted: 10/17/2023] [Indexed: 01/05/2024] Open
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor. Recent findings highlighted the significance of viral microRNAs (miRs) in regulating post-transcriptional mRNA expression in various human conditions. Although HSV1 encodes viral miRs and affects the central nervous system, no study investigated the roles of HSV1-encoding miRs in GBM development. This study applied in silico approaches to investigate whether HSV1-encoding miRs are involved in GBM development and, if so, how they regulate tumor-suppressive/oncogenes expression in GBM. This study leveraged bioinformatics approaches to identify the potential effect of HSV1 miRs in GBM development. The GSE158284, GSE153679, and GSE182109 datasets were analyzed to identify differentially expressed genes in GBM tissues and cell lines using the limma package in the R software. The GSE182109 dataset was analyzed to determine gene expression at the single-cell levels using the Seurat package in the R software. The TCGA-GTEX, GDSC, CTRP, immunogenetic, and enrichment analyses were performed to study the impact of identified viral HSV1 miRs targets in GBM development. hsv1-miR-H6-3p is upregulated in GBM and can be responsible for EPB41L1 and SH3PXD2A downregulation in GBM tissues. Also, hsv1-miR-H1-5p is upregulated in GBM and can decrease the expression of MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC in GBM development. The single-cell RNA sequencing analyses have demonstrated that MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC are expressed in astrocytes residing in the GBM microenvironment. This study provides novel insights into the potential roles of HSV1 miRs in GBM pathogenesis and offers a reference for further studies on the significance of HSV1 miRs in GBM development.
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Affiliation(s)
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- European Virus Bioinformatics Center (EVBC), 07743, Jena, Germany
| | | | - Oronzo Brunetti
- Medical Oncology Unit-IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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7
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miRNAs in Herpesvirus Infection: Powerful Regulators in Small Packages. Viruses 2023; 15:v15020429. [PMID: 36851643 PMCID: PMC9965283 DOI: 10.3390/v15020429] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/29/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
microRNAs are a class of small, single-stranded, noncoding RNAs that regulate gene expression. They can be significantly dysregulated upon exposure to any infection, serving as important biomarkers and therapeutic targets. Numerous human DNA viruses, along with several herpesviruses, have been found to encode and express functional viral microRNAs known as vmiRNAs, which can play a vital role in host-pathogen interactions by controlling the viral life cycle and altering host biological pathways. Viruses have also adopted a variety of strategies to prevent being targeted by cellular miRNAs. Cellular miRNAs can act as anti- or proviral components, and their dysregulation occurs during a wide range of infections, including herpesvirus infection. This demonstrates the significance of miRNAs in host herpesvirus infection. The current state of knowledge regarding microRNAs and their role in the different stages of herpes virus infection are discussed in this review. It also delineates the therapeutic and biomarker potential of these microRNAs in future research directions.
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8
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Thakur A, Kumar M. AntiVIRmiR: A repository of host antiviral miRNAs and their expression along with experimentally validated viral miRNAs and their targets. Front Genet 2022; 13:971852. [PMID: 36159991 PMCID: PMC9493126 DOI: 10.3389/fgene.2022.971852] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
miRNAs play an essential role in promoting viral infections as well as modulating the antiviral defense. Several miRNA repositories have been developed for different species, e.g., human, mouse, and plant. However, 'VIRmiRNA' is the only existing resource for experimentally validated viral miRNAs and their targets. We have developed a 'AntiVIRmiR' resource encompassing data on host/virus miRNA expression during viral infection. This resource with 22,741 entries is divided into four sub-databases viz., 'DEmiRVIR', 'AntiVmiR', 'VIRmiRNA2' and 'VIRmiRTar2'. 'DEmiRVIR' has 10,033 differentially expressed host-viral miRNAs for 21 viruses. 'AntiVmiR' incorporates 1,642 entries for host miRNAs showing antiviral activity for 34 viruses. Additionally, 'VIRmiRNA2' includes 3,340 entries for experimentally validated viral miRNAs from 50 viruses along with 650 viral isomeric sequences for 14 viruses. Further, 'VIRmiRTar2' has 7,726 experimentally validated targets for viral miRNAs against 21 viruses. Furthermore, we have also performed network analysis for three sub-databases. Interactions between up/down-regulated human miRNAs and viruses are displayed for 'AntiVmiR' as well as 'DEmiRVIR'. Moreover, 'VIRmiRTar2' interactions are shown among different viruses, miRNAs, and their targets. We have provided browse, search, external hyperlinks, data statistics, and useful analysis tools. The database available at https://bioinfo.imtech.res.in/manojk/antivirmir would be beneficial for understanding the host-virus interactions as well as viral pathogenesis.
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Affiliation(s)
- Anamika Thakur
- Virology Unit and Bioinformatics Centre, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39-A, Chandigarh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Manoj Kumar
- Virology Unit and Bioinformatics Centre, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39-A, Chandigarh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Zhang T, Chen Z, Deng J, Xu K, Che D, Lin J, Jiang P, Gu X, Xu B. Epstein-Barr virus-encoded microRNA BART22 serves as novel biomarkers and drives malignant transformation of nasopharyngeal carcinoma. Cell Death Dis 2022; 13:664. [PMID: 35907914 PMCID: PMC9338958 DOI: 10.1038/s41419-022-05107-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 01/21/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy ubiquitously associated with Epstein-Barr virus (EBV). EBV generates various viral microRNAs (miRNAs) by processing the BHRF1 and BamHI A rightward (BART) transcripts. These BART miRNAs are abundantly expressed in NPC, but their functions and molecular mechanisms remain largely unknown. Our study found that the EBV-encoded microRNA BART-22 was significantly upregulated in NPC tissues and positively correlated with tumor progression. Furthermore, we found that EBV-miR-BART-22 was a significant predictor of poor prognosis in NPC. A reliable nomogram model to predict the preoperative overall survival (OS) of NPC patients was established. The area under the receiver operating characteristic (ROC) curve value for 5-year survival was 0.91. Elevated levels of EBV-miR-BART-22 significantly promoted the epithelial-mesenchymal transition (EMT) and metastasis of NPC cells in vivo and in vitro. We found that EBV-miR-BART-22 directly targets the 3'-UTR of MOSPD2 mRNA to promote the EMT and metastasis of NPC cells by activating the Wnt/β-catenin signaling pathway. Our findings provide a potential prognostic biomarker and new insight into the molecular mechanisms of NPC metastasis.
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Affiliation(s)
- Ting Zhang
- Department of Laboratory Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Zui Chen
- Department of Laboratory Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Jing Deng
- Department of Laboratory Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Kaixiong Xu
- Department of Laboratory Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Di Che
- Department of Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jiamin Lin
- Department of Laboratory Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Ping Jiang
- Department of Laboratory Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Xiaoqiong Gu
- Department of Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
| | - Banglao Xu
- Department of Laboratory Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China.
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Viral Encoded miRNAs in Tumorigenesis: Theranostic Opportunities in Precision Oncology. Microorganisms 2022; 10:microorganisms10071448. [PMID: 35889167 PMCID: PMC9321719 DOI: 10.3390/microorganisms10071448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV- and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tumorigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic biomarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology.
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11
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Abusalah MAH, Irekeola AA, Hanim Shueb R, Jarrar M, Yean Yean C. Prognostic Epstein-Barr Virus (EBV) miRNA biomarkers for survival outcome in EBV-associated epithelial malignancies: Systematic review and meta-analysis. PLoS One 2022; 17:e0266893. [PMID: 35436288 PMCID: PMC9015129 DOI: 10.1371/journal.pone.0266893] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/29/2022] [Indexed: 11/19/2022] Open
Abstract
Background
The EBV-associated epithelial tumours consist 80% of all EBV-associated cancer, where the nasopharyngeal cancer (NPC) and EBV-associated gastric carcinoma (EBVaGC) are considered as the most frequent EBV-associated epithelial tumours. It has been shown that the BART-encoded miRNAs are abundantly expressed in EBV-associated epithelial tumours, hence, these miRNAs may serve as diagnostic and prognostic biomarkers for EBV-associated epithelial tumours. Therefore, the purpose of this systematic review and meta-analysis is to assess these EBV miRNAs as prognostic biomarkers for NPC and GC.
Method
This systematic review was developed based on PRISMA guidelines and utilizing PubMed, Web of Science, Scopus, Cochrane, and Google scholar databases. The retrieved articles were thoroughly screened in accordance with the selection criteria. The hazard ratio (HR) and 95% confidence interval (CI) for patient survival outcomes were used to evaluate EBV miRNA expression levels. To assess the risk of bias, funnel plot symmetry and Egger’s bias test were employed.
Result
Eleven studies met the selection criteria for inclusion, and four were included in the meta-analysis. Most of the articles considered in this study were from China, with one study from South Korea. The overall pooled effect size estimation (HR) for upregulated EBV miRNAs was 3.168 (95% CI: 2.020–4.969), demonstrating that upregulated EBV miRNA expression enhanced the mortality risk in NPC and GC patients by three times.
Conclusion
To the best of our knowledge, this is the first meta-analysis that investigates the significance of EBV miRNAs as prognostic biomarkers in NPC and GC patients. The pooled effect estimates of HR of the various studies revealed that higher EBV miRNA expression in NPC and GC may result in a worse survival outcome. To assess the clinical significance of EBV miRNAs as prognostic biomarkers, larger-scale prospective studies are needed.
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Affiliation(s)
- Mai Abdel Haleem Abusalah
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti SainsMalaysia, Kelantan, Malaysia
| | - Ahmad Adebayo Irekeola
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti SainsMalaysia, Kelantan, Malaysia
- Microbiology Unit, Department of Biological Sciences, College of Natural and Applied Sciences, Summit University Offa, Offa, Kwara State, Nigeria
| | - Rafidah Hanim Shueb
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti SainsMalaysia, Kelantan, Malaysia
| | - Mu’taman Jarrar
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Chan Yean Yean
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti SainsMalaysia, Kelantan, Malaysia
- * E-mail: ,
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12
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Lin C, Lin K, Zhang B, Su Y, Guo Q, Lu T, Xu Y, Lin S, Zong J, Pan J. OUP accepted manuscript. Oncologist 2022; 27:e340-e349. [PMID: 35380720 PMCID: PMC8982379 DOI: 10.1093/oncolo/oyac024] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/13/2021] [Indexed: 11/23/2022] Open
Abstract
Background Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-associated tumor that is highly common in southern China. Our previous sequencing data demonstrated that the EBV-encoded microRNA BART8-3p was most upregulated in nasopharyngeal carcinoma (NPC) and was closely associated with the metastasis of NPC. However, the values of plasma BART8-3p in NPC patients have not yet been well characterized. Material and Methods We quantified plasma BART8-3p expression by quantitative real-time PCR in 205 newly diagnosed NPC patients. Kaplan-Meier analysis was used to compare overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) between the groups. Results Plasma pretreatment BART8-3p was highly expressed in NPC patients compared with healthy controls. Pretreatment BART8-3p yielded a 92% predictive value for detecting NPC. Importantly, BART8-3p decreased dramatically after therapy relative to pretreatment levels. High levels of pretreatment or post-treatment BART8-3p were associated with worse OS, DMFS, and LRRFS. Multivariate analysis showed that high pretreatment or post-treatment BART8-3p was an independent unfavorable prognostic marker for OS (HR 3.82, 95% CI 1.77-8.24, P = .001 or HR 2.74, 95% CI 1.27-5.91, P = .010), DMFS (HR 2.82, 95% CI 1.36-5.85, P = .005 or HR 3.27, 95% CI 1.57-6.81, P = .002), and LRRFS (HR 1.94, 95% CI 1.12-3.35, P = .018 or HR 2.03, 95% CI 1.14-3.62, P = .016) in NPC. Subgroup analysis revealed that for patients with locally advanced NPC with high levels of pretreatment BART8-3p (n = 58), more cycles of chemotherapy (≥6 cycles) tended to prolong OS (P = .070). Over 50% (6/11) patients with high levels of post-treatment BART8-3p presented distant metastasis. Conclusion Plasma BART8-3p is a promising biomarker for the detection and prognosis of NPC.
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Affiliation(s)
- Cheng Lin
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
- The School of Clinical Medicine and Fujian Medical University, Fuzhou, People’s Republic of China
| | - Keyu Lin
- Department of Radiation Biology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ying Su
- Department of Radiation Biology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
| | - Qiaojuan Guo
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
| | - Tianzhu Lu
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
| | - Yuanji Xu
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
| | - Shaojun Lin
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
| | - Jingfeng Zong
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
- Corresponding author: Jianji Pan and Jingfeng Zong, Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital No. 420 Fuma Road, Fuzhou 350014, People’s Republic of China. ;
| | - Jianji Pan
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, People’s Republic of China
- Corresponding author: Jianji Pan and Jingfeng Zong, Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital No. 420 Fuma Road, Fuzhou 350014, People’s Republic of China. ;
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Valverde A, Seal A, Nares S, Shukla D, Naqvi AR. Human herpesvirus-encoded MicroRNA in host-pathogen interaction. Adv Biol Regul 2021; 82:100829. [PMID: 34560402 PMCID: PMC11646283 DOI: 10.1016/j.jbior.2021.100829] [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: 06/21/2021] [Revised: 08/28/2021] [Accepted: 09/13/2021] [Indexed: 11/17/2022]
Abstract
Human herpesviruses (HHV) are ubiquitous, linear dsDNA viruses that establish lifelong latency, disrupted by sporadic reactivation. HHV have evolved diverse ingenious mechanisms to evade robust host defenses. Incorporation of unique stem loop sequences that generate viral microRNAs (v-miRs) exemplifies one such evolutionary adaptation in HHV. These noncoding RNAs can control cellular and viral transcriptomes highlighting their ability in shaping host-HHV interactions. We summarize recent developments in functional characterization of HHV-encoded miRNAs in shaping the outcome of host-pathogen interaction. Non-immunogenic dissemination of v-miRs through exosomes confer added advantage to HHV in incessant modulation of host microenvironment. This review delineates the mechanistic role of v-miRs in facilitating viral persistence and tropism by targeting genes associated with cellular (apoptosis, angiogenesis, cell migration, etc.) and viral life cycle (latency, lytic and reactivation). Burgeoning evidences indicate plausible association of v-miRs in various immune-mediated diseases (nasopharyngeal carcinoma, neurological disorders, periodontal diseases, etc.) and herpesvirus-related malignancies indicating their broad-spectrum impact on host cellular pathways. We propose to exploit tisssue and systemic levels of v-miRs as diagnostic and prognostic markers for cancers and immune-mediated diseases. Therapeutic targeting of v-miRs will advance the promising outcomes of preclinical discoveries to bedside application.
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Affiliation(s)
- Araceli Valverde
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Alexandra Seal
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Salvador Nares
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Deepak Shukla
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, United States; Department of Ophthalmology and Visual Sciences, University of Illinois Medical Center, Chicago, IL, United States
| | - Afsar Raza Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States.
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Luo WJ, He SW, Zou WQ, Zhao Y, He QM, Yang XJ, Guo R, Mao YP. Epstein-Barr virus microRNA BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7. Exp Biol Med (Maywood) 2021; 246:2618-2629. [PMID: 34424090 DOI: 10.1177/15353702211037261] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Non-keratinizing nasopharyngeal carcinoma, the major subtype of nasopharyngeal carcinoma, is characterized by low differentiation and a close relation to Epstein-Barr virus infection, which indicates a link between Epstein-Barr virus oncogenesis and loss of differentiation, and raises our interest in investigating the involvement of Epstein-Barr virus in nasopharyngeal carcinoma dedifferentiation. Our previous study showed abundant expression of an Epstein-Barr virus-encoded microRNA, BART10-3p, in nasopharyngeal carcinoma tissues, but the association between BART10-3p and nasopharyngeal carcinoma differentiation remains unknown. Here, we examined the expression and prognostic value of BART10-3p, and undertook bioinformatics analysis and functional assays to investigate the influence of BART10-3p on nasopharyngeal carcinoma differentiation and proliferation and the underpinning mechanism. Microarray analysis identified BART10-3p as the most significantly upregulated Epstein-Barr virus-encoded microRNA in nasopharyngeal carcinoma tissues and the upregulation was confirmed in two public datasets. The expression of BART10-3p was an independent unfavorable prognosticator in nasopharyngeal carcinoma and its integration with the clinical stage showed improved prognosis predictive performance. Bioinformatics analysis suggested a potential role of BART10-3p in tumor differentiation and progression. Functional assays demonstrated that BART10-3p could promote nasopharyngeal carcinoma cell dedifferentiation, epithelial-mesenchymal transition, and proliferation in vitro, and tumorigenicity in vivo. Mechanistically, BART10-3p directly targeted the 3'UTR of ALK7 and suppressed its expression. Reconstitution of ALK7 rescued BART10-3p-induced malignant phenotypes. Overall, our study demonstrates that BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7, suggesting a promising therapeutic opportunity to reverse the malignant phenotypes of nasopharyngeal carcinoma.
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Affiliation(s)
- Wei-Jie Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Shi-Wei He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Wen-Qing Zou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yin Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Qing-Mei He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Xiao-Jing Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Rui Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yan-Ping Mao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
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15
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Lung RWM, Tong JHM, Ip LM, Lam KH, Chan AWH, Chak WP, Chung LY, Yeung WW, Hau PM, Chau SL, Tsao SW, Lau KM, Lo KW, To KF. EBV-encoded miRNAs can sensitize nasopharyngeal carcinoma to chemotherapeutic drugs by targeting BRCA1. J Cell Mol Med 2020; 24:13523-13535. [PMID: 33074587 PMCID: PMC7701581 DOI: 10.1111/jcmm.16007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 09/24/2020] [Accepted: 09/29/2020] [Indexed: 12/14/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated epithelial malignancy. The high expression of BART‐miRNAs (miR‐BARTs) during latent EBV infection in NPC strongly supports their pathological importance in cancer progression. Recently, we found that several BART‐miRNAs work co‐operatively to modulate the DNA damage response (DDR) by reducing Ataxia‐telangiectasia‐mutated (ATM) activity. In this study, we further investigated the role of miR‐BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down‐regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2‐3p, BART12, BART17‐5p and BART19‐3p in BRCA1 expression. The ectopic expression of these four miR‐BARTs suppressed endogenous BRCA1 expression in EBV‐negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR‐BARTs activities in C666‐1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR‐BART17‐5p and miR‐BART19‐3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA‐damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR‐BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.
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Affiliation(s)
- Raymond Wai-Ming Lung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Joanna Hung-Man Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Lok-Man Ip
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka-Hei Lam
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Anthony Wing-Hung Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Wing-Po Chak
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Lau-Ying Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Walter Wai Yeung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Pok-Man Hau
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Shuk-Ling Chau
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Sai-Wah Tsao
- Department of Biomedical Sciences and Center of Nasopharyngeal Carcinoma Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China
| | - Kin-Mang Lau
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Kwok-Wai Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
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16
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Wardana T, Gunawan L, Herawati C, Oktriani R, Anwar SL, Astuti I, Aryandhono T, Mubarika S. Circulation EBV Mir-Bart-7 Relating to Clinical Manifestation in Nasopharyngeal Carcinoma. Asian Pac J Cancer Prev 2020; 21:2777-2782. [PMID: 32986380 PMCID: PMC7779452 DOI: 10.31557/apjcp.2020.21.9.2777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 09/25/2020] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVE Nasopharyngeal Carcinoma (NPC) is an endemic head and neck malignancy in Asia Pacific regions that is associated with chronic infection by Epstein-Barr virus (EBV). EBV miR-BART-7 is a microRNA (miRNA) encoded by EBV that regulates malignant behavior of NPC. However, the role and function of miR-BART7 are not clear, particularly the relation of circulating levels and patient's clinical presentation. METHODS Circulating miR-BART-7 levels were measured by using qRT-PCR and were correlated with clinical and pathological data. RESULT Of 52 NPC patients included in this study, 85% were diagnosed in the late stages (Stage III-IV). 73% of tumors were non-keratinizing undifferentiated NPC, 92% of tumors were WHO class III histology and all cases were EBV-IgA positive. Over-expression of miR-BART7-3p was correlated with positive regional lymph nodes in newly diagnosed (4.61 fold changes, p <0.05). CONCLUSION Over-expression of circulating EBV miR-BART7 correlated with positive regional lymph nodes reflecting the diagnostic and prognostic values of circulating miR-BART7 for patients with NPC.
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Affiliation(s)
- Tirta Wardana
- Department of Biomedicine, School of Dentistry, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Indonesia.
| | - Lisa Gunawan
- Postgraduate Student, Center for Biotechnology, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Cita Herawati
- Department of Ear, Nose and Throat, Dharmais National Cancer Hospital, Jakarta, Indonesia.
| | - Risky Oktriani
- Department of Biochemistry, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Sumadi Lukman Anwar
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Indwiani Astuti
- Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Teguh Aryandhono
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Sofia Mubarika
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
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Richardo T, Prattapong P, Ngernsombat C, Wisetyaningsih N, Iizasa H, Yoshiyama H, Janvilisri T. Epstein-Barr Virus Mediated Signaling in Nasopharyngeal Carcinoma Carcinogenesis. Cancers (Basel) 2020; 12:2441. [PMID: 32872147 PMCID: PMC7565514 DOI: 10.3390/cancers12092441] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 12/14/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most common tumors occurring in China and Southeast Asia. Etiology of NPC seems to be complex and involves many determinants, one of which is Epstein-Barr virus (EBV) infection. Although evidence demonstrates that EBV infection plays a key role in NPC carcinogenesis, the exact relationship between EBV and dysregulation of signaling pathways in NPC needs to be clarified. This review focuses on the interplay between EBV and NPC cells and the corresponding signaling pathways, which are modulated by EBV oncoproteins and non-coding RNAs. These altered signaling pathways could be critical for the initiation and progression of NPC.
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Affiliation(s)
- Timmy Richardo
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany;
- Department of Biomedicine, Indonesia International Institute for Life Science (i3L), Jakarta 13210, Indonesia;
- Department of Microbiology, Shimane University, Izumo 693-8501, Japan; (H.I.); (H.Y.)
| | - Pongphol Prattapong
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (P.P.); (C.N.)
| | - Chawalit Ngernsombat
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (P.P.); (C.N.)
| | - Nurulfitri Wisetyaningsih
- Department of Biomedicine, Indonesia International Institute for Life Science (i3L), Jakarta 13210, Indonesia;
| | - Hisashi Iizasa
- Department of Microbiology, Shimane University, Izumo 693-8501, Japan; (H.I.); (H.Y.)
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University, Izumo 693-8501, Japan; (H.I.); (H.Y.)
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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The Oncogenic Role of miR-BART19-3p in Epstein-Barr Virus-Associated Diseases. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5217039. [PMID: 32714979 PMCID: PMC7354642 DOI: 10.1155/2020/5217039] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/18/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022]
Abstract
Accumulating evidence so far has shown that EBV's miRNAs have been found to be involved in cancer progression. However, the comprehensive EBV miRNA expression profiles and their biological significance in EBV-associated diseases are not well documented. A comprehensive profiling of EBV-encoded miRNAs expressed in CAEBV, EBV-HLH, and nasopharyngeal carcinoma (NPC) patients was constructed, and the results showed that miR-BART19-3p was upregulated in all these diseases. Ectopic expression of miR-BART19-3p induced EBV-negative cell proliferation and suppressed cell apoptosis. Molecularly, adenomatous polyposis coli (APC) was identified to be a direct target of miR-BART19-3p, and APC mRNA expression was inversely correlated with miR-BART19-3p in CAEBV samples. Our results demonstrated that miR-BART19-3p contributes to the tumorigenesis of EBV-associated diseases and may be a potential therapeutic target.
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19
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EBV-miR-BART10-3p and EBV-miR-BART22 promote metastasis of EBV-associated gastric carcinoma by activating the canonical Wnt signaling pathway. Cell Oncol (Dordr) 2020; 43:901-913. [PMID: 32533512 DOI: 10.1007/s13402-020-00538-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) constitutes the largest subpopulation in EBV-associated tumors worldwide. To date, 44 mature EBV-encoded microRNAs (EBV miRNAs) have been identified, but their roles in EBVaGC development are still poorly understood. In this study, we aimed to investigate the roles and targets of ebv-miR-BART10-3p (BART10-3p) and ebv-miR-BART22 (BART22) in EBVaGC. METHODS EBV miRNA expression in EBVaGCs was evaluated by deep sequencing and qRT-PCR, and relationships between BART10-3p or BART22 expression and clinicolpathological characteristics and survival rates of patients with EBVaGC were analyzed. The roles of BART10-3p and BART22 and their underlying mechanisms were further investigated through exogenous overexpression or silencing in EBVaGC cells, and validated in clinical EBVaGC tissue samples. RESULTS BART10-3p and BART22 were found to be highly expressed in the EBVaGC cell lines SNU719 and YCCEL1. Higher expression of BART10-3p or BART22 in primary EBVaGC samples was significantly associated with lymph node metastasis and a worse 5-year overall survival. BART10-3p and BART22 promoted cell migration and invasion by targeting adenomatous polyposis coli (APC) and Dickkopf 1 (DKK1), thereby activating the Wnt signaling pathway and, consequently, upregulating downstream Twist and downregulating downstream E-cadherin. In 874 primary gastric carcinoma samples, APC and DKK1 were found to be lower expressed in EBVaGC than in EBV-negative samples, and their expression levels were inversely correlated with those of BART10-3p and BART22 in 71 EBVaGC samples. CONCLUSIONS From our data we conclude that BART10-3p and BART22 play vital roles in promoting EBVaGC metastasis by targeting APC and DKK1 and, subsequently, activating the Wnt signaling pathway, thereby providing novel prognostic biomarkers and potential therapeutic targets for EBVaGC.
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miRNAs: EBV Mechanism for Escaping Host's Immune Response and Supporting Tumorigenesis. Pathogens 2020; 9:pathogens9050353. [PMID: 32397085 PMCID: PMC7281681 DOI: 10.3390/pathogens9050353] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/25/2020] [Accepted: 05/04/2020] [Indexed: 12/18/2022] Open
Abstract
Epstein-Barr virus (EBV) or human herpesvirus 4 (HHV-4) is a ubiquitous human oncogenic virus, and the first human virus found to express microRNAs (miRNAs). Its genome contains two regions encoding more than 40 miRNAs that regulate expression of both viral and human genes. There are numerous evidences that EBV miRNAs impact immune response, affect antigen presentation and recognition, change T- and B-cell communication, drive antibody production during infection, and have a role in cell apoptosis. Moreover, the ability of EBV to induce B-cell transformation and take part in mechanisms of oncogenesis in humans is well known. Although EBV infection is associated with development of various diseases, the role of its miRNAs is still not understood. There is abundant data describing EBV miRNAs in nasopharyngeal carcinoma and several studies that have tried to evaluate their role in gastric carcinoma and lymphoma. This review aims to summarize so far known data about the role of EBV miRNAs in altered regulation of gene expression in human cells in EBV-associated diseases.
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Barbu MG, Condrat CE, Thompson DC, Bugnar OL, Cretoiu D, Toader OD, Suciu N, Voinea SC. MicroRNA Involvement in Signaling Pathways During Viral Infection. Front Cell Dev Biol 2020; 8:143. [PMID: 32211411 PMCID: PMC7075948 DOI: 10.3389/fcell.2020.00143] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 02/20/2020] [Indexed: 12/15/2022] Open
Abstract
The study of miRNAs started in 1993, when Lee et al. observed their involvement in the downregulation of a crucial protein known as LIN-14 in the nematode Caenorhabditis elegans. Since then, great progress has been made regarding research on microRNAs, which are now known to be involved in the regulation of various physiological and pathological processes in both animals and humans. One such example is represented by their interaction with various signaling pathways during viral infections. It has been observed that these pathogens can induce the up-/downregulation of various host miRNAs in order to elude the host's immune system. In contrast, some miRNAs studied could have an antiviral effect, enabling the defense mechanisms to fight the infection or, at the very least, they could induce the pathogen to enter a latent state. At the same time, some viruses encode their own miRNAs, which could further modulate the host's signaling pathways, thus favoring the survival and replication of the virus. The goal of this extensive literature review was to present how miRNAs are involved in the regulation of various signaling pathways in some of the most important and well-studied human viral infections. Further on, knowing which miRNAs are involved in various viral infections and what role they play could aid in the development of antiviral therapeutic agents for certain diseases that do not have a definitive cure in the present. The clinical applications of miRNAs are extremely important, as miRNAs targeted inhibition may have substantial therapeutic impact. Inhibition of miRNAs can be achieved through many different methods, but chemically modified antisense oligonucleotides have shown the most prominent effects. Though scientists are far from completely understanding all the molecular mechanisms behind the complex cross-talks between miRNA pathways and viral infections, the general knowledge is increasing on the different roles played by miRNAs during viral infections.
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Affiliation(s)
- Madalina Gabriela Barbu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Carmen Elena Condrat
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Dana Claudia Thompson
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Oana Larisa Bugnar
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Dragos Cretoiu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Oana Daniela Toader
- Division of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, Bucharest, Romania
| | - Nicolae Suciu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
- Division of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, Bucharest, Romania
| | - Silviu Cristian Voinea
- Department of Surgical Oncology, Institute of Oncology Prof. Dr. Alexandru Trestioreanu, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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22
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Hasham K, Ahmed N, Zeshan B. Circulating microRNAs in oncogenic viral infections: potential diagnostic biomarkers. SN APPLIED SCIENCES 2020. [DOI: 10.1007/s42452-020-2251-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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23
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Yoon JH, Min K, Lee SK. Epstein-Barr Virus miR-BART17-5p Promotes Migration and Anchorage-Independent Growth by Targeting Kruppel-Like Factor 2 in Gastric Cancer. Microorganisms 2020; 8:microorganisms8020258. [PMID: 32075248 PMCID: PMC7074886 DOI: 10.3390/microorganisms8020258] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/12/2020] [Accepted: 02/13/2020] [Indexed: 12/24/2022] Open
Abstract
Epstein-Barr virus (EBV) infects more than 90% of the global population and is associated with a variety of tumors including nasopharyngeal carcinoma, Hodgkin lymphoma, natural killer/T lymphoma, and gastric carcinoma. In EBV-associated gastric cancer (EBVaGC), highly expressed EBV BamHI A rightward transcripts (BART) miRNAs may contribute to tumorigenesis with limited viral antigens. Despite previous studies on the targets of BART miRNAs, the functions of all 44 BART miRNAs have not been fully clarified. Here, we used RNA sequencing data from the Cancer Genome Atlas to find genes with decreased expression in EBVaGC. Furthermore, we used AGS cells infected with EBV to determine whether expression was reduced by BART miRNA. We showed that the expression of Kruppel-like factor 2 (KLF2) is lower in AGS-EBV cells than in the AGS control. Using bioinformatics analysis, four BART miRNAs were selected to check whether they suppress KLF2 expression. We found that only miR-BART17-5p directly down-regulated KLF2 and promoted gastric carcinoma cell migration and anchorage-independent growth. Our data suggest that KLF2 functions as a tumor suppressor in EBVaGC and that miR-BART17-5p may be a valuable target for effective EBVaGC treatment.
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Affiliation(s)
| | | | - Suk Kyeong Lee
- Correspondence: ; Tel.: +82-2-2258-7480; Fax: +82-504-201-2396
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24
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Jiang C, Li L, Xiang YQ, Lung ML, Zeng T, Lu J, Tsao SW, Zeng MS, Yun JP, Kwong DLW, Guan XY. Epstein-Barr Virus miRNA BART2-5p Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing RND3. Cancer Res 2020; 80:1957-1969. [PMID: 32060148 DOI: 10.1158/0008-5472.can-19-0334] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 07/08/2019] [Accepted: 02/11/2020] [Indexed: 11/16/2022]
Abstract
Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-related malignancy. Recently, we found that the EBV-encoded miRNA BART2-5p was increased in the serum of patients with preclinical nasopharyngeal carcinoma and that the copy number positively correlated with disease progression. In this study, we established its role in nasopharyngeal carcinoma progression and explored underlying mechanisms and clinical significance. BART2-5p was an independent unfavorable prognostic factor for progression-free survival and its circulating abundance positively associated with distant metastasis. Ectopic expression of BART2-5p promoted migration and invasion of EBV-negative nasopharyngeal carcinoma cells, whereas genetic downregulation of BART2-5p in EBV-positive nasopharyngeal carcinoma cells decreased aggressiveness. Mechanistically, BART2-5p targeted RND3, a negative regulator of Rho signaling. Downregulation of RND3 phenocopied the effect of BART2-5p and reconstitution of RND3 rescued the phenotype. By suppressing RND3, BART2-5p activated Rho signaling to enhance cell motility. These findings suggest a novel role for EBV miRNA BART2-5p in promoting nasopharyngeal carcinoma metastasis and its potential value as a prognostic indicator or therapeutic target. SIGNIFICANCE: This study shows that EBV-encoded BART2-5p miRNA suppresses expression of the RND3 Rho family GTPase, consequently promoting ROCK signaling, cell motility, and metastatic behavior of NPC cells.
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Affiliation(s)
- Chen Jiang
- 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, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Clinical Oncology, The University of Hong Kong, Hong Kong SAR, China
| | - Lei Li
- 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, China.,Department of Clinical Oncology, The University of Hong Kong, Hong Kong SAR, China
| | - Yan-Qun Xiang
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Maria Li Lung
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong SAR, China
| | - Tingting Zeng
- 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, China
| | - Jiabin Lu
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Sai Wah Tsao
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
| | - Mu-Sheng Zeng
- 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, China
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dora L W Kwong
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong SAR, China
| | - Xin-Yuan Guan
- 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, China. .,Department of Clinical Oncology, The University of Hong Kong, Hong Kong SAR, China
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25
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Min K, Kim JY, Lee SK. Epstein-Barr virus miR-BART1-3p suppresses apoptosis and promotes migration of gastric carcinoma cells by targeting DAB2. Int J Biol Sci 2020; 16:694-707. [PMID: 32025216 PMCID: PMC6990914 DOI: 10.7150/ijbs.36595] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 12/18/2019] [Indexed: 12/13/2022] Open
Abstract
Although Epstein-Barr virus (EBV) is known to encode over 40 different miRNAs of its own, the roles of most EBV miRNAs remain unknown. Disabled homolog 2 (DAB2) is a putative tumor suppressor, but its role in gastric carcinoma (GC), especially in EBV-associated GC, needs to be clarified. Our qRT-PCR and mRNA microarray results showed that DAB2 expression was down-regulated in EBV-positive GC cells compared to EBV-negative cells. Four BART miRNAs that might target DAB2 were predicted, and we found, using a luciferase reporter assay, that miR-BART1-3p directly targeted the 3'-UTR of DAB2. The miR-BART1-3p transfection decreased DAB2 expression at both mRNA and protein levels, while transfection of an inhibitor of miR-BART1-3p, miR-BART1-3p(i), increased DAB2 expression. In addition, miR-BART1-3p as well as siDAB2 increased migration and decreased apoptosis. Meanwhile, miR-BART1-3p(i) or pcDNA3.1-DAB2 transfection decreased migration and increased apoptosis in EBV-infected GC cells. Furthermore, decreased migration by miR-BART1-3p(i) was abrogated by co-transfected siDAB2, while decreased migration by miR-BART1-3p(i) was further suppressed by a co-transfected DAB2 over-expression vector. Our data suggest that miR-BART1-3p plays an important role in the tumorigenesis of EBV-associated GC by directly targeting DAB2.
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Affiliation(s)
- Kyoungmi Min
- Department of Medical Life Sciences, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jun Yeob Kim
- Department of Medical Life Sciences, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Suk Kyeong Lee
- Department of Medical Life Sciences, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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26
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Wu L, Wang J, Zhu D, Zhang S, Zhou X, Zhu W, Zhu J, He X. Circulating Epstein-Barr virus microRNA profile reveals novel biomarker for nasopharyngeal carcinoma diagnosis. Cancer Biomark 2020; 27:365-375. [PMID: 31958073 DOI: 10.3233/cbm-190160] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Nasopharyngeal carcinoma (NPC), a tumor quite prevalent in Asia, is closely associated with Epstein-Barr virus (EBV) infection status. Many NPC patients are not able to be treated in time when being diagnosed at an advanced stage. EBV-encoded microRNAs are reliable sources of biomarkers for NPC diagnosis. In this study, we conducted circulating EBV microRNAs profiling by quantitative reverse transcription polymerase chain reaction (qRT-PCR) among plasma samples of 159 NPC patients versus 145 normal controls (NCs) and serum samples of 60 NPC patients versus 60 NCs. Among the 44 mature EBV-encoded miRNAs, only miR-BART19-3p in plasma was proved to be significantly up-regulated in NPC patients (P< 0.05; fold change (FC) > 2.0). The area under the receiver operating characteristic curve (AUC) for the signature to discriminate NPC patients from NCs was 0.848 with the sensitivity and specificity being 71.7% and 72.3%, respectively. The identified biomarker was analyzed in tissue specimens (44 NPC VS. 32 NCs) and proved to be consistently up-regulated in NPC tumor tissues. Bioinformatics analysis was further conducted to predict the potential targets of miR-BART-19-3p, which provided some hints to its close relationship with NPC development. In conclusion, we identified a novel biomarker - plasma miR-BART19-3p for the detection of NPC.
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Affiliation(s)
- Lirong Wu
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Jingyi Wang
- Department of Breast Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Danxia Zhu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Shiyu Zhang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jun Zhu
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Xia He
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
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27
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Fani M, Zandi M, Rezayi M, Khodadad N, Langari H, Amiri I. The Role of microRNAs in the Viral Infections. Curr Pharm Des 2019; 24:4659-4667. [PMID: 30636585 DOI: 10.2174/1381612825666190110161034] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) are non-coding RNAs with 19 to 24 nucleotides which are evolutionally conserved. MicroRNAs play a regulatory role in many cellular functions such as immune mechanisms, apoptosis, and tumorigenesis. The main function of miRNAs is the post-transcriptional regulation of gene expression via mRNA degradation or inhibition of translation. In fact, many of them act as an oncogene or tumor suppressor. These molecular structures participate in many physiological and pathological processes of the cell. The virus can also produce them for developing its pathogenic processes. It was initially thought that viruses without nuclear replication cycle such as Poxviridae and RNA viruses can not code miRNA, but recently, it has been proven that RNA viruses can also produce miRNA. The aim of this articles is to describe viral miRNAs biogenesis and their effects on cellular and viral genes.
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Affiliation(s)
- Mona Fani
- Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Milad Zandi
- Department of Virology, School of Public Health, Tehran University of Medical Science, Tehran, Iran
| | - Majid Rezayi
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nastaran Khodadad
- Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hadis Langari
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iraj Amiri
- Computational Optics Research Group, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam.,Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
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28
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Zhang X, Ye Y, Fu M, Zheng B, Qiu Q, Huang Z. Implication of viral microRNAs in the genesis and diagnosis of Epstein-Barr virus-associated tumors. Oncol Lett 2019; 18:3433-3442. [PMID: 31516561 PMCID: PMC6732978 DOI: 10.3892/ol.2019.10713] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 06/26/2019] [Indexed: 12/13/2022] Open
Abstract
The Epstein-Barr virus (EBV) is tightly associated with a variety of human tumors, including Burkitt lymphoma and acquired immune deficiency syndrome-related lymphoma of B-cell origin, as well as nasopharyngeal carcinoma and gastric cancer of epithelial origin. The virus latently infects the host cells and expresses proteins and non-coding RNAs to achieve malignancy. MicroRNAs (miRNAs or miRs) are small RNAs consisting of 19-25 nucleotides, which directly bind to the 3'-untranslated region of mRNAs to promote degradation and inhibit translation of mRNAs. EBV-encoded miRs are generated from two regions of the viral genome, within the apoptosis regulator BHRF1 gene locus and near the BamHI A region in a latency type-dependent manner. In addition, EBV-encoded miRs epigenetically regulate the expression of molecules that are effectors of the cell cycle progression, migration, apoptosis and innate immunity, serving a vital role in supporting viral replication and occurrence of EBV-associated tumors. The feasibility of using such miRs as biomarkers for the diagnosis and prognosis of EBV-associated tumors is currently under investigation.
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Affiliation(s)
- Xiangning Zhang
- Department of Pathophysiology, Chinese-American Collaborative Cancer Institute, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Yudong Ye
- Department of Otolaryngology, Dongguan City People's Hospital, Dongguan, Guangdong 523059, P.R. China
| | - Ming Fu
- Department of Otolaryngology, Dongguan City People's Hospital, Dongguan, Guangdong 523059, P.R. China
| | - Biying Zheng
- Department of Clinical Microbiology, College of Laboratory Medicine, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Qianhui Qiu
- Department of Otolaryngology, Pearl River Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Zunnan Huang
- Department of Pathophysiology, Chinese-American Collaborative Cancer Institute, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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29
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Wang M, Gu B, Chen X, Wang Y, Li P, Wang K. The Function and Therapeutic Potential of Epstein-Barr Virus-Encoded MicroRNAs in Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 17:657-668. [PMID: 31400608 PMCID: PMC6698931 DOI: 10.1016/j.omtn.2019.07.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 05/14/2019] [Accepted: 07/06/2019] [Indexed: 02/06/2023]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that infects over 90% of the global population. EBV is considered a contributory factor in a variety of malignancies including nasopharyngeal carcinoma, gastric carcinoma, Burkitt lymphoma, and Hodgkin’s lymphoma. Notably, EBV was the first virus found to encode microRNAs (miRNAs). Increasing evidence indicates that EBV-encoded miRNAs contribute to the carcinogenesis and development of EBV-associated malignancies. EBV miRNAs have been shown to inhibit the expression of genes involved in cell proliferation, apoptosis, invasion, and immune signaling pathways. Therefore, EBV miRNAs perform a significant function in the complex host-virus interaction and EBV-driven carcinogenesis. However, the integrated mechanisms underlying the roles of EBV miRNAs in carcinogenesis remain to be further explored. In this review, we describe recent advances regarding the involvement of EBV miRNAs in the pathogenesis of EBV-associated malignancies and discuss their potential utility as cancer biomarkers. An in-depth investigation into the pro-carcinogenic role of EBV miRNAs will expand our knowledge of the biological processes associated with virus-driven tumors and contribute to the development of novel therapeutic strategies for the treatment of EBV-associated malignancies.
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Affiliation(s)
- Man Wang
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China.
| | - Bianli Gu
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Xinzhe Chen
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
| | - Yefu Wang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Peifeng Li
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
| | - Kun Wang
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China.
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30
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Liu MZ, Fang SG, Huang W, Wang HY, Tian YM, Huang RD, Sun Z, Zhao C, Lu TX, Huang Y, Han F. Clinical characteristics and prognostic value of pre-retreatment plasma epstein-barr virus DNA in locoregional recurrent nasopharyngeal carcinoma. Cancer Med 2019; 8:4633-4643. [PMID: 31268626 PMCID: PMC6712460 DOI: 10.1002/cam4.2339] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 05/02/2019] [Accepted: 05/22/2019] [Indexed: 01/05/2023] Open
Abstract
PURPOSE To define the clinical characteristics and prognostic value of pre-retreatment plasma Epstein-Barr virus (EBV) DNA, we investigated EBV status in locoregional recurrent nasopharyngeal carcinoma (lrNPC) patients. METHODS Between April 2008 and August 2016, the data of patients with nonmetastatic lrNPC were retrospectively reviewed. The survival indexes of patients between different pre-retreatment EBV status groups were compared. RESULTS A total of 401 patients with nonmetastatic lrNPC were enrolled, and 197 (49.1%) patients had detectable pre-retreatment plasma EBV DNA. Treatment included radiotherapy alone (n = 37 patients), surgery alone (n = 105), radiotherapy (n = 208), surgery combined with radiotherapy (n = 20), chemotherapy and targeted therapy (n = 31). Median follow-up was 32 months. The 3-year locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates for the entire cohort were 64.8%, 89.4%, and 58.8%, respectively. The estimated 3-year LRRFS, DMFS, and OS rates for the pre EBV-positive group vs the pre EBV-negative group were 54.2% vs 75.0% (P < 0.001), 86.6% vs 91.9% (P = 0.05), 51.6% vs 65.9% (P = 0.01), respectively. Among patients in the clinical stage rI/II, there were 17 patients in the radiotherapy alone group and 49 patients in the surgery alone group. And there was no significant difference in overall survival between radiotherapy and surgery, even among the different pre-EBV statuses (P > 0.05). In terms of long-term toxic and side effects, the incidence of radioactive temporal lobe injury in the radiotherapy group was higher than that in the surgery group (35.3% vs 8.2%, P < 0.001), and no statistically significant difference was found in other long-term toxic and side effects. CONCLUSIONS The positive rate of pre-retreatment plasma EBV DNA in lrNPC is lower than primary NPC. The prognosis of EBV DNA negative group is better than positive group. For locally early-stage lrNPC, regardless of EBV DNA status, radiotherapy and surgery are available options and both can achieve better long-term survival.
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Affiliation(s)
- Ming-Zhu Liu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Shuo-Gui Fang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Wei Huang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Han-Yu Wang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Yun-Ming Tian
- Department of Radiation Oncology, Hui Zhou Municipal Centre Hospital, Huizhou, Guangdong Province, People's Republic of China
| | - Run-Da Huang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Zhuang Sun
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Chong Zhao
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Tai-Xiang Lu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Ying Huang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
| | - Fei Han
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People's Republic of China.,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong Province, People's Republic of China
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31
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Cone AS, York SB, Meckes DG. Extracellular Vesicles in Epstein-Barr Virus Pathogenesis. CURRENT CLINICAL MICROBIOLOGY REPORTS 2019; 6:121-131. [PMID: 32051811 DOI: 10.1007/s40588-019-00123-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Purpose of review Epstein-Barr virus (EBV) is a known determinant for numerous malignancies and may contribute to autoimmune diseases. The underlining mechanisms behind EBV pathologies is not completely understood. Recently, extracellular vesicles (EVs) released from infected cells have been found to produce profound effects on cellular microenvironments. Therefore, in this review we sought to critically evaluate the roles of EVs in EBV pathogenesis and assess their potential therapeutic and diagnostic utility. Recent findings EBV-altered EVs are capable of activating signaling cascades and phenotypic changes in recipient cells through the transfer of viral proteins and RNAs. Moreover, several EV-associated microRNAs have encouraging prognostic or diagnostic potential in EBV-associated cancers. Summary Current evidence suggests that EBV-modified EVs affect viral pathogenesis and cancer progression. However, further research is needed to investigate the direct role of both viral and host products on recipient cells and the mechanisms driving viral protein and RNA EV packaging and content modification.
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Affiliation(s)
- Allaura S Cone
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | - Sara B York
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | - David G Meckes
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
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Hussein HAM, Alfhili MA, Pakala P, Simon S, Hussain J, McCubrey JA, Akula SM. miRNAs and their roles in KSHV pathogenesis. Virus Res 2019; 266:15-24. [PMID: 30951791 DOI: 10.1016/j.virusres.2019.03.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 03/26/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman Disease (MCD). Recent mechanistic advances have discerned the importance of microRNAs in the virus-host relationship. KSHV has two modes of replication: lytic and latent phase. KSHV entry into permissive cells, establishment of infection, and maintenance of latency are contingent upon successful modulation of the host miRNA transcriptome. Apart from host cell miRNAs, KSHV also encodes viral miRNAs. Among various cellular and molecular targets, miRNAs are appearing to be key players in regulating viral pathogenesis. Therefore, the use of miRNAs as novel therapeutics has gained considerable attention as of late. This innovative approach relies on either mimicking miRNA species by identical oligonucleotides, or selective silencing of miRNA with specific oligonucleotide inhibitors. Here, we provide an overview of KSHV pathogenesis at the molecular level with special emphasis on the various roles miRNAs play during virus infection.
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Affiliation(s)
- Hosni A M Hussein
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States; Faculty of Science, Al Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Mohammad A Alfhili
- Department of Medicine (Division of Hematology/Oncology), Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia
| | - Pranaya Pakala
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Sandra Simon
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Jaffer Hussain
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - James A McCubrey
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Shaw M Akula
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States.
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33
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Song L, Chen L, Luan Q, Kong Q. miR-144-3p facilitates nasopharyngeal carcinoma via crosstalk with PTEN. J Cell Physiol 2019; 234:17912-17924. [PMID: 30834525 DOI: 10.1002/jcp.28424] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 02/06/2019] [Accepted: 02/14/2019] [Indexed: 12/27/2022]
Abstract
AIMS This study aims to investigate the role of miR-144-3p and phosphatase and tensin homolog (PTEN) in nasopharyngeal carcinoma (NPC), along with their crosstalk with the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) pathway. METHODS Quantitative reverse transcription polymerase chain reaction and western blot were used to measure the gene expression at the transcriptional and translational levels. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay were used to examine cell proliferation via standard protocol. Transwell assay was conducted to examine cell invasiveness. A flow cytometer was used to determine cell apoptosis. Dual-Luciferase Reporter Gene Assay (SLDL-100) was used to confirm the target relationship between miR-144-3p and PTEN. Xenografts were used to detect the in vivo effects of the molecules of interest. RESULTS miR-144-3p was significantly overexpressed, whereas PTEN was more underexpressed in tumor tissues than in adjacent tissues. miR-144-3p promoted the proliferation and invasion of NPC cells and inhibited apoptosis by directly targeting PTEN, which improves PI3K-Akt signaling. miR-144-3p forced epithelial-mesenchymal transition in NPC. CONCLUSION miR-144-3p promotes the progression of NPC by directly targeting PTEN via crosstalk with PI3K-Akt signaling.
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Affiliation(s)
- Li Song
- Department of Otorhinolaryngology Head and Neck Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
| | - Lijie Chen
- Department of Otolaryngology, Shandong Energy Zibo Mining Group Co, Ltd General Hospital, Zibo, Shandong, China
| | - Qiang Luan
- Department of Otolaryngology, Traditional Chinese Medicine Hospital of Muping District of Yantai City, Yantai, Shandong, China
| | - Qingdong Kong
- Department of Otorhinolaryngology Head and Neck Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
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34
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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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35
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Dong M, Chen JN, Huang JT, Gong LP, Shao CK. The roles of EBV-encoded microRNAs in EBV-associated tumors. Crit Rev Oncol Hematol 2019; 135:30-38. [PMID: 30819444 DOI: 10.1016/j.critrevonc.2019.01.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 01/22/2019] [Accepted: 01/22/2019] [Indexed: 12/19/2022] Open
Abstract
Epstein-Barr virus (EBV) is believed to be a pathogen causing a number of human cancers, but the pathogenic mechanisms remain unclear. An increasing number of studies have indicated that EBV-encoded microRNAs (EBV miRNAs) are expressed in a latency type- and tumor type-dependent manner, playing important roles in the development and progression of EBV-associated tumors. By targeting one or more genes of the virus and the host, EBV miRNAs are responsible for the deregulation of a variety of viral and host cell biological processes, including viral replication, latency maintenance, immune evasion, cell apoptosis and metabolism, and tumor proliferation and metastasis. In addition, some EBV miRNAs can be used as excellent diagnostic, prognostic and treatment efficacy predictive biomarkers for EBV-associated tumors. More importantly, EBV miRNA-targeting therapeutics have emerged and have been developing rapidly, which may open a new era in the treatment of EBV-associated tumors in the near future.
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Affiliation(s)
- Min Dong
- Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Jian-Ning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Jun-Ting Huang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Li-Ping Gong
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Chun-Kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
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Epstein-Barr virus-coded miR-BART13 promotes nasopharyngeal carcinoma cell growth and metastasis via targeting of the NKIRAS2/NF-κB pathway. Cancer Lett 2019; 447:33-40. [PMID: 30684592 DOI: 10.1016/j.canlet.2019.01.022] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 01/05/2019] [Accepted: 01/17/2019] [Indexed: 12/27/2022]
Abstract
Based on analysis of Epstein-Barr virus (EBV) BART microRNA expression profiles, we previously reported that EBV-encoded miR-BART13 is upregulated in nasopharyngeal carcinoma (NPC) plasma specimens. However, the effects and molecular mechanisms of miR-BART13 in NPC remain largely unknown. We found that miR-BART13 was significantly upregulated in NPC tissue specimens. Ectopic expression of miR-BART13 promoted NPC cell proliferation, epithelial mesenchymal transition, and metastasis in vitro, and facilitated xenograft tumor growth and lung metastasis in vivo. Molecularly, NF-κB inhibitor interacting Ras-like 2 (NKIRAS2), a negative regulator of the NF-κB signaling, was identified to be a direct target of miR-BART13 in NPC cells, and NKIRAS2 mRNA and protein expression was inversely correlated with miR-BART13 in NPC tissues, respecitvely. Furthermore, the NF-κB signaling pathway was activated by miR-BART13. By rescued experiments, reconstitution of NKIRAS2 expression abrogated all the phenotypes upregulated by miR-BART13, and attenuated activity of NF-κB signaling pathway activated by miR-BART13 in NPC cells. Our findings indicated the newly identified miR-BART13/NKIRAS2/NF-κB signaling axis may provide further insights into better understanding of NPC initiation and development, and targeting of this pathway could be further studied as a therapeutic strategy for NPC patients.
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37
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Epstein-Barr Virus Infection of Cell Lines Derived from Diffuse Large B-Cell Lymphomas Alters MicroRNA Loading of the Ago2 Complex. J Virol 2019; 93:JVI.01297-18. [PMID: 30429351 DOI: 10.1128/jvi.01297-18] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 11/05/2018] [Indexed: 12/15/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoid tumor which is occasionally Epstein-Barr virus (EBV) positive and is further subtyped as activated B-cell DLBCL (ABC-DLBCL) and germinal center B-cell DLBCL (GCB-DLBCL), which has implications for prognosis and treatment. We performed Ago2 RNA immunoprecipitation followed by high-throughput RNA sequencing (Ago2-RIP-seq) to capture functionally active microRNAs (miRNAs) in EBV-negative ABC-DLBCL and GCB-DLBCL cell lines and their EBV-infected counterparts. In parallel, total miRNA profiles of these cells were determined to capture the cellular miRNA profile for comparison with the functionally active profile. Selected miRNAs with differential abundances were validated using real-time quantitative PCR (RT-qPCR) and Northern blotting. We found 6 miRNAs with differential abundances (2 upregulated and 4 downregulated miRNAs) between EBV-negative and -positive ABC-DLBCL cells and 12 miRNAs with differential abundances (3 upregulated and 9 downregulated miRNAs) between EBV-negative and -positive GCB-DLBCL cells. Eight and twelve miRNAs were confirmed using RT-qPCR in ABC-DLBCL and GCB-DLBCL cells, respectively. Selected miRNAs were analyzed in additional type I/II versus type III EBV latency DLBCL cell lines. Furthermore, upregulation of miR-221-3p and downregulation of let7c-5p in ABC-DLBCL cells and upregulation of miR-363-3p and downregulation of miR-423-5p in GCB-DLBCL cells were verified using RIP-Northern blotting. Our comprehensive sequence analysis of the DLBCL miRNA profiles identified sets of deregulated miRNAs by Ago2-RIP-seq. Our Ago2-IP-seq miRNA profile could be considered an important data set for the detection of deregulated functionally active miRNAs in DLBCLs and could possibly lead to the identification of miRNAs as biomarkers for the classification of DLBCLs or even as targets for personalized targeted treatment.IMPORTANCE Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive tumor of lymphoid origin which is occasionally Epstein-Barr virus (EBV) positive. MicroRNAs are found in most multicellular organisms and even in viruses such as EBV. They regulate the synthesis of proteins by binding to their cognate mRNA. MicroRNAs are tethered to their target mRNAs by "Argonaute" proteins. Here we compared the overall miRNA content of the Ago2 complex by differential loading to the overall content of miRNAs in two DLBCL cell lines and their EBV-converted counterparts. In all cell lines, the Ago2 load was different from the overall expression of miRNAs. In addition, the loading of the Ago2 complex was changed upon infection with EBV. This indicates that the virus not only changes the overall content of miRNAs but also influences the expression of proteins by affecting the Ago complexes.
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38
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Gao W, Wong TS, Lv KX, Zhang MJ, Tsang RKY, Chan JYW. Detection of Epstein-Barr virus (EBV)-encoded microRNAs in plasma of patients with nasopharyngeal carcinoma. Head Neck 2018; 41:780-792. [PMID: 30548946 DOI: 10.1002/hed.25544] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 08/03/2018] [Accepted: 09/28/2018] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) latently infected by Epstein-Barr virus (EBV) expresses 40 EBV BART microRNAs (miRNAs). Difference in diagnostic efficacy of these miRNAs on NPC detection was observed. Here, we performed a comprehensive evaluation on the efficacy of these miRNAs. METHODS Quantitative polymerase chain reaction was performed on plasma nucleic acid isolated from patients with NPC and noncancer donors. RESULTS For primary NPC, BART2-5P, BART6-3P, BART7-3P, BART7-5P, BART9-5P, BART11-3P, BART17-5P, and BART19-5P were significantly elevated. For recurrent NPC, plasma levels of BART2-3P, BART2-5P, BART5-3P, BART5-5P, BART6-3P, BART8-3P, BART9-5P, BART17-5P, BART19-3P, and BART20-3P were significantly increased. Area under curve (AUC) analysis showed that BART19-5P had the best performance to identify NPC which was serologically EBV DNA undetectable. For recurrent NPC, BART8-3P and BART10-3P had highest AUC value for identifying cancer in EBV DNA undetectable plasma. CONCLUSION Our data supported the use of circulating EBV miRNAs in NPC and recurrent NPC detection.
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Affiliation(s)
- Wei Gao
- Division of Head and Neck, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Thian-Sze Wong
- Division of Head and Neck, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Ke-Xing Lv
- Division of Head and Neck, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China
| | - Min-Juan Zhang
- Division of Head and Neck, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Raymond King-Yin Tsang
- Division of Head and Neck, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Jimmy Yu-Wai Chan
- Division of Head and Neck, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
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39
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Jiang C, Chen J, Xie S, Zhang L, Xiang Y, Lung M, Kam NW, Kwong DLW, Cao S, Guan XY. Evaluation of circulating EBV microRNA BART2-5p in facilitating early detection and screening of nasopharyngeal carcinoma. Int J Cancer 2018; 143:3209-3217. [PMID: 29971780 DOI: 10.1002/ijc.31642] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/19/2018] [Accepted: 04/17/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Chen Jiang
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Jinna Chen
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Shanghang Xie
- Department of Epidemiology, Cancer Prevention Center; State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Lifang Zhang
- Department of Epidemiology, Cancer Prevention Center; State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Yanqun Xiang
- Department of Nasopharyngeal Carcinoma; Sun Yat-Sen University Cancer Center; Guangzhou China
| | - Maria Lung
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Ngar-Woon Kam
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Dora Lai-wan Kwong
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Sumei Cao
- Department of Epidemiology, Cancer Prevention Center; State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Xin-Yuan Guan
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center; Guangzhou China
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40
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Yin H, Qu J, Peng Q, Gan R. Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis. Med Microbiol Immunol 2018; 208:573-583. [PMID: 30386928 PMCID: PMC6746687 DOI: 10.1007/s00430-018-0570-1] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 10/13/2018] [Indexed: 12/11/2022]
Abstract
The early stage of oncogenesis is linked to the disorder of the cell cycle. Abnormal gene expression often leads to cell cycle disorders, resulting in malignant transformation of human cells. Epstein–Barr virus (EBV) is associated with a diverse range of human neoplasms, such as malignant lymphoma, nasopharyngeal carcinoma and gastric cancer. EBV mainly infects human lymphocytes and oropharyngeal epithelial cells. EBV is latent in lymphocytes for a long period of time, is detached from the cytoplasm by circular DNA, and can integrate into the chromosome of cells. EBV expresses a variety of latent genes during latent infection. The interaction between EBV latent genes and oncogenes leads to host cell cycle disturbances, including the promotion of G1/S phase transition and inhibition of cell apoptosis, thereby promoting the development of EBV-associated neoplasms. Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis involve diverse genes and signal pathways. Here, we review the molecular mechanisms of EBV-driven cell cycle progression and promoting oncogenesis.
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Affiliation(s)
- Huali Yin
- Medical School, Cancer Research Institute, Key Laboratory of Tumor Cellular and Molecular Pathology of Hunan Province, University of South China, Chang Sheng Xi Avenue 28, Hengyang, 421001, Hunan, People's Republic of China.,Department of Pathology, Central Hospital of Shaoyang, Hunan, China
| | - Jiani Qu
- Medical School, Cancer Research Institute, Key Laboratory of Tumor Cellular and Molecular Pathology of Hunan Province, University of South China, Chang Sheng Xi Avenue 28, Hengyang, 421001, Hunan, People's Republic of China
| | - Qiu Peng
- Medical School, Cancer Research Institute, Key Laboratory of Tumor Cellular and Molecular Pathology of Hunan Province, University of South China, Chang Sheng Xi Avenue 28, Hengyang, 421001, Hunan, People's Republic of China
| | - Runliang Gan
- Medical School, Cancer Research Institute, Key Laboratory of Tumor Cellular and Molecular Pathology of Hunan Province, University of South China, Chang Sheng Xi Avenue 28, Hengyang, 421001, Hunan, People's Republic of China.
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41
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Sun L, Meckes DG. Methodological Approaches to Study Extracellular Vesicle miRNAs in Epstein⁻Barr Virus-Associated Cancers. Int J Mol Sci 2018; 19:ijms19092810. [PMID: 30231493 PMCID: PMC6164614 DOI: 10.3390/ijms19092810] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 09/14/2018] [Accepted: 09/14/2018] [Indexed: 02/07/2023] Open
Abstract
Epstein Barr-virus (EBV) was the first virus identified to be associated with human cancer in 1964 and is found ubiquitously throughout the world's population. It is now established that EBV contributes to the development and progression of multiple human cancers of both lymphoid and epithelial cell origins. EBV encoded miRNAs play an important role in tumor proliferation, angiogenesis, immune escape, tissue invasion, and metastasis. Recently, EBV miRNAs have been found to be released from infected cancer cells in extracellular vesicles (EVs) and regulate gene expression in neighboring uninfected cells present in the tumor microenvironment and possibly at distal sites. As EVs are abundant in many biological fluids, the viral and cellular miRNAs present within EBV-modified EVs may serve as noninvasion markers for cancer diagnosis and prognosis. In this review, we discuss recent advances in EV isolation and miRNA detection, and provide a complete workflow for EV purification from plasma and deep-sequencing for biomarker discovery.
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Affiliation(s)
- Li Sun
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
| | - David G Meckes
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
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42
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Fan C, Tang Y, Wang J, Xiong F, Guo C, Wang Y, Xiang B, Zhou M, Li X, Wu X, Li Y, Li X, Li G, Xiong W, Zeng Z. The emerging role of Epstein-Barr virus encoded microRNAs in nasopharyngeal carcinoma. J Cancer 2018; 9:2852-2864. [PMID: 30123354 PMCID: PMC6096363 DOI: 10.7150/jca.25460] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 06/16/2018] [Indexed: 12/24/2022] Open
Abstract
Epstein-Barr virus (EBV) is an oncogenic herpes virus that is closely associated with the initiation and development of nasopharyngeal carcinoma (NPC), lymphoma and other malignant tumors. EBV encodes 44 mature miRNAs that regulate viral and host cell gene expression and plays a variety of roles in biological functions and the development of cancer. In this review, we summarized the biological functions and molecular mechanisms of Epstein-Barr virus-encoded microRNAs (EBV miRNAs) in tumor immune evasion, proliferation, anti-apoptosis, invasion, metastasis and as a potential biomarker for NPC diagnosis and prognosis. The knowledge generated by EBV miRNAs can be used for EBV miRNA-based precision cancer treatments in the near future.
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Affiliation(s)
- Chunmei Fan
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yanyan Tang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China
| | - Jinpeng Wang
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China
| | - Fang Xiong
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Can Guo
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China
| | - Yumin Wang
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China
| | - Bo Xiang
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China
| | - Ming Zhou
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China
| | - Xiayu Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xu Wu
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,Department of Chemistry, University of North Dakota, Grand Forks, North Dakota, USA
| | - Yong Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Xiaoling Li
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Xiong
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Science,, Central South University, Changsha, Hunan, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
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43
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Infection of Epstein⁻Barr Virus in Type III Latency Modulates Biogenesis of Exosomes and the Expression Profile of Exosomal miRNAs in the Burkitt Lymphoma Mutu Cell Lines. Cancers (Basel) 2018; 10:cancers10070237. [PMID: 30029522 PMCID: PMC6071279 DOI: 10.3390/cancers10070237] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 12/15/2022] Open
Abstract
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates the profile of microRNAs in the cells, little is known about the microRNAs in exosomes released from infected cells. Here, we characterized the expression profile of intracellular and exosomal microRNAs in EBV-negative, and two related EBV-infected Burkitt lymphoma cell lines having type I and type III latency by next-generation sequencing. We found that the biogenesis of exosomes is upregulated in type III latently infected cells compared with EBV-negative and type I latently infected cells. We also observed that viral and several specific host microRNAs were predominantly incorporated in the exosomes released from the cells in type III latency. We confirmed that multiple viral microRNAs were transferred to the epithelial cells cocultured with EBV-infected B cells. Our findings indicate that EBV infection, in particular in type III latency, modulates the biogenesis of exosomes and the profile of exosomal microRNAs, potentially contributing to phenotypic changes in cells receiving these exosomes.
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44
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Polakovicova I, Jerez S, Wichmann IA, Sandoval-Bórquez A, Carrasco-Véliz N, Corvalán AH. Role of microRNAs and Exosomes in Helicobacter pylori and Epstein-Barr Virus Associated Gastric Cancers. Front Microbiol 2018; 9:636. [PMID: 29675003 PMCID: PMC5895734 DOI: 10.3389/fmicb.2018.00636] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 03/19/2018] [Indexed: 12/17/2022] Open
Abstract
Emerging evidence suggests that chronic inflammation caused by pathogen infection is connected to the development of various types of cancer. It is estimated that up to 20% of all cancer deaths is linked to infections and inflammation. In gastric cancer, such triggers can be infection of the gastric epithelium by either Helicobacter pylori (H. pylori), a bacterium present in half of the world population; or by Epstein-Barr virus (EBV), a double-stranded DNA virus which has recently been associated with gastric cancer. Both agents can establish lifelong inflammation by evolving to escape immune surveillance and, under certain conditions, contribute to the development of gastric cancer. Non-coding RNAs, mainly microRNAs (miRNAs), influence the host innate and adaptive immune responses, though long non-coding RNAs and viral miRNAs also alter these processes. Reports suggest that chronic infection results in altered expression of host miRNAs. In turn, dysregulated miRNAs modulate the host inflammatory immune response, favoring bacterial survival and persistence within the gastric mucosa. Given the established roles of miRNAs in tumorigenesis and innate immunity, they may serve as an important link between H. pylori- and EBV-associated inflammation and carcinogenesis. Example of this is up-regulation of miR-155 in H. pylori and EBV infection. The tumor environment contains a variety of cells that need to communicate with each other. Extracellular vesicles, especially exosomes, allow these cells to deliver certain type of information to other cells promoting cancer growth and metastasis. Exosomes have been shown to deliver not only various types of genetic information, mainly miRNAs, but also cytotoxin-associated gene A (CagA), a major H. pylori virulence factor. In addition, a growing body of evidence demonstrates that exosomes contain genetic material of viruses and viral miRNAs and proteins such as EBV latent membrane protein 1 (LMP1) which are delivered into recipient cells. In this review, we focus on the dysregulated H. pylori- and EBV-associated miRNAs while trying to unveil possible causal mechanisms. Moreover, we discuss the role of exosomes as vehicles for miRNA delivery in H. pylori- and EBV-related carcinogenesis.
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Affiliation(s)
- Iva Polakovicova
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sofia Jerez
- Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ignacio A Wichmann
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Nicolás Carrasco-Véliz
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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45
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Wang M, Yu F, Wu W, Wang Y, Ding H, Qian L. Epstein-Barr virus-encoded microRNAs as regulators in host immune responses. Int J Biol Sci 2018; 14:565-576. [PMID: 29805308 PMCID: PMC5968849 DOI: 10.7150/ijbs.24562] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/06/2018] [Indexed: 12/12/2022] Open
Abstract
Epstein-Barr virus (EBV) is an oncogenic virus that infects over 90% of the world's adult population. EBV can establish life-long latent infection in host due to the balance between EBV and host immune system. EBV latency is associated with various malignancies such as nasopharyngeal carcinoma, gastric carcinoma and Burkitt's lymphoma. EBV is the first human virus that has the capability to encode microRNAs (miRNAs). Remarkably, EBV-encoded miRNAs are abundantly expressed in latently-infected cells and serve important function in viral infection and pathogenesis. Increasing evidence indicates that EBV miRNAs target the host mRNAs involved in cell proliferation, apoptosis and transformation. EBV miRNAs also inhibit the expression of viral antigens, thereby enabling infected cells to escape immune recognition. Intriguingly, EBV miRNAs directly suppress host antiviral immunity by interfering with antigen presentation and immune cell activation. This review will update the current knowledge about EBV miRNAs implicated in host immune responses. An in-depth understanding of the functions of EBV miRNAs in host antiviral immunity will shed light on the EBV-host interactions and provide potential therapeutic targets for the treatment of EBV-associated malignancies.
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Affiliation(s)
- Man Wang
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
| | - Fei Yu
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
| | - Wei Wu
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
| | - Yu Wang
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
| | - Han Ding
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
| | - Lili Qian
- Institute for Translational Medicine, Medical College of Qingdao University, Dengzhou Road 38, Qingdao 266021, China
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46
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Abstract
Nasopharyngeal carcinoma (NPC) is a head and neck cancer that represents a major health burden in Southern China and Southeast Asia. Although the close association of NPC with Epstein-Barr virus (EBV) infection has been demonstrated, its exact role in the pathogenesis of this malignancy is still unclear. The expression of EBV-encoded microRNAs, especially BART miRNAs, which are encoded from the BamHI-A region of the viral genome, is detected at a high level in NPC. miRNAs are small noncoding mRNAs that can positively regulate the virus to ensure accurate expression of viral genomes and to modify the gene expression of host cells by negative regulation. Accumulating evidence suggests that ebv-mir-BARTs play a critical role in host cell survival, immune escape, cell proliferation, cell apoptosis, and cancer metabolism, promoting the generation of NPC. This review will summarize our current understanding of the nature and function of ebv-mir-BARTs in NPC.
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47
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Epstein-Barr virus stably confers an invasive phenotype to epithelial cells through reprogramming of the WNT pathway. Oncotarget 2018. [PMID: 29535816 PMCID: PMC5828208 DOI: 10.18632/oncotarget.23824] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated carcinomas, such as nasopharyngeal carcinoma (NPC), exhibit an undifferentiated and metastatic phenotype. To determine viral contributions involved in the invasive phenotype of EBV-associated carcinomas, EBV-infected human telomerase-immortalized normal oral keratinocytes (NOK) were investigated. EBV-infected NOK were previously shown to undergo epigenetic reprogramming involving CpG island hypermethylation and delayed responsiveness to differentiation. Here, we show that EBV-infected NOK acquired an invasive phenotype that was epigenetically retained after viral loss. The transcription factor lymphoid enhancer factor 1 (LEF1) and the secreted ligand WNT5A, expressed in NPC, were increased in EBV-infected NOK with sustained expression for more than 20 passages after viral loss. Increased LEF1 levels involved four LEF1 variants, and EBV-infected NOK showed a lack of responsiveness to β-catenin activation. Although forced expression of WNT5A and LEF1 enhanced the invasiveness of parental NOK, LEF1 knockdown reversed the invasive phenotype of EBV-infected NOK in the presence of WNT5A. Viral reprogramming of LEF1 and WNT5A was observed several passages after EBV infection, suggesting that LEF1 and WNT5A may provide a selective advantage to virally-infected cells. Our findings suggest that EBV epigenetically reprogrammed epithelial cells with features of basal, wound healing keratinocytes, with LEF1 contributing to the metastatic phenotype of EBV-associated carcinomas.
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48
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Piedade D, Azevedo-Pereira JM. MicroRNAs as Important Players in Host-Adenovirus Interactions. Front Microbiol 2017; 8:1324. [PMID: 28769895 PMCID: PMC5511817 DOI: 10.3389/fmicb.2017.01324] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 06/30/2017] [Indexed: 12/20/2022] Open
Abstract
MicroRNAs (miRNAs) are powerful regulators of gene expression and fine-tuning genes in all tissues. Cellular miRNAs can control 100s of biologic processes (e.g., morphogenesis of embryonic structures, differentiation of tissue-specific cells, and metabolic control in specific cell types) and have been involved in the regulation of nearly all cellular pathways. Inherently to their involvement in different physiologic processes, miRNAs deregulation has been associated with several diseases. Moreover, several viruses have been described as either, avoid and block cellular miRNAs or synthesize their own miRNA to facilitate infection and pathogenesis. Adenoviruses genome encodes two non-coding RNAs, known as viral-associated (VA) RNAI and VA RNAII, which seem to play an important role either by blocking important proteins from miRNA pathway, such as Exportin-5 and Dicer, or by targeting relevant cellular factors. Drastic changes in cellular miRNA expression profile are also noticeable and several cellular functions are affected by these changes. This review focuses on the mechanisms underlying the biogenesis and molecular interactions of miRNAs providing basic concepts of their functions as well as in the interplay between miRNAs and human adenoviruses.
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Affiliation(s)
- Diogo Piedade
- Host-Pathogen Interaction Unit, iMed.ULisboa, Faculdade de Farmácia, Universidade de LisboaLisboa, Portugal
| | - José M Azevedo-Pereira
- Host-Pathogen Interaction Unit, iMed.ULisboa, Faculdade de Farmácia, Universidade de LisboaLisboa, Portugal
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49
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Zhao Z, Liu W, Liu J, Wang J, Luo B. The effect of EBV on WIF1, NLK, and APC gene methylation and expression in gastric carcinoma and nasopharyngeal cancer. J Med Virol 2017; 89:1844-1851. [PMID: 28543390 DOI: 10.1002/jmv.24863] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 05/07/2017] [Indexed: 12/27/2022]
Abstract
Epstein-Barr virus (EBV) is an important DNA tumor virus that is associated with approximately 10% of gastric carcinomas and 99% of nasopharyngeal cancers (NPC). DNA methylation and microRNAs (miRNAs) are the most studied epigenetic mechanisms that can prompt disease susceptibility. This study aimed to detect the effect of EBV on Wnt inhibitory factor 1 (WIF1), Nemo-like kinase (NLK), and adenomatous polyposis coli (APC) gene methylation, and expression in gastric carcinoma and NPC. The WIF1, NLK, and APC gene mRNA expression levels were measured by real-time quantitative RT-PCR in four EBV-positive cell lines and four EBV-negative cell lines. Bisulfite genomic sequencing or methylation-specific PCR was used to detect the methylation status of the WIF1, NLK, and APC promoters. All cell lines were treated with 5-azacytidine (5-aza-dC), miR-BART19-3p mimics or an inhibitor, and analyzed by flow cytometry and MTT cell proliferation assays. The WIF1, NLK, and APC promoters were hypermethylated in all eight cell lines. 5-Aza-dC displayed a growth inhibitory effect on cells . After transfection with miR-BART19-3p mimics, the expression of WIF1, and APC decreased, and the cellular proliferation rate increased. After transfection with the miR-BART19-3p inhibitor, the expression levels were higher, and the cell growth was inhibited. In the NPC and GC cell lines, the promoters of WIF1, NLK, and APC are highly methylated, and the expression of these three genes is regulated by miR-BART19-3p. The activity of the Wnt pathway in EBV-associated tumors may be enhanced by miR-BART19-3p.
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Affiliation(s)
- Zhenzhen Zhao
- Department of Medical Microbiology, Qingdao University Medical College, Qingdao, China
| | - Wen Liu
- Department of Medical Microbiology, Qingdao University Medical College, Qingdao, China
| | - Jincheng Liu
- Department of Medical Microbiology, Qingdao University Medical College, Qingdao, China
| | - Jiayi Wang
- Department of Medical Microbiology, Qingdao University Medical College, Qingdao, China
| | - Bing Luo
- Department of Medical Microbiology, Qingdao University Medical College, Qingdao, China
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50
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Assadian F, Kamel W, Laurell G, Svensson C, Punga T, Akusjärvi G. Expression profile of Epstein-Barr virus and human adenovirus small RNAs in tonsillar B and T lymphocytes. PLoS One 2017; 12:e0177275. [PMID: 28542273 PMCID: PMC5444648 DOI: 10.1371/journal.pone.0177275] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 04/25/2017] [Indexed: 12/24/2022] Open
Abstract
We have used high-throughput small RNA sequencing to characterize viral small RNA expression in purified tonsillar B and T lymphocytes isolated from patients tested positive for Epstein-Barr virus (EBV) or human adenovirus (HAdV) infections, respectively. In the small set of patients analyzed, the expression profile of EBV and HAdV miRNAs could not distinguish between patients diagnosed with tonsillar hypertrophy or chronic/recurrent tonsillitis. The EBV miR-BART expression profile among the patients diagnosed with tonsillar diseases resembles most closely the pattern seen in EBV+ tumors (Latency II/I). The miR-BARTs that appear to be absent in normal EBV infected cells are essentially all detectable in the diseased tonsillar B lymphocytes. In the EBV+ B cells we detected 44 EBV miR-BARTs derived from the proposed BART precursor hairpins whereof five are not annotated in miRBase v21. One previously undetected miRNA, BART16b-5p, originates from the miR-BART16 precursor hairpin as an alternative 5´ miR-BART16 located precisely upstream of the annotated miR-BART16-5p. Further, our analysis revealed an extensive sequence variation among the EBV miRNAs with isomiRs having a constant 5´ end but alternative 3´ ends. A range of small RNAs was also detected from the terminal stem of the EBER RNAs and the 3´ part of v-snoRNA1. During a lytic HAdV infection in established cell lines the terminal stem of the viral non-coding VA RNAs are processed to highly abundant viral miRNAs (mivaRNAs). In contrast, mivaRNA expression in HAdV positive tonsillar T lymphocytes was very low. The small RNA profile further showed that the 5´ mivaRNA from VA RNAI and the 3´ mivaRNA from VA RNAII were as predicted, whereas the 3´ mivaRNA from VA RNAI showed an aberrant processing upstream of the expected Dicer cleavage site.
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Affiliation(s)
- Farzaneh Assadian
- Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Wael Kamel
- Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Göran Laurell
- Department of Surgical Sciences, Otorhinolaryngology and Head and Neck Surgery, Uppsala University, Uppsala, Sweden
| | - Catharina Svensson
- Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Tanel Punga
- Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Göran Akusjärvi
- Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
- * E-mail:
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