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Li P, Cao X, Wu J, Liu X, Mao S, Yuan L, Shang Y. Detection and analysis of enzootic nasal tumor virus 2 in China. J Vet Diagn Invest 2025; 37:244-251. [PMID: 39757844 PMCID: PMC11701905 DOI: 10.1177/10406387241310204] [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] [Indexed: 01/07/2025] Open
Abstract
Enzootic nasal tumor virus 2 (ENTV2), the etiologic agent of enzootic nasal adenocarcinoma (ENA) in goats, is highly prevalent in China and causes significant economic losses to the goat industry. Here we describe the occurrence of ENA on a Dazu black goat farm in Chongqing City. At autopsy, nasal cavity masses were observed within the nose of an affected goat; histologically, the tumor was a nasal adenocarcinoma. The qPCR results demonstrated unequivocally that ENTV2 was the primary pathogen responsible for the tumor in this goat. We also collected nasal swab samples from all 180 goats on the farm; 9 goats tested positive for ENTV2. We generated the sequence of the full-length genome of ENTV2 (named ENTV2CQ, GenBank OR024676) with 7,469 nucleotides from nasal tumors from our case. ENTV2CQ shared the highest nucleotide identity with a previously sequenced isolate, ENTV2FJ (GenBank MK559457.1). ENTV2CQ and ENTV2FJ are located in the same major phylogenetic branch, mainly related to isolates from China from 2015 to 2022, and their phylogeny may be clustered geographically.
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Affiliation(s)
- Pengfei Li
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Xiaoan Cao
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jinyan Wu
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Xiaobo Liu
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Shouhui Mao
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Ligang Yuan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China
| | - Youjun Shang
- State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
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Toma C, Popa R, Ciobanu L, Baldea I, Amorim I, Bochynska D, Wolfe A, Negoescu A, Gal C, Taulescu M. Overexpression of IL-6 and STAT3 may provide new insights into ovine pulmonary adenocarcinoma development. BMC Vet Res 2025; 21:29. [PMID: 39833798 PMCID: PMC11744984 DOI: 10.1186/s12917-024-04429-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/04/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Ovine pulmonary adenocarcinoma (OPA) is caused by Jaagsiekte sheep retrovirus (JSRV) and is considered an important potential animal model for human lung cancer. The precise mechanisms of OPA oncogenesis are still uncertain. The transcription factor signal transducer and activator of transcription 3 (STAT3) is activated by interleukin-6 (IL-6) in many cancers, but this aspect is unknown in OPA. We therefore aimed to evaluate the expression of IL-6 and STAT3 in OPA for its potential role in pulmonary carcinogenesis. RESULTS Lung tissues from 9 grossly normal and JRSV-negative sheep and 20 cases of JSRV-positive OPA sheep were included in the study. Tissue samples were stained with antibodies against IL-6, STAT3, and JSRV-MA. IL-6 and STAT3 were further quantified in both groups using Western Blot (WB). Immunohistochemically, IL‑6 was expressed in stromal, inflammatory, and epithelial cells in all cases of OPA, while STAT3 immunoexpression was restricted to epithelial cells. In the OPA group, the percentage of immunolabelled cells for STAT3 accounted for a mean value of 96%. Using the H-SCORE method, 95% of cases were considered positive for STAT3 expression. Control tissues showed multifocal and weak immunoexpression for both markers. Using WB analyses, a highly significant amount of both IL-6 (p = 0.0078) and STAT3 (p < 0.0001) proteins were present in lung neoplasms, by comparison to the control lungs. CONCLUSIONS Our data showed overexpression of IL-6 and STAT3 in lung tissues from OPA compared to lungs from JSRV-negative sheep. These results suggest a potential role of IL6-STAT3 in OPA carcinogenesis.
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Affiliation(s)
- Corina Toma
- Department of Veterinary Pathology, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania.
| | - Roxana Popa
- Department of Veterinary Pathology, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania
| | - Lidia Ciobanu
- Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Cluj-Napoca, Romania
| | - Ioana Baldea
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj- Napoca, Romania
| | - Irina Amorim
- Department of Pathology and Molecular Immunology of the Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal
| | - Diana Bochynska
- Ross University School of Veterinary Medicine, Basseterre, St. Kitts and Nevis
| | - Alan Wolfe
- Pathobiology Section, School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - Andrada Negoescu
- Department of Veterinary Pathology, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania
| | - Claudiu Gal
- Department of Veterinary Pathology, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania
- Synevovet laboratory, Bucharest, Romania
| | - Marian Taulescu
- Department of Veterinary Pathology, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania
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Pei B, Liu P, Peng S, Zhou F. Mendelian randomization analyses support causal relationships between HPV infection and colorectal cancer. Discov Oncol 2024; 15:795. [PMID: 39692780 DOI: 10.1007/s12672-024-01639-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND Human Papillomavirus (HPV) infections leading to a variety of diseases are a global public health issue.Despite the well-established link between HPV infection and cervical and anogenital cancers, there is ongoing debate regarding the relationship between HPV infection and colorectal cancer (CRC). METHODS We evaluated the causal connection between HPV infection and CRC utilizing five Mendelian randomization (MR) methods. Genome-wide association studies (GWAS) datasets for HPV were obtained from the IEU Open GWAS project. A large summary of colorectal adenocarcinoma and colorectal cancer data from the FinnGen database was used as the outcome. RESULTS Our analysis revealed a significant association between genetically predicted HPV-16 infection and the risk of paternal colorectal adenocarcinoma (HPV-16: OR 1.058, 95% CI 1.013-1.102; p = 0.011), as well as CRC (HPV-16: OR 1.045, 95% CI 1.005-1.085; p = 0.025). CONCLUSION These findings provide compelling evidence for a causal effect of HPV infection on the development of CRC. Further investigations into the underlying mechanisms and elucidation of this association are necessary to identify viable interventions for the prevention and treatment of HPV-associated CRC.
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Affiliation(s)
- Bo Pei
- Department of Oncology, Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Oncology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, China
| | - Peijun Liu
- Department of Respiratory and Critical Care Medicine, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, China
| | - Shixuan Peng
- Department of Oncology, The First People's Hospital of Xiangtan City, Xiangtan, 411101, Hunan, China
- Department of Oncology, Graduate Collaborative Training Base of The First People's Hospital of Xiangtan City, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Fuxiang Zhou
- Department of Oncology, Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China.
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Nishiura H, Nakajima T, Saito S, Kato A, Hatai H, Ochiai K. Assessing avian leukosis virus proviral load and lesion correlates in fowl glioma-inducing virus-infected Japanese bantam chickens. J Vet Diagn Invest 2023; 35:484-491. [PMID: 37452573 PMCID: PMC10467450 DOI: 10.1177/10406387231186954] [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] [Indexed: 07/18/2023] Open
Abstract
The fowl glioma-inducing virus prototype (FGVp) and its variants, which belong to avian leukosis virus subgroup A (ALV-A), induce cardiomyocyte abnormalities and gliomas in chickens. However, the molecular mechanisms underlying these myocardial changes remain unclear, and ALV-induced tumorigenesis, which is caused by proviral insertional mutagenesis, does not explain the early development of cardiac changes in infected chickens. We established a quantitative PCR (qPCR) assay to measure ALV-A proviral loads in the brains and hearts of FGV-infected Japanese bantam chickens and compared these results with morphologic lesions. Four of 22 bantams had both gliomas and cardiac lesions. Hearts with cardiac lesions had a higher proviral load (10.3 ± 2.7 proviral copies/nucleus) than those without cardiac lesions (0.4 ± 0.4), suggesting that the proviral load in hearts is correlated with the frequency of myocardial changes. Our qPCR method may be useful in the study of ALV-induced cardiomyocyte abnormalities.
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Affiliation(s)
- Hayate Nishiura
- Laboratory of Veterinary Pathology, Faculty of Agriculture, Iwate University, Morioka, Iwate, Japan
| | - Tomoe Nakajima
- Laboratory of Veterinary Pathology, Faculty of Agriculture, Iwate University, Morioka, Iwate, Japan
| | - Shun Saito
- Laboratory of Veterinary Pathology, Faculty of Agriculture, Iwate University, Morioka, Iwate, Japan
| | - Azusa Kato
- Laboratory of Veterinary Pathology, Faculty of Agriculture, Iwate University, Morioka, Iwate, Japan
| | - Hitoshi Hatai
- Farm Animal Clinical Skills and Disease Control Center, Faculty of Agriculture, Iwate University, Morioka, Iwate, Japan
| | - Kenji Ochiai
- Laboratory of Veterinary Pathology, Faculty of Agriculture, Iwate University, Morioka, Iwate, Japan
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Teng M, Zhu ZJ, Yao Y, Nair V, Zhang GP, Luo J. Critical roles of non-coding RNAs in lifecycle and biology of Marek's disease herpesvirus. SCIENCE CHINA. LIFE SCIENCES 2023; 66:251-268. [PMID: 36617590 PMCID: PMC9838510 DOI: 10.1007/s11427-022-2258-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/05/2022] [Indexed: 01/10/2023]
Abstract
Over the past two decades, numerous non-coding RNAs (ncRNAs) have been identified in different biological systems including virology, especially in large DNA viruses such as herpesviruses. As a representative oncogenic alphaherpesvirus, Marek's disease virus (MDV) causes an important immunosuppressive and rapid-onset neoplastic disease of poultry, namely Marek's disease (MD). Vaccinations can efficiently prevent the onset of MD lymphomas and other clinical disease, often heralded as the first successful example of vaccination-based control of cancer. MDV infection is also an excellent model for research into virally-induced tumorigenesis. Recently, great progress has been made in understanding the functions of ncRNAs in MD biology. Herein, we give a review of the discovery and identification of MDV-encoded viral miRNAs, focusing on the genomics, expression profiles, and emerging critical roles of MDV-1 miRNAs as oncogenic miRNAs (oncomiRs) or tumor suppressor genes involved in the induction of MD lymphomas. We also described the involvements of host cellular miRNAs, lincRNAs, and circRNAs participating in MDV life cycle, pathogenesis, and/or tumorigenesis. The prospects, strategies, and new techniques such as the CRISPR/Cas9-based gene editing applicable for further investigation into the ncRNA-mediated regulatory mechanisms in MDV pathogenesis/oncogenesis were also discussed, together with the possibilities of future studies on antiviral therapy and the development of new efficient MD vaccines.
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Affiliation(s)
- Man Teng
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Rural Affairs of China & Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, 450002, China
- UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, 450002, China
| | - Zhi-Jian Zhu
- School of Biological and Food Processing Engineering, Huanghuai University, Zhumadian, 463000, China
| | - Yongxiu Yao
- The Pirbright Institute & UK-China Centre of Excellence for Research on Avian Diseases, Pirbright, Ash Road, Guildford, Surrey, GU24 0NF, UK
| | - Venugopal Nair
- The Pirbright Institute & UK-China Centre of Excellence for Research on Avian Diseases, Pirbright, Ash Road, Guildford, Surrey, GU24 0NF, UK
| | - Gai-Ping Zhang
- International Joint Research Center of National Animal Immunology & College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, China
- Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, 225009, China
| | - Jun Luo
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Rural Affairs of China & Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, 450002, China.
- UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, 450002, China.
- Key Laboratory of Animal Disease and Public Safety, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471003, China.
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Bevilacqua G. The Viral Origin of Human Breast Cancer: From the Mouse Mammary Tumor Virus (MMTV) to the Human Betaretrovirus (HBRV). Viruses 2022; 14:1704. [PMID: 36016325 PMCID: PMC9412291 DOI: 10.3390/v14081704] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/25/2022] [Accepted: 07/29/2022] [Indexed: 02/04/2023] Open
Abstract
A Human Betaretrovirus (HBRV) has been identified in humans, dating as far back as about 4500 years ago, with a high probability of it being acquired by our species around 10,000 years ago, following a species jump from mice to humans. HBRV is the human homolog of the MMTV (mouse mammary tumor virus), which is the etiological agent of murine mammary tumors. The hypothesis of a HMTV (human mammary tumor virus) was proposed about 50 years ago, and has acquired a solid scientific basis during the last 30 years, with the demonstration of a robust link with breast cancer and with PBC, primary biliary cholangitis. This article summarizes most of what is known about MMTV/HMTV/HBRV since the discovery of MMTV at the beginning of last century, to make evident both the quantity and the quality of the research supporting the existence of HBRV and its pathogenic role. Here, it is sufficient to mention that scientific evidence includes that viral sequences have been identified in breast-cancer samples in a worldwide distribution, that the complete proviral genome has been cloned from breast cancer and patients with PBC, and that saliva contains HBRV, as a possible route of inter-human infection. Controversies that have arisen concerning results obtained from human tissues, many of them outdated by new scientific evidence, are critically discussed and confuted.
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Parisi F, Freer G, Mazzanti CM, Pistello M, Poli A. Mouse Mammary Tumor Virus (MMTV) and MMTV-like Viruses: An In-depth Look at a Controversial Issue. Viruses 2022; 14:v14050977. [PMID: 35632719 PMCID: PMC9147501 DOI: 10.3390/v14050977] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/02/2022] [Accepted: 05/04/2022] [Indexed: 02/01/2023] Open
Abstract
Since its discovery as a milk factor, mouse mammary tumor virus (MMTV) has been shown to cause mammary carcinoma and lymphoma in mice. MMTV infection depends upon a viral superantigen (sag)-induced immune response and exploits the immune system to establish infection in mammary epithelial cells when they actively divide. Simultaneously, it avoids immune responses, causing tumors through insertional mutagenesis and clonal expansion. Early studies identified antigens and sequences belonging to a virus homologous to MMTV in human samples. Several pieces of evidence fulfill a criterion for a possible causal role for the MMTV-like virus in human breast cancer (BC), though the controversy about whether this virus was linked to BC has raged for over 40 years in the literature. In this review, the most important issues related to MMTV, from its discovery to the present days, are retraced to fully explore such a controversial issue. Furthermore, the hypothesis of an MMTV-like virus raised the question of a potential zoonotic mouse–man transmission. Several studies investigate the role of an MMTV-like virus in companion animals, suggesting their possible role as mediators. Finally, the possibility of an MMTV-like virus as a cause of human BC opens a new era for prevention and therapy.
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Affiliation(s)
- Francesca Parisi
- Dipartimento di Scienze Veterinarie, Università di Pisa, Viale Delle Piagge, 2, 56124 Pisa, Italy;
| | - Giulia Freer
- Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Via Savi 10, 56126 Pisa, Italy; (G.F.); (M.P.)
| | - Chiara Maria Mazzanti
- Fondazione Pisana per la Scienza, Via Ferruccio Giovannini, 13, 56017 San Giuliano Terme, Italy;
| | - Mauro Pistello
- Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Via Savi 10, 56126 Pisa, Italy; (G.F.); (M.P.)
| | - Alessandro Poli
- Dipartimento di Scienze Veterinarie, Università di Pisa, Viale Delle Piagge, 2, 56124 Pisa, Italy;
- Correspondence:
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Coffin J, Blomberg J, Fan H, Gifford R, Hatziioannou T, Lindemann D, Mayer J, Stoye J, Tristem M, Johnson W. ICTV Virus Taxonomy Profile: Retroviridae 2021. J Gen Virol 2021; 102:001712. [PMID: 34939563 PMCID: PMC8744268 DOI: 10.1099/jgv.0.001712] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 01/09/2023] Open
Abstract
Viruses in the family Retroviridae are found in a wide variety of vertebrate hosts. Enveloped virions are 80-100 nm in diameter with an inner core containing the viral genome and replicative enzymes. Core morphology is often characteristic for viruses within the same genus. Replication involves reverse transcription and integration into host cell DNA, resulting in a provirus. Integration into germline cells can result in a heritable provirus known as an endogenous retrovirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Retroviridae, which is available at ictv.global/report/retroviridae.
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Affiliation(s)
| | | | - Hung Fan
- University of California, Irvine, CA 92697-3905, USA
| | | | | | | | - Jens Mayer
- University of Saarland, 66421 Homburg/Saar, Germany
| | - Jonathan Stoye
- Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | | | | | - ICTV Report Consortium
- Tufts University, Boston, MA 2111, USA
- Uppsala University, Sweden
- University of California, Irvine, CA 92697-3905, USA
- Center for Virus Research, Glasgow G61 1QH, UK
- The Rockefeller University, New York, NY10065, USA
- Technische Universität Dresden, Dresden, 01307, Germany
- University of Saarland, 66421 Homburg/Saar, Germany
- Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
- Imperial College London, Berkshire, SL5 7PY, UK
- Boston College, Chestnut Hill, MA 02467, USA
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Notsu K, El Daous H, Mitoma S, Norimine J, Sekiguchi S. A pooled testing system to rapidly identify cattle carrying the elite controller BoLA-DRB3*009:02 haplotype against bovine leukemia virus infection. HLA 2021; 99:12-24. [PMID: 34837483 PMCID: PMC9543338 DOI: 10.1111/tan.14502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 11/30/2022]
Abstract
As genetically resistant individuals, the “elite controllers” (ECs) of human immunodeficiency virus infection have been focused on as the keys to developing further functional treatments in medicine. In the livestock production field, identifying the ECs of bovine leukemia virus (BLV) infection in cattle is desired to stop BLV transmission chains on farms. Cattle carrying the bovine leukocyte antigen (BoLA)‐DRB3*009:02 allele (DRB3*009:02) have a strong possibility of being BLV ECs. Most of cattle carrying this allele maintain undetectable BLV proviral loads and do not shed virus even when infected. BLV ECs can act as transmission barriers when placed between uninfected and infected cattle in a barn. To identify cattle carrying DRB3*009:02 in large populations more easily, we developed a pooled testing system. It employs a highly sensitive, specific real‐time PCR assay and TaqMan MGB probes (DRB3*009:02‐TaqMan assay). Using this system, we determined the percentage of DRB3*009:02‐carrying cattle on Kyushu Island, Japan. Our pooled testing system detected cattle carrying the DRB3*009:02 allele from a DNA pool containing one DRB3*009:02‐positive animal and 29 cattle with other alleles. Its capacity is sufficient for herd‐level screening for DRB3*009:02‐carrying cattle. The DRB3*009:02‐TaqMan assay showed high‐discriminative sensitivity and specificity toward DRB3*009:02, making it suitable for identifying DRB3*009:02‐carrying cattle in post‐screening tests on individuals. We determined that the percentage of DRB3*009:02‐carrying cattle in Kyushu Island was 10.56%. With its ease of use and reliable detection, this new method strengthens the laboratory typing for DRB3*009:02‐carrying cattle. Thus, our findings support the use of BLV ECs in the field.
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Affiliation(s)
- Kosuke Notsu
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Hala El Daous
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan.,Faculty of Veterinary Medicine, Benha University, Toukh, Egypt
| | - Shuya Mitoma
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Junzo Norimine
- Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.,Center for Animal Disease Control, University of Miyazaki, Miyazaki, Japan
| | - Satoshi Sekiguchi
- Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.,Center for Animal Disease Control, University of Miyazaki, Miyazaki, Japan
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10
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Parisi F, Muscatello LV, Civita P, Lessi F, Menicagli M, Millanta F, Brunetti B, Benazzi C, Sarli G, Freer G, Pistello M, Mazzanti CM, Poli A. Pathological Features and Molecular Phenotype of MMTV Like-Positive Feline Mammary Carcinomas. Animals (Basel) 2021; 11:ani11102821. [PMID: 34679842 PMCID: PMC8532932 DOI: 10.3390/ani11102821] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Mouse mammary tumour virus-like (MMTV-like) is suspected to be involved in human breast cancer and feline mammary carcinomas (FMCs). We previously reported the identification of MMTV-like sequences and viral protein in six of 78 FMCs collected in Tuscany, Italy. To corroborate this finding, FMCs samples collected from a different geographic area were investigated. MMTV-like sequences and p14 protein were identified in three of 24 FMCs collected at the University of Bologna, one tubular carcinoma, one tubulopapillary carcinoma and one ductal carcinoma. All the examined FMCs from Pisa and Bologna were submitted to immunohistochemistry for molecular phenotype characterization. Of the nine positive FMCs, six were basal-like and three luminal-like. This study highlights the presence of MMTV-like sequences and protein in FMCs of different geographic areas. The characterization of molecular phenotype could contribute to understand the possible role of MMTV-like virus in FMC biological behaviour. Abstract In the last few years MMTV-like nucleotide sequences were detected in some feline and canine mammary tumours. Due to the confirmed role of cats in the epidemiology of the MMTV-like virus, the aim of this study was to investigate the main pathological features of positive feline mammary carcinomas (FMCs). Twenty-four FMCs were collected at the University of Bologna, submitted to laser microdissection and analysed by nested fluorescence-PCR using primer sets specific for MMTV env sequence. For immunohistochemistry, an antibody against MMTV protein 14 (p14) was used. MMTV-like sequences were detected in three out of 24 FMCs (12.5%), one tubular carcinoma, one tubulopapillary carcinoma and one ductal carcinoma. All PCR-positive tumours were also positive for p14. Multiple nucleotide alignment has shown similarity to MMTV ranging from 98% to 100%. All the 102 examined FMCs were submitted to immunohistochemistry for molecular phenotyping. Of the nine MMTV-like positive FMCs, six were basal-like and three luminal-like. Our results demonstrate MMTV-like sequences and protein in FMCs of different geographic areas. Molecular phenotyping could contribute to understand the possible role of MMTV-like virus in FMC tumor biology.
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Affiliation(s)
- Francesca Parisi
- Department of Veterinary Sciences, University of Pisa, Viale delle Piagge n. 2, 56124 Pisa, Italy; (F.P.); (F.M.)
| | - Luisa Vera Muscatello
- Department of Veterinary Sciences, University of Bologna, Via Tolara di sopra n. 43, 40064 Ozzano dell’Emilia, Italy; (L.V.M.); (B.B.); (C.B.); (G.S.)
| | - Prospero Civita
- School of Pharmacy and Pharmaceutical Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF14 4EP, UK;
| | - Francesca Lessi
- Fondazione Pisana per la Scienza Onlus, Via Ferruccio Giovannini n. 13, 56017 San Giuliano Terme, Italy; (F.L.); (M.M.); (C.M.M.)
| | - Michele Menicagli
- Fondazione Pisana per la Scienza Onlus, Via Ferruccio Giovannini n. 13, 56017 San Giuliano Terme, Italy; (F.L.); (M.M.); (C.M.M.)
| | - Francesca Millanta
- Department of Veterinary Sciences, University of Pisa, Viale delle Piagge n. 2, 56124 Pisa, Italy; (F.P.); (F.M.)
| | - Barbara Brunetti
- Department of Veterinary Sciences, University of Bologna, Via Tolara di sopra n. 43, 40064 Ozzano dell’Emilia, Italy; (L.V.M.); (B.B.); (C.B.); (G.S.)
| | - Cinzia Benazzi
- Department of Veterinary Sciences, University of Bologna, Via Tolara di sopra n. 43, 40064 Ozzano dell’Emilia, Italy; (L.V.M.); (B.B.); (C.B.); (G.S.)
| | - Giuseppe Sarli
- Department of Veterinary Sciences, University of Bologna, Via Tolara di sopra n. 43, 40064 Ozzano dell’Emilia, Italy; (L.V.M.); (B.B.); (C.B.); (G.S.)
| | - Giulia Freer
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Savi n. 10, 56126 Pisa, Italy; (G.F.); (M.P.)
| | - Mauro Pistello
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Savi n. 10, 56126 Pisa, Italy; (G.F.); (M.P.)
| | - Chiara Maria Mazzanti
- Fondazione Pisana per la Scienza Onlus, Via Ferruccio Giovannini n. 13, 56017 San Giuliano Terme, Italy; (F.L.); (M.M.); (C.M.M.)
| | - Alessandro Poli
- Department of Veterinary Sciences, University of Pisa, Viale delle Piagge n. 2, 56124 Pisa, Italy; (F.P.); (F.M.)
- Correspondence:
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11
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El Tekle G, Bernasocchi T, Unni AM, Bertoni F, Rossi D, Rubin MA, Theurillat JP. Co-occurrence and mutual exclusivity: what cross-cancer mutation patterns can tell us. Trends Cancer 2021; 7:823-836. [PMID: 34031014 DOI: 10.1016/j.trecan.2021.04.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/25/2021] [Accepted: 04/30/2021] [Indexed: 12/19/2022]
Abstract
Cancer is the dysregulated proliferation of cells caused by acquired mutations in key driver genes. The most frequently mutated driver genes promote tumorigenesis in various organisms, cell types, and genetic backgrounds. However, recent cancer genomics studies also point to the existence of context-dependent driver gene functions, where specific mutations occur predominately or even exclusively in certain tumor types or genetic backgrounds. Here, we review examples of co-occurring and mutually exclusive driver gene mutation patterns across cancer genomes and discuss their underlying biology. While co-occurring driver genes typically activate collaborating oncogenic pathways, we identify two distinct biological categories of incompatibilities among the mutually exclusive driver genes depending on whether the mutated drivers trigger the same or divergent tumorigenic pathways. Finally, we discuss possible therapeutic avenues emerging from the study of incompatible driver gene mutations.
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Affiliation(s)
- Geniver El Tekle
- Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, TI 6500, Switzerland
| | - Tiziano Bernasocchi
- Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, TI 6500, Switzerland
| | - Arun M Unni
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Francesco Bertoni
- Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, TI 6500, Switzerland
| | - Davide Rossi
- Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, TI 6500, Switzerland; Oncology Institute of Southern Switzerland, Bellinzona, TI 6500, Switzerland
| | - Mark A Rubin
- Department for BioMedical Research, Precision Oncology Laboratory, University of Bern, Bern, Switzerland; Bern Center for Precision Medicine, University of Bern and Inselspital, Bern, Switzerland
| | - Jean-Philippe Theurillat
- Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, TI 6500, Switzerland.
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12
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Murashko MM, Stasevich EM, Schwartz AM, Kuprash DV, Uvarova AN, Demin DE. The Role of RNA in DNA Breaks, Repair and Chromosomal Rearrangements. Biomolecules 2021; 11:biom11040550. [PMID: 33918762 PMCID: PMC8069526 DOI: 10.3390/biom11040550] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 03/31/2021] [Accepted: 04/07/2021] [Indexed: 12/28/2022] Open
Abstract
Incorrect reparation of DNA double-strand breaks (DSB) leading to chromosomal rearrangements is one of oncogenesis's primary causes. Recently published data elucidate the key role of various types of RNA in DSB formation, recognition and repair. With growing interest in RNA biology, increasing RNAs are classified as crucial at the different stages of the main pathways of DSB repair in eukaryotic cells: nonhomologous end joining (NHEJ) and homology-directed repair (HDR). Gene mutations or variation in expression levels of such RNAs can lead to local DNA repair defects, increasing the chromosome aberration frequency. Moreover, it was demonstrated that some RNAs could stimulate long-range chromosomal rearrangements. In this review, we discuss recent evidence demonstrating the role of various RNAs in DSB formation and repair. We also consider how RNA may mediate certain chromosomal rearrangements in a sequence-specific manner.
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Affiliation(s)
- Matvey Mikhailovich Murashko
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (M.M.M.); (E.M.S.); (A.M.S.); (D.V.K.); (A.N.U.)
| | - Ekaterina Mikhailovna Stasevich
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (M.M.M.); (E.M.S.); (A.M.S.); (D.V.K.); (A.N.U.)
| | - Anton Markovich Schwartz
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (M.M.M.); (E.M.S.); (A.M.S.); (D.V.K.); (A.N.U.)
- Moscow Institute of Physics and Technology, Department of Molecular and Biological Physics, 141701 Moscow, Russia
| | - Dmitriy Vladimirovich Kuprash
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (M.M.M.); (E.M.S.); (A.M.S.); (D.V.K.); (A.N.U.)
| | - Aksinya Nicolaevna Uvarova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (M.M.M.); (E.M.S.); (A.M.S.); (D.V.K.); (A.N.U.)
| | - Denis Eriksonovich Demin
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (M.M.M.); (E.M.S.); (A.M.S.); (D.V.K.); (A.N.U.)
- Correspondence:
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13
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Maeda N, Inoshima Y, De Las Heras M, Maenaka K. Enzootic nasal tumor virus type 2 envelope of goats acts as a retroviral oncogene in cell transformation. Virus Genes 2020; 57:50-59. [PMID: 33151445 DOI: 10.1007/s11262-020-01808-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/30/2020] [Indexed: 11/26/2022]
Abstract
Enzootic nasal tumor virus type 1 (ENTV-1) (ovine nasal tumor virus) and ENTV-2 (caprine nasal tumor virus) are known to be causative agents of enzootic nasal adenocarcinoma (ENA) in sheep and goats, respectively. Although the nucleotide and amino acid sequences of ENTV-1 and ENTV-2 are quite similar, they are recognized as phylogenetically distinct viruses. The envelope protein of ENTV-1 functions as an oncoprotein in the in vitro transformation of epithelial cells and fibroblasts. Thus, it is the primary determinant of in vivo tumorigenesis in ENA. As per our knowledge, no previous studies have reported in detail the role of ENTV-2 in ENA tumorigenesis. Here, in order to investigate the molecular mechanism of caprine ENA oncogenesis by ENTV-2, we have attempted to identify the transforming potential of ENTV-2 envelope, and investigated the activation of cell signaling pathways in oncogenic transformation. Our findings confirmed that ENTV-2 envelope was capable of inducing oncogenic transformation of rat cell lines in vitro. Further, we found that MAPK, Akt, and p38 were constitutively activated in ENTV-2 envelope-transformed clone cells. In addition, inhibitor experiments revealed that MEK-MAPK and PI3K-Akt signaling pathways are involved in the ENTV-2 envelope-induced cell transformation. These data indicate that ENTV-2 envelope could induce oncogenic transformation by signaling pathways that are also utilized by ENTV-1 envelope.
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Affiliation(s)
- Naoyoshi Maeda
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | | | - Katsumi Maenaka
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
- Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
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14
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Razin SV, Gavrilov AA, Iarovaia OV. Modification of Nuclear Compartments and the 3D Genome in the Course of a Viral Infection. Acta Naturae 2020; 12:34-46. [PMID: 33456976 PMCID: PMC7800604 DOI: 10.32607/actanaturae.11041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/07/2020] [Indexed: 12/17/2022] Open
Abstract
The review addresses the question of how the structural and functional compartmentalization of the cell nucleus and the 3D organization of the cellular genome are modified during the infection of cells with various viruses. Particular attention is paid to the role of the introduced changes in the implementation of the viral strategy to evade the antiviral defense systems and provide conditions for viral replication. The discussion focuses on viruses replicating in the cell nucleus. Cytoplasmic viruses are mentioned in cases when a significant reorganization of the nuclear compartments or the 3D genome structure occurs during an infection with these viruses.
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Affiliation(s)
- S. V. Razin
- Institute of Gene Biology Russian Academy of Sciences
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15
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Abstract
Mosaicism refers to the occurrence of two or more genomes in an individual derived from a single zygote. Germline mosaicism is a mutation that is limited to the gonads and can be transmitted to offspring. Somatic mosaicism is a postzygotic mutation that occurs in the soma, and it may occur at any developmental stage or in adult tissues. Mosaic variation may be classified in six ways: (a) germline or somatic origin, (b) class of DNA mutation (ranging in scale from single base pairs to multiple chromosomes), (c) developmental context, (d) body location(s), (e) functional consequence (including deleterious, neutral, or advantageous), and (f) additional sources of mosaicism, including mitochondrial heteroplasmy, exogenous DNA sources such as vectors, and epigenetic changes such as imprinting and X-chromosome inactivation. Technological advances, including single-cell and other next-generation sequencing, have facilitated improved sensitivity and specificity to detect mosaicism in a variety of biological contexts.
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Affiliation(s)
- Jeremy Thorpe
- Department of Neurology, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA; , .,Program in Biochemistry, Cellular, and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA;
| | - Ikeoluwa A Osei-Owusu
- Department of Neurology, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA; , .,Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA;
| | | | - Rossella Tupler
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.,Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy;
| | - Jonathan Pevsner
- Department of Neurology, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA; , .,Program in Biochemistry, Cellular, and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA; .,Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA; .,Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
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16
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Abstract
Sickle cell disease and the ß-thalassemias are caused by mutations of the ß-globin gene and represent the most frequent single gene disorders worldwide. Even in European countries with a previous low frequency of these conditions the prevalence has substantially increased following large scale migration from Africa and the Middle East to Europe. The hemoglobin diseases severely limit both, life expectancy and quality of life and require either life-long supportive therapy if cure cannot be achieved by allogeneic stem cell transplantation. Strategies for ex vivo gene therapy aiming at either re-establishing normal ß-globin chain synthesis or at re-activating fetal γ-globin chain and HbF expression are currently in clinical development. The European Medicine Agency (EMA) conditionally licensed gene addition therapy based on lentiviral transduction of hematopoietic stem cells in 2019 for a selected group of patients with transfusion dependent non-ß° thalassemia major without a suitable stem cell donor. Gene therapy thus offers a relevant chance to this group of patients for whom cure has previously not been on the horizon. In this review, we discuss the potential and the challenges of gene addition and gene editing strategies for the hemoglobin diseases.
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17
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Merrick BA, Phadke DP, Bostrom MA, Shah RR, Wright GM, Wang X, Gordon O, Pelch KE, Auerbach SS, Paules RS, DeVito MJ, Waalkes MP, Tokar EJ. KRAS-retroviral fusion transcripts and gene amplification in arsenic-transformed, human prostate CAsE-PE cancer cells. Toxicol Appl Pharmacol 2020; 397:115017. [PMID: 32344290 PMCID: PMC7606314 DOI: 10.1016/j.taap.2020.115017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/16/2020] [Accepted: 04/19/2020] [Indexed: 01/03/2023]
Abstract
CAsE-PE cells are an arsenic-transformed, human prostate epithelial line containing oncogenic mutations in KRAS compared to immortalized, normal KRAS parent cells, RWPE-1. We previously reported increased copy number of mutated KRAS in CAsE-PE cells, suggesting gene amplification. Here, KRAS flanking genomic and transcriptomic regions were sequenced in CAsE-PE cells for insight into KRAS amplification. Comparison of DNA-Seq and RNA-Seq showed increased reads from background aligning to all KRAS exons in CAsE-PE cells, while a uniform DNA-Seq read distribution occurred in RWPE-1 cells with normal transcript expression. We searched for KRAS fusions in DNA and RNA sequencing data finding a portion of reads aligning to KRAS and viral sequence. After generation of cDNA from total RNA, short and long KRAS probes were generated to hybridize cDNA and KRAS enriched fragments were PacBio sequenced. More KRAS reads were captured from CAsE-PE cDNA versus RWPE-1 by each probe set. Only CAsE-PE cDNA showed KRAS viral fusion transcripts, primarily mapping to LTR and endogenous retrovirus sequences on either 5'- or 3'-ends of KRAS. Most KRAS viral fusion transcripts contained 4 to 6 exons but some PacBio sequences were in unusual orientations, suggesting viral insertions within the gene body. Additionally, conditioned media was extracted for potential retroviral particles. RNA-Seq of culture media isolates identified KRAS retroviral fusion transcripts in CAsE-PE media only. Truncated KRAS transcripts suggested multiple retroviral integration sites occurred within the KRAS gene producing KRAS retroviral fusions of various lengths. Findings suggest activation of endogenous retroviruses in arsenic carcinogenesis should be explored.
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Affiliation(s)
- B Alex Merrick
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States.
| | - Dhiral P Phadke
- Sciome, LLC, Research Triangle Park, North Carolina, United States
| | - Meredith A Bostrom
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Ruchir R Shah
- Sciome, LLC, Research Triangle Park, North Carolina, United States
| | - Garron M Wright
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Xinguo Wang
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Oksana Gordon
- David H. Murdock Research Institute, Kannapolis, North Carolina, United States
| | - Katherine E Pelch
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Scott S Auerbach
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Richard S Paules
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Michael J DeVito
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Michael P Waalkes
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
| | - Erik J Tokar
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
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18
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Ghosh S, Brown AM, Jenkins C, Campbell K. Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges. APPLIED BIOSAFETY 2020; 25:7-18. [PMID: 36033383 PMCID: PMC9134621 DOI: 10.1177/1535676019899502] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
Introduction National Institutes of Health (NIH) defines gene therapy as an experimental technique that uses genes to treat or prevent disease. Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be effective and safe. Methods Applications of viral vectors and nonviral gene delivery systems have found an encouraging new beginning in gene therapy in recent years. Although several viral vectors and nonviral gene delivery systems have been developed in the past 3 decades, no one delivery system can be applied in gene therapy to all cell types in vitro and in vivo. Furthermore, the use of viral vector systems (both in vitro and in vivo) present unique occupational health and safety challenges. In this review article, we discuss the biosafety challenges and the current framework of risk assessment for working with the viral vector systems. Discussion The recent advances in the field of gene therapy is exciting, but it is important for scientists, institutional biosafety committees, and biosafety officers to safeguard public trust in the use of this technology in clinical trials and make conscious efforts to engage the public through ongoing forums and discussions.
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Affiliation(s)
- Sumit Ghosh
- The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Alex M. Brown
- The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Chris Jenkins
- Clinical Biosafety Services, A Division of Sabai Global, Wildwood, MO, USA
| | - Katie Campbell
- The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
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19
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Li W, Yang L, Harris RS, Lin L, Olson TL, Hamele CE, Feith DJ, Loughran TP, Poss M. Retrovirus insertion site analysis of LGL leukemia patient genomes. BMC Med Genomics 2019; 12:88. [PMID: 31208405 PMCID: PMC6580525 DOI: 10.1186/s12920-019-0549-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 06/06/2019] [Indexed: 02/08/2023] Open
Abstract
Background Large granular lymphocyte (LGL) leukemia is an uncommon cancer characterized by sustained clonal proliferation of LGL cells. Antibodies reactive to retroviruses have been documented in the serum of patients with LGL leukemia. Culture or molecular approaches have to date not been successful in identifying a retrovirus. Methods Because a retrovirus must integrate into the genome of an infected cell, we focused our efforts on detecting a novel retrovirus integration site in the clonally expanded LGL cells. We present a new computational tool that uses long-insert mate pair sequence data to search the genome of LGL leukemia cells for retrovirus integration sites. We also utilize recently published methods to interrogate the status of polymorphic human endogenous retrovirus type K (HERV-K) provirus in patient genomes. Results Our data show that there are no new retrovirus insertions in LGL genomes of LGL leukemia patients. However, our insertion call tool did detect four HERV-K provirus integration sites that are polymorphic in the human population but absent from the human reference genome, hg19. To determine if the prevalence of these or other polymorphic proviral HERV-Ks differed between LGL leukemia patients and the general population, we used a recently developed tool that reports sites in the human genome occupied by a known proviral HERV-K. We report that there are significant differences in the number of polymorphic HERV-Ks in the genomes of LGL leukemia patients of European origin compared to individuals with European ancestry in the 1000 genomes (KGP) data. Conclusions Our study confirms that the clonal expansion of LGL cells in LGL leukemia is not driven by the integration of a new infectious or endogenous retrovirus, although we do not rule out that these cells are responding to retroviral antigens produced in other cell types. However, our computational analyses revealed that the genomes of LGL leukemia patients carry a higher burden of polymorphic HERV-K proviruses compare to individuals from KGP of European ancestry. Our research emphasizes the merits of comprehensive genomic assessment of HERV-K in cancer samples and suggests that further analyses to determine contributions of HERV-K to LGL leukemia are warranted. Electronic supplementary material The online version of this article (10.1186/s12920-019-0549-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Weiling Li
- The School of Electrical Engineering and Computer Science, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Lei Yang
- Department of Biology, The Pennsylvania State University, University Park, PA, 16802, USA.,Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Robert S Harris
- Department of Biology, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Lin Lin
- Department of Statistics, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Thomas L Olson
- University of Virginia Cancer Center and Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia, 22908, USA
| | - Cait E Hamele
- University of Virginia Cancer Center and Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia, 22908, USA
| | - David J Feith
- University of Virginia Cancer Center and Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia, 22908, USA
| | - Thomas P Loughran
- University of Virginia Cancer Center and Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia, 22908, USA
| | - Mary Poss
- Department of Biology, The Pennsylvania State University, University Park, PA, 16802, USA. .,Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. .,University of Virginia Cancer Center and Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia, 22908, USA.
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20
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The Roles of Matricellular Proteins in Oncogenic Virus-Induced Cancers and Their Potential Utilities as Therapeutic Targets. Int J Mol Sci 2017; 18:ijms18102198. [PMID: 29065446 PMCID: PMC5666879 DOI: 10.3390/ijms18102198] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/17/2017] [Accepted: 10/18/2017] [Indexed: 12/13/2022] Open
Abstract
Matricellular proteins differ from other classical extracellular matrix proteins; for instance, they are transiently expressed as soluble proteins rather than being constitutively expressed in pathological conditions, such as acute viral infections. Accumulating studies have revealed that matricellular proteins, including osteopontin and tenascin-C, both of which interact with integrin heterodimers, are involved in inflammatory diseases, autoimmune disorders, and cancers. The concentrations of these matricellular proteins are elevated in the plasma of patients with certain types of cancers, indicating that they play important roles in oncogenesis. Chronic viral infections are associated with certain cancers, which are distinct from non-viral cancers. Viral oncogenes play critical roles in the development and progression of such cancers. It is vital to investigate the mechanisms of tumorigenesis and, particularly, the mechanism by which viral proteins induce tumor progression. Viral proteins have been shown to influence not only the viral-infected cancer cells, but also the stromal cells and matricellular proteins that constitute the extracellular matrix that surrounds tumor tissues. In this review, we summarize the recent progress on the involvement of matricellular proteins in oncogenic virus-induced cancers to elucidate the mechanism of oncogenesis and consider the possible role of matricellular proteins as therapeutic targets in virus-induced cancers.
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21
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Wang Y, Fang L, Li J, Li Y, Cui S, Sun X, Chang S, Zhao P, Cui Z. Rescue of avian leukosis subgroup-J-associated acutely transforming viruses carrying different lengths of the v-fps oncogene and analysis of their tumorigenicity. Arch Virol 2016; 161:3473-3481. [PMID: 27654667 DOI: 10.1007/s00705-016-3035-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 08/26/2016] [Indexed: 01/14/2023]
Abstract
In our previous study, six subgroup J strains of avian leukosis virus (ALV-J)-associated acutely transforming viruses carrying different lengths of the v-fps oncogene, designated as Fu-J and Fu-J1-5, were isolated and characterized from fibrosarcomas in ALV-J-infected chickens. In the present study, the oncogenic potential of Fu-J and Fu-J1-5 was investigated using a reverse genetics technique. Six replication-defective viruses, named rFu-J and rFu-J1-5, were rescued with the replication-competent rescued ALV-J strain rSDAU1005 as a helper virus by co-transfection of chicken embryo fibroblast monolayers with infectious clone plasmids. Experimental bird studies were performed, demonstrating that only the rescued rFu-J virus carrying the complete v-fps oncogene with rSDAU1005 as the helper virus could induce acute fibrosarcoma after inoculation in specific-pathogen-free (SPF) chickens. These results provide direct evidence that the replication-defective acutely transforming Fu-J virus, with the complete v-fps oncogene, was associated with acute fibrosarcoma in chickens infected with ALV-J in the field, as reported previously.
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Affiliation(s)
- Yixin Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Lichun Fang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Jianliang Li
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Yang Li
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Shuai Cui
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Xiaolong Sun
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Shuang Chang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Peng Zhao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China
| | - Zhizhong Cui
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Daizong Road No. 61, Tai'an, Shandong, 271018, China.
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22
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Abstract
Extracellular vesicles (EVs) released by various cells are small phospholipid membrane-enclosed entities that can carry miRNA. They are now central to research in many fields of biology because they seem to constitute a new system of cell-cell communication. Physical and chemical characteristics of many EVs, as well as their biogenesis pathways, resemble those of retroviruses. Moreover, EVs generated by virus-infected cells can incorporate viral proteins and fragments of viral RNA, being thus indistinguishable from defective (noninfectious) retroviruses. EVs, depending on the proteins and genetic material incorporated in them, play a significant role in viral infection, both facilitating and suppressing it. Deciphering the mechanisms of EV-cell interactions may facilitate the design of EVs that inhibit viral infection and can be used as vehicles for targeted drug delivery.
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Robinson LA, Jaing CJ, Pierce Campbell C, Magliocco A, Xiong Y, Magliocco G, Thissen JB, Antonia S. Molecular evidence of viral DNA in non-small cell lung cancer and non-neoplastic lung. Br J Cancer 2016; 115:497-504. [PMID: 27415011 PMCID: PMC4985355 DOI: 10.1038/bjc.2016.213] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 06/16/2016] [Accepted: 06/20/2016] [Indexed: 01/02/2023] Open
Abstract
Background: Although ∼20% of human cancers are caused by microorganisms, only suspicion exists for a microbial cause of lung cancer. Potential infectious agents were investigated in non-small cell lung cancer (NSCLC) and non-neoplastic lung. Methods: Seventy NSCLC tumours (33 squamous cell carcinomas, 17 adenocarcinomas, 10 adenocarcinomas with lepidic spread, and 10 oligometastases) and 10 non-neoplastic lung specimens were evaluated for molecular evidence of microorganisms. Tissues were subjected to the Lawrence Livermore Microbial Detection Array, an oncovirus panel of the International Agency for Research on Cancer, and human papillomavirus (HPV) genotyping. Associations were examined between microbial prevalence, clinical characteristics, and p16 and EGFR expression. Results: Retroviral DNA was observed in 85% squamous cell carcinomas, 47% adenocarcinomas, and 10% adenocarcinomas with lepidic spread. Human papillomavirus DNA was found in 69% of squamous cell carcinomas with 30% containing high-risk HPV types. No significant viral DNA was detected in non-neoplastic lung. Patients with tumours containing viral DNA experienced improved long-term survival compared with patients with viral DNA-negative tumours. Conclusions: Most squamous cell carcinomas and adenocarcinomas contained retroviral DNA and one-third of squamous cell carcinomas contained high-risk HPV DNA. Viral DNA was absent in non-neoplastic lung. Trial results encourage further study of the viral contribution to lung carcinogenesis.
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Affiliation(s)
- Lary A Robinson
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida 33612-9416, USA.,Center for Infection Research in Cancer (CIRC), Moffitt Cancer Center, Tampa, Florida 33612-9416, USA
| | - Crystal J Jaing
- Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94559-9698, USA
| | - Christine Pierce Campbell
- Center for Infection Research in Cancer (CIRC), Moffitt Cancer Center, Tampa, Florida 33612-9416, USA.,Department of Epidemiology, Moffitt Cancer Center, Tampa, Florida 33612-9416, USA
| | - Anthony Magliocco
- Department of Pathology, Moffitt Cancer Center, Tampa, Florida 33612-9416, USA
| | - Yin Xiong
- Department of Pathology, Moffitt Cancer Center, Tampa, Florida 33612-9416, USA
| | - Genevra Magliocco
- Department of Pathology, Moffitt Cancer Center, Tampa, Florida 33612-9416, USA
| | - James B Thissen
- Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94559-9698, USA
| | - Scott Antonia
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida 33612-9416, USA
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Youssef G, Wallace WAH, Dagleish MP, Cousens C, Griffiths DJ. Ovine pulmonary adenocarcinoma: a large animal model for human lung cancer. ILAR J 2016; 56:99-115. [PMID: 25991702 DOI: 10.1093/ilar/ilv014] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Recent progress in understanding the molecular pathogenesis of this disease has resulted in novel therapeutic strategies targeting specific groups of patients. Further studies are required to provide additional advances in diagnosis and treatment. Animal models are valuable tools for studying oncogenesis in lung cancer, particularly during the early stages of disease where tissues are rarely available from human cases. Mice have traditionally been used for studying lung cancer in vivo, and a variety of spontaneous and transgenic models are available. However, it is recognized that other species may also be informative for studies of cancer. Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer of sheep caused by retrovirus infection and has several features in common with adenocarcinoma of humans, including a similar histological appearance and activation of common cell signaling pathways. Additionally, the size and organization of human lungs are much closer to those of sheep lungs than to those of mice, which facilitates experimental approaches in sheep that are not available in mice. Thus OPA presents opportunities for studying lung tumor development that can complement conventional murine models. Here we describe the potential applications of OPA as a model for human lung adenocarcinoma with an emphasis on the various in vivo and in vitro experimental systems available.
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Affiliation(s)
- Gehad Youssef
- Gehad Youssef, BSc, is a research scientist at the Moredun Research Institute, Edinburgh, UK. William A. H. Wallace, MBChB(Hons), PhD, FRCPE, FRCPath, is a consultant pathologist at the Royal Infirmary of Edinburgh and Honorary Reader in Pathology, Edinburgh University, UK; Mark P. Dagleish BVM&S, PhD, MRCVS, FRCPath, is Head of Pathology at the Moredun Research Institute, Edinburgh, UK. Chris Cousens, PhD, is a senior research scientist at the Moredun Research Institute, Edinburgh, UK, and David J. Griffiths, PhD, is a principal research scientist at the Moredun Research Institute, Edinburgh, UK
| | - William A H Wallace
- Gehad Youssef, BSc, is a research scientist at the Moredun Research Institute, Edinburgh, UK. William A. H. Wallace, MBChB(Hons), PhD, FRCPE, FRCPath, is a consultant pathologist at the Royal Infirmary of Edinburgh and Honorary Reader in Pathology, Edinburgh University, UK; Mark P. Dagleish BVM&S, PhD, MRCVS, FRCPath, is Head of Pathology at the Moredun Research Institute, Edinburgh, UK. Chris Cousens, PhD, is a senior research scientist at the Moredun Research Institute, Edinburgh, UK, and David J. Griffiths, PhD, is a principal research scientist at the Moredun Research Institute, Edinburgh, UK
| | - Mark P Dagleish
- Gehad Youssef, BSc, is a research scientist at the Moredun Research Institute, Edinburgh, UK. William A. H. Wallace, MBChB(Hons), PhD, FRCPE, FRCPath, is a consultant pathologist at the Royal Infirmary of Edinburgh and Honorary Reader in Pathology, Edinburgh University, UK; Mark P. Dagleish BVM&S, PhD, MRCVS, FRCPath, is Head of Pathology at the Moredun Research Institute, Edinburgh, UK. Chris Cousens, PhD, is a senior research scientist at the Moredun Research Institute, Edinburgh, UK, and David J. Griffiths, PhD, is a principal research scientist at the Moredun Research Institute, Edinburgh, UK
| | - Chris Cousens
- Gehad Youssef, BSc, is a research scientist at the Moredun Research Institute, Edinburgh, UK. William A. H. Wallace, MBChB(Hons), PhD, FRCPE, FRCPath, is a consultant pathologist at the Royal Infirmary of Edinburgh and Honorary Reader in Pathology, Edinburgh University, UK; Mark P. Dagleish BVM&S, PhD, MRCVS, FRCPath, is Head of Pathology at the Moredun Research Institute, Edinburgh, UK. Chris Cousens, PhD, is a senior research scientist at the Moredun Research Institute, Edinburgh, UK, and David J. Griffiths, PhD, is a principal research scientist at the Moredun Research Institute, Edinburgh, UK
| | - David J Griffiths
- Gehad Youssef, BSc, is a research scientist at the Moredun Research Institute, Edinburgh, UK. William A. H. Wallace, MBChB(Hons), PhD, FRCPE, FRCPath, is a consultant pathologist at the Royal Infirmary of Edinburgh and Honorary Reader in Pathology, Edinburgh University, UK; Mark P. Dagleish BVM&S, PhD, MRCVS, FRCPath, is Head of Pathology at the Moredun Research Institute, Edinburgh, UK. Chris Cousens, PhD, is a senior research scientist at the Moredun Research Institute, Edinburgh, UK, and David J. Griffiths, PhD, is a principal research scientist at the Moredun Research Institute, Edinburgh, UK
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25
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Wang Y, Li J, Li Y, Fang L, Sun X, Chang S, Zhao P, Cui Z. Identification of avian leukosis virus subgroup J-associated acutely transforming viruses carrying the v-src oncogene in layer chickens. J Gen Virol 2016; 97:1240-1248. [PMID: 26842006 DOI: 10.1099/jgv.0.000420] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
To elucidate the molecular basis for the rapid oncogenicity of an acutely transforming avian leukosis virus (ALV), isolated from fibrosarcomas in Hy-Line Brown commercial layer chickens infected with ALV subgroup J (ALV-J), the complete genomic structure of the provirus was determined. In addition to ALV-J replication-complete virus SDAU1102, five proviral DNA genomes, named SJ-1, SJ-2, SJ-3, SJ-4 and SJ-5, carrying different lengths of the v-src oncogene were amplified from original tumours and chicken embryo fibroblasts (CEFs) infected with viral stocks. The genomic sequences of the SJ-1-SJ-5 provirus were closely related to that of SDAU1102 but were defective. The results of Western blot analysis and immunohistochemical staining also showed overexpression of the p60v-src protein in infected CEFs and tumour tissue. To the best of our knowledge, this is the first report of the isolation and identification of acutely transforming viruses carrying the v-src oncogene with ALV-J as the helper virus. It also offers insight into the generation of acutely transforming ALVs carrying the v-src oncogene.
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Affiliation(s)
- Yixin Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
| | - Jianliang Li
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
| | - Yang Li
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
| | - Lichun Fang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
| | - Xiaolong Sun
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
| | - Shuang Chang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
| | - Peng Zhao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
| | - Zhizhong Cui
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University,Daizong Road No. 61, Tai'an, Shandong, 271018, PRChina
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Monot M, Archer F, Gomes M, Mornex JF, Leroux C. Advances in the study of transmissible respiratory tumours in small ruminants. Vet Microbiol 2015; 181:170-7. [PMID: 26340900 DOI: 10.1016/j.vetmic.2015.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Sheep and goats are widely infected by oncogenic retroviruses, namely Jaagsiekte Sheep RetroVirus (JSRV) and Enzootic Nasal Tumour Virus (ENTV). Under field conditions, these viruses induce transformation of differentiated epithelial cells in the lungs for Jaagsiekte Sheep RetroVirus or the nasal cavities for Enzootic Nasal Tumour Virus. As in other vertebrates, a family of endogenous retroviruses named endogenous Jaagsiekte Sheep RetroVirus (enJSRV) and closely related to exogenous Jaagsiekte Sheep RetroVirus is present in domestic and wild small ruminants. Interestingly, Jaagsiekte Sheep RetroVirus and Enzootic Nasal Tumour Virus are able to promote cell transformation, leading to cancer through their envelope glycoproteins. In vitro, it has been demonstrated that the envelope is able to deregulate some of the important signaling pathways that control cell proliferation. The role of the retroviral envelope in cell transformation has attracted considerable attention in the past years, but it appears to be highly dependent of the nature and origin of the cells used. Aside from its health impact in animals, it has been reported for many years that the Jaagsiekte Sheep RetroVirus-induced lung cancer is analogous to a rare, peculiar form of lung adenocarcinoma in humans, namely lepidic pulmonary adenocarcinoma. The implication of a retrovirus related to Jaagsiekte Sheep RetroVirus is still controversial and under investigation, but the identification of an infectious agent associated with the development of lepidic pulmonary adenocarcinomas might help us to understand cancer development. This review explores the mechanisms of induction of respiratory cancers in small ruminants and the possible link between retrovirus and lepidic pulmonary adenocarcinomas in humans.
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Affiliation(s)
- M Monot
- INRA UMR754-Université Lyon 1, Retrovirus and Comparative Pathology, France; Université de Lyon, France
| | - F Archer
- INRA UMR754-Université Lyon 1, Retrovirus and Comparative Pathology, France; Université de Lyon, France
| | - M Gomes
- INRA UMR754-Université Lyon 1, Retrovirus and Comparative Pathology, France; Université de Lyon, France
| | - J-F Mornex
- INRA UMR754-Université Lyon 1, Retrovirus and Comparative Pathology, France; Université de Lyon, France; Hospices Civils de Lyon, France
| | - C Leroux
- INRA UMR754-Université Lyon 1, Retrovirus and Comparative Pathology, France; Université de Lyon, France.
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Koonin EV, Dolja VV, Krupovic M. Origins and evolution of viruses of eukaryotes: The ultimate modularity. Virology 2015; 479-480:2-25. [PMID: 25771806 PMCID: PMC5898234 DOI: 10.1016/j.virol.2015.02.039] [Citation(s) in RCA: 342] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/19/2015] [Accepted: 02/20/2015] [Indexed: 01/04/2023]
Abstract
Viruses and other selfish genetic elements are dominant entities in the biosphere, with respect to both physical abundance and genetic diversity. Various selfish elements parasitize on all cellular life forms. The relative abundances of different classes of viruses are dramatically different between prokaryotes and eukaryotes. In prokaryotes, the great majority of viruses possess double-stranded (ds) DNA genomes, with a substantial minority of single-stranded (ss) DNA viruses and only limited presence of RNA viruses. In contrast, in eukaryotes, RNA viruses account for the majority of the virome diversity although ssDNA and dsDNA viruses are common as well. Phylogenomic analysis yields tangible clues for the origins of major classes of eukaryotic viruses and in particular their likely roots in prokaryotes. Specifically, the ancestral genome of positive-strand RNA viruses of eukaryotes might have been assembled de novo from genes derived from prokaryotic retroelements and bacteria although a primordial origin of this class of viruses cannot be ruled out. Different groups of double-stranded RNA viruses derive either from dsRNA bacteriophages or from positive-strand RNA viruses. The eukaryotic ssDNA viruses apparently evolved via a fusion of genes from prokaryotic rolling circle-replicating plasmids and positive-strand RNA viruses. Different families of eukaryotic dsDNA viruses appear to have originated from specific groups of bacteriophages on at least two independent occasions. Polintons, the largest known eukaryotic transposons, predicted to also form virus particles, most likely, were the evolutionary intermediates between bacterial tectiviruses and several groups of eukaryotic dsDNA viruses including the proposed order "Megavirales" that unites diverse families of large and giant viruses. Strikingly, evolution of all classes of eukaryotic viruses appears to have involved fusion between structural and replicative gene modules derived from different sources along with additional acquisitions of diverse genes.
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Affiliation(s)
- Eugene V Koonin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
| | - Valerian V Dolja
- Department of Botany and Plant Pathology, Oregon State University, Corvallis, OR 97331, USA.
| | - Mart Krupovic
- Institut Pasteur, Unité Biologie Moléculaire du Gène chez les Extrêmophiles, Department of Microbiology, Paris 75015, France.
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Viruses in cancer cell plasticity: the role of hepatitis C virus in hepatocellular carcinoma. Contemp Oncol (Pozn) 2015; 19:A62-7. [PMID: 25691824 PMCID: PMC4322526 DOI: 10.5114/wo.2014.47132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Viruses are considered as causative agents of a significant proportion of human cancers. While the very stringent criteria used for their classification probably lead to an underestimation, only six human viruses are currently classified as oncogenic. In this review we give a brief historical account of the discovery of oncogenic viruses and then analyse the mechanisms underlying the infectious causes of cancer. We discuss viral strategies that evolved to ensure virus propagation and spread can alter cellular homeostasis in a way that increases the probability of oncogenic transformation and acquisition of stem cell phenotype. We argue that a useful way of analysing the convergent characteristics of viral infection and cancer is to examine how viruses affect the so-called cancer hallmarks. This view of infectious origin of cancer is illustrated by examples from hepatitis C infection, which is associated with a high proportion of hepatocellular carcinoma.
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Entrican G, Wattegedera SR, Griffiths DJ. Exploiting ovine immunology to improve the relevance of biomedical models. Mol Immunol 2014; 66:68-77. [PMID: 25263932 PMCID: PMC4368439 DOI: 10.1016/j.molimm.2014.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/19/2014] [Accepted: 09/01/2014] [Indexed: 12/29/2022]
Abstract
Sheep make a valuable contribution to immunology research. Lessons to be learned from studying infections in the natural host. Factors to consider when selecting biomedical models. Animal models of human disease are important tools in many areas of biomedicine; for example, in infectious disease research and in the development of novel drugs and medical devices. Most studies involving animals use rodents, in particular congenic mice, due to the availability of a wide number of strains and the ease with which they can be genetically manipulated. The use of mouse models has led to major advances in many fields of research, in particular in immunology but despite these advances, no animal model can exactly reproduce all the features of human disease. It is increasingly becoming recognised that in many circumstances mice do not provide the best model and that alternative species may be more appropriate. Here, we describe the relative merits of sheep as biomedical models for human physiology and disease in comparison to mice, with a particular focus on reproductive and respiratory pathogens.
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Affiliation(s)
- Gary Entrican
- Moredun Research Institute, Pentlands Science Park, Bush Loan, Edinburgh EH26 0PZ, Scotland, UK.
| | - Sean R Wattegedera
- Moredun Research Institute, Pentlands Science Park, Bush Loan, Edinburgh EH26 0PZ, Scotland, UK
| | - David J Griffiths
- Moredun Research Institute, Pentlands Science Park, Bush Loan, Edinburgh EH26 0PZ, Scotland, UK
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Wegman-Points LJ, Teoh-Fitzgerald MLT, Mao G, Zhu Y, Fath MA, Spitz DR, Domann FE. Retroviral-infection increases tumorigenic potential of MDA-MB-231 breast carcinoma cells by expanding an aldehyde dehydrogenase (ALDH1) positive stem-cell like population. Redox Biol 2014; 2:847-54. [PMID: 25009786 PMCID: PMC4085353 DOI: 10.1016/j.redox.2014.06.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 06/01/2014] [Accepted: 06/05/2014] [Indexed: 01/08/2023] Open
Abstract
Retroviral transformation has been associated with pro-proliferative oncogenic signaling in human cells. The current study demonstrates that transduction of human breast carcinoma cells (MDA-MB231) with LXSN and QCXIP retroviral vectors causes significant increases in growth rate, clonogenic fraction, and aldehyde dehydrogenase-1 positive cells (ALDH1+), which is associated with increased steady-state levels of cancer stem cell populations. Furthermore, this retroviral-induced enhancement of cancer cell growth in vitro was also accompanied by a significant increase in xenograft tumor growth rate in vivo. The retroviral induced increases in cancer cell growth rate were partially inhibited by treatment with 100 U/ml polyethylene glycol-conjugated-(PEG)-superoxide dismutase and/or PEG-catalase. These results show that retroviral infection of MDA-MB231 human breast cancer cells is capable of enhancing cell proliferation and cancer stem cell populations as well as suggesting that modulation of reactive oxygen species-induced pro-survival signaling pathways may be involved in these effects.
Retroviral infection causes persistent ROS production in breast cancer cells. Retroviral infected cells display increased clonogenic fraction and tumorigenic potential. The ALDH1+ mammary cancer stem cell population is increased in infected cells. The above effects of retroviral infection can be inhibited with antioxidant enzymes.
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Affiliation(s)
- Lauren J Wegman-Points
- Department of Health and Human Physiology, University of Iowa, Iowa City, IA 52240, United States ; Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, United States
| | - Melissa L T Teoh-Fitzgerald
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States ; Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, United States
| | - Gaowei Mao
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, United States ; University of Pittsburg, United States
| | - Yueming Zhu
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, United States ; Northwestern University Medical School, United States
| | - Melissa A Fath
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, United States
| | - Douglas R Spitz
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, United States
| | - Frederick E Domann
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, United States
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Cardiac pathology and molecular epidemiology by avian leukosis viruses in Japan. PLoS One 2014; 9:e86546. [PMID: 24466146 PMCID: PMC3900567 DOI: 10.1371/journal.pone.0086546] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 12/11/2013] [Indexed: 12/19/2022] Open
Abstract
Epidemiological studies suggest that retroviruses, including human immunodeficiency virus type 1, are associated with cardiomyopathy and myocarditis, but a causal relationship remains to be established. We encountered unusual cardiomyocyte hypertrophy and mitosis in Japanese native fowls infected with subgroup A of the avian leukosis viruses (ALVs-A), which belong to the genus Alpharetrovirus of the family Retroviridae and mainly induce lymphoid neoplasm in chickens. The affected hearts were evaluated by histopathology and immunohistochemistry, viral isolation, viral genome sequencing and experimental infection. There was non-suppurative myocarditis in eighteen fowls and seven of them had abnormal cardiomyocytes, which were distributed predominantly in the left ventricular wall and showed hypertrophic cytoplasm and atypical large nuclei. Nuclear chains and mitosis were frequently noted in these cardiomyocytes and immunohistochemistry for proliferating cell nuclear antigen supported the enhancement of mitotic activity. ALVs were isolated from all affected cases and phylogenic analysis of envSU genes showed that the isolates were mainly classified into two different clusters, suggesting viral genome diversity. In ovo experimental infection with two of the isolates was demonstrated to cause myocarditis and cardiomyocyte hypertrophy similar to those in the naturally occurring lesions and cardiac hamartoma (rhabdomyoma) in a shorter period of time (at 70 days of age) than expected. These results indicate that ALVs cause myocarditis as well as cardiomyocyte abnormality in chickens, implying a pathogenetic mechanism different from insertional mutagenesis and the existence of retrovirus-induced heart disorder.
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Pathological and evolutionary implications of retroviruses as mobile genetic elements. Genes (Basel) 2013; 4:573-82. [PMID: 24705263 PMCID: PMC3927575 DOI: 10.3390/genes4040573] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 09/27/2013] [Accepted: 10/08/2013] [Indexed: 11/17/2022] Open
Abstract
Retroviruses, a form of mobile genetic elements, have important roles in disease and primate evolution. Exogenous retroviruses, such as human immunodeficiency virus (HIV), have significant pathological implications that have created a massive public health challenge in recent years. Endogenous retroviruses (ERVs), which are the primary focus of this review, can also be pathogenic, as well as being beneficial to a host in some cases. Furthermore, retroviruses may have played a key role in primate evolution that resulted in the incorporation of these elements into the human genome. Retroviruses are mobile genetic elements that have important roles in disease and primate evolution. We will further discuss the pathogenic potential of retroviruses, including their role in cancer biology, and will briefly summarize their evolutionary implications.
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Coelho AVC, Brandão LAC, Guimarães RL, Loureiro P, de Lima Filho JL, de Alencar LCA, Crovella S, Segat L. Mannose binding lectin and mannose binding lectin-associated serine protease-2 genes polymorphisms in human T-lymphotropic virus infection. J Med Virol 2013; 85:1829-35. [PMID: 23861212 DOI: 10.1002/jmv.23656] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2013] [Indexed: 01/10/2023]
Abstract
Variations in genes involved in the immune response pathways may influence the interaction between viruses (such as Human T-lymphotropic virus, HTLV-1) and the host. The mannose binding lectin (MBL) and its associated serine protease type 2 (MASP-2) promote the activation of the lectin pathway of the complement system. As the interaction of complement system with HTLV-1 is not well understood, the MBL2 promoter/exon 1 polymorphisms and a MASP2 missense polymorphism were examined in a Northeast Brazilian population, looking for a possible relationship between these variations and the susceptibility to HTLV-1 infection. The present study describes an association between a polymorphism in the MASP2 gene and susceptibility to HTLV-1 infection, and provides further evidence of an association between the MBL2 gene and HTLV-1 infection. These findings suggest an important role of the complement system activation, via the lectin pathway, in the susceptibility to HTLV-1 infection.
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Murgai M, Thomas J, Cherepanova O, Delviks-Frankenberry K, Deeble P, Pathak VK, Rekosh D, Owens G. Xenotropic MLV envelope proteins induce tumor cells to secrete factors that promote the formation of immature blood vessels. Retrovirology 2013; 10:34. [PMID: 23537062 PMCID: PMC3681559 DOI: 10.1186/1742-4690-10-34] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 03/07/2013] [Indexed: 12/20/2022] Open
Abstract
Background Xenotropic Murine leukemia virus-Related Virus (XMRV) is a γ-retrovirus initially reported to be present within familial human prostate tumors and the blood of patients with chronic fatigue syndrome. Subsequent studies however were unable to replicate these findings, and there is now compelling evidence that the virus evolved through rare retroviral recombination events in human tumor cell lines established through murine xenograft experiments. There is also no direct evidence that XMRV infection has any functional effects that contribute to tumor pathogenesis. Results Herein we describe an additional xenotropic MLV, “B4rv”, found in a cell line derived from xenograft experiments with the human prostate cancer LNCaP cell line. When injected subcutaneously in nude mice, LNCaP cells infected with XMRV or B4rv formed larger tumors that were highly hemorrhagic and displayed poor pericyte/smooth muscle cell (SMC) investment, markers of increased metastatic potential. Conditioned media derived from XMRV- or B4rv-infected LNCaPs, but not an amphotropic MLV control virus infected LNCaPs, profoundly decreased expression of marker genes in cultured SMC, consistent with inhibition of SMC differentiation/maturation. Similar effects were seen with a chimeric virus of the amphotropic MLV control virus containing the XMRV env gene, but not with an XMRV chimeric virus containing the amphotropic MLV env gene. UV-inactivated XMRV and pseudovirions that were pseudotyped with XMRV envelope protein also produce conditioned media that down-regulated SMC marker gene expression in vitro. Conclusions Together these results indicate that xenotropic MLV envelope proteins are sufficient to induce the production of factors by tumor cells that suppress vascular SMC differentiation, providing evidence for a novel mechanism by which xenotropic MLVs might alter tumor pathogenesis by disrupting tumor vascular maturation. Although it is highly unlikely that either XMRV or B4Rv themselves infect humans and are pathogenic, the results suggest that xenograft approaches commonly used in the study of human cancer promote the evolution of novel retroviruses with pathogenic properties.
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Affiliation(s)
- Meera Murgai
- Robert M, Berne Cardiovascular Research Center, University of Virginia, School of Medicine Charlottesville, Charlottesville, VA 22908, USA
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Magden E, Miller C, MacMillan M, Bielefeldt-Ohmann H, Avery A, Quackenbush SL, Vandewoude S. Acute virulent infection with feline immunodeficiency virus (FIV) results in lymphomagenesis via an indirect mechanism. Virology 2013; 436:284-94. [PMID: 23290868 DOI: 10.1016/j.virol.2012.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Revised: 10/30/2012] [Accepted: 12/04/2012] [Indexed: 10/27/2022]
Abstract
Four cats (24%) experimentally infected with FIV unexpectedly developed neoplastic changes within four months of inoculation. While FIV has previously been associated with neoplasia, the rapidity and high attack rate seen here is highly unusual. PCR for antigen receptor rearrangements (PARR) detected clonally rearranged T cells in two animals diagnosed with B cell follicular lymphoma by classical means. All cats were negative for feline leukemia virus; gamma-herpesvirus DNA was not amplified using degenerate primers. FIV proviral load in neoplastic tissue was two orders of magnitude lower than in the periphery, lower in neoplastic vs non-neoplastic lymph node, and clonal integration was not detected. We hypothesize that neoplasia was secondary to FIV immune dysregulation, and show that PARR can augment our capacity to phenotype these tumors and distinguish follicular hyperplasia from lymphoma. Age of exposure and relative virulence of the inoculum likely contributed to this unusual presentation of FIV infection.
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Mullins CS, Linnebacher M. Human endogenous retroviruses and cancer: causality and therapeutic possibilities. World J Gastroenterol 2012; 18:6027-6035. [PMID: 23155332 PMCID: PMC3496880 DOI: 10.3748/wjg.v18.i42.6027] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Revised: 09/10/2012] [Accepted: 09/19/2012] [Indexed: 02/06/2023] Open
Abstract
A substantial part of the human genome is derived from transposable elements; remnants of ancient retroviral infections. Conservative estimates set the percentage of human endogenous retroviruses (HERVs) in the genome at 8%. For the most part, the interplay between mutations, epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic cells. We first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and therapy. It has been shown that at least in some cases, tumor cells expressing HERV open reading frames (ORFs) thus gain tumor-promoting functions. However, since these proteins are not expressed in healthy tissues, they become prime target structures. Of potential pharmacological interest are the prevention of HERV transposition, the inhibition of HERV-encoded protein expression and the interference with these proteins' activities. Evidence from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity boundaries. The development of new tumor (immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side effects. Finally, we postulate on main future research streams in order to stimulate discussion on this hot topic.
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Hull S, Lim J, Hamil A, Nitta T, Fan H. Analysis of jaagsiekte sheep retrovirus (JSRV) envelope protein domains in transformation. Virus Genes 2012; 45:508-17. [PMID: 22864547 DOI: 10.1007/s11262-012-0793-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Accepted: 07/18/2012] [Indexed: 12/01/2022]
Abstract
Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a transmissible lung cancer in sheep. A unique feature is that JSRV envelope protein is also the oncogene for this virus. Previous studies have identified the cytoplasmic tail (CT) of the envelope transmembrane (TM) protein as critical for transformation although other regions of Env have also been implicated. In this study, the roles of other Env regions in transformation were investigated. Chimeras between JSRV Env and the Env of a related non-oncogenic endogenous retrovirus (enJSRV, 5F16) were used. A chimera containing the membrane-spanning region (MSR) of enJSRV inserted into JSRV Env showed substantially reduced transformation, indicating that the MSR plays a role in transformation. Transformation by this chimera was highly dependent on both Ras/Raf/MEK/MAPK and PI3K/Akt/mTOR signaling. A chimera containing the two amino acids in the TM ectodomain that distinguish JSRV and enJSRV showed modestly reduced transformation. Chimeras in the SU protein indicated that the amino terminal region of SU contributes to transformation, while the C-terminal part is not important. To test if Env trimerization is important for transformation, we mutated a leucine-rich sequence in the putative trimerization domain in the ectodomain of TM (Tri-M). This mutant could not transform cells and it did not oligomerize. However, Tri-M could complement a non-transforming mutant CT mutant (Y590F) so oligomerization is not necessary for at least some aspects of transformation. These experiments provide new insight into the regions and residues of JSRV Env protein necessary for oncogenic transformation.
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Affiliation(s)
- Stacey Hull
- Cancer Research Institute, Sprague Hall, University of California-Irvine, CA 92697-3900, USA
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Three murine leukemia virus integration regions within 100 kilobases upstream of c-myb are proximal to the 5' regulatory region of the gene through DNA looping. J Virol 2012; 86:10524-32. [PMID: 22811527 DOI: 10.1128/jvi.01077-12] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Retroviruses integrated into genomic DNA participate in long-range gene activation from as far away as several hundred kilobases. Hypotheses have been put forth to account for these phenomena, but data have not been provided to support a physical mechanism that explains long-range activation. In murine leukemia virus-induced myeloid leukemia in mice, integrated proviruses have been found upstream of c-myb in three regions, named Mml1, Mml2, and Mml3 (25, 50, and 70 kb upstream, respectively). The transcription factor c-Myb is an oncogene whose dysregulation and/or mutation can lead to human leukemia. We hypothesized that the murine c-myb upstream region contains regulatory elements accessed by the retrovirus. To identify regulatory sites in the murine c-myb upstream region, we looked by chromatin immunoprecipitation with microarray technology (ChIP-on-chip) for histone modifications implicating gene activation in normal cells. H3K4me3, H3K4me1, and H3K9/14ac were enriched at Mml1 and/or Mml2 in the myeloblastic cell line M1, which expresses c-myb. The enrichment of all of these histone marks decreased with differentiation-induced downregulation of the gene in M1 cells but increased and spread in tumor cells containing integrated provirus. Importantly, using chromosome conformation capture (3C)-quantitative PCR assays, interactions between the 5' region, including the promoter and all Mml sites (Mml1, Mml2, and Mml3), were detected due to DNA looping in M1 cells and tumor cells with provirus in Mml1, Mml2, or Mml3. Therefore, our study provides a new mechanism of retrovirus insertional mutagenesis whereby spatial chromatin organization allows distally located provirus, with its own enhancer elements, to access the 5' regulatory region of the gene.
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Emerging viruses in the Felidae: shifting paradigms. Viruses 2012; 4:236-57. [PMID: 22470834 PMCID: PMC3315214 DOI: 10.3390/v4020236] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Revised: 12/21/2011] [Accepted: 01/11/2012] [Indexed: 12/20/2022] Open
Abstract
The domestic cat is afflicted with multiple viruses that serve as powerful models for human disease including cancers, SARS and HIV/AIDS. Cat viruses that cause these diseases have been studied for decades revealing detailed insight concerning transmission, virulence, origins and pathogenesis. Here we review recent genetic advances that have questioned traditional wisdom regarding the origins of virulent Feline infectious peritonitis (FIP) diseases, the pathogenic potential of Feline Immunodeficiency Virus (FIV) in wild non-domestic Felidae species, and the restriction of Feline Leukemia Virus (FeLV) mediated immune impairment to domestic cats rather than other Felidae species. The most recent interpretations indicate important new evolutionary conclusions implicating these deadly infectious agents in domestic and non-domestic felids.
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40
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Restrepo CS, Chen MM, Martinez-Jimenez S, Carrillo J, Restrepo C. Chest neoplasms with infectious etiologies. World J Radiol 2011; 3:279-88. [PMID: 22224176 PMCID: PMC3251813 DOI: 10.4329/wjr.v3.i12.279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 09/19/2011] [Accepted: 10/11/2011] [Indexed: 02/06/2023] Open
Abstract
A wide spectrum of thoracic tumors have known or suspected viral etiologies. Oncogenic viruses can be classified by the type of genomic material they contain. Neoplastic conditions found to have viral etiologies include post-transplant lymphoproliferative disease, lymphoid granulomatosis, Kaposi’s sarcoma, Castleman’s disease, recurrent respiratory papillomatosis, lung cancer, malignant mesothelioma, leukemia and lymphomas. Viruses involved in these conditions include Epstein-Barr virus, human herpes virus 8, human papillomavirus, Simian virus 40, human immunodeficiency virus, and Human T-lymphotropic virus. Imaging findings, epidemiology and mechanism of transmission for these diseases are reviewed in detail to gain a more thorough appreciation of disease pathophysiology for the chest radiologist.
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Lack of Detection of Xenotropic Murine Leukemia Virus-Related Virus in HIV-1 Lymphoma Patients. Adv Virol 2011; 2011:797820. [PMID: 22312354 PMCID: PMC3265315 DOI: 10.1155/2011/797820] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Accepted: 07/11/2011] [Indexed: 12/03/2022] Open
Abstract
Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus reported to be associated with human prostate cancer and chronic fatigue syndrome. Since retroviruses cause various cancers, and XMRV replication might be facilitated by HIV-1 co-infection, we asked whether certain patients with HIV-associated lymphomas are infected with XMRV. Analysis of PMBCs and plasma from 26 patients failed to detect XMRV by PCR, ELISA, or Western blot, suggesting a lack of association between XMRV and AIDS-associated lymphomas.
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Maeda N, Inoshima Y, Oouchi S, Uede T. Surveillance of Jaagsiekte sheep retrovirus in sheep in Hokkaido, the northern island of Japan. J Vet Med Sci 2011; 73:1493-5. [PMID: 21712639 DOI: 10.1292/jvms.11-0133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Surveillance of jaagsiekte sheep retrovirus (JSRV) infection was performed by polymerase chain reaction (PCR) of blood DNA samples collected from 40 sheep and goats in 10 different flocks in Hokkaido, the northern island of Japan. No exogenous (oncogenic) JSRV sequence was detected by PCR in these samples, while the ovine endogenous retrovirus sequence was successfully amplified in all samples. Our paper is the first demonstration of JSRV surveillance in Japan and shows no evidence of oncogenic JSRV infection in sheep and goats in Hokkaido.
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Affiliation(s)
- Naoyoshi Maeda
- Division of Molecular Immunology, Institute for Genetic Medicine, HokkaidoUniversity, Kita-15, Nishi-7, Kita-ku, Sapporo 060–0815, Japan
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Magden E, Quackenbush SL, VandeWoude S. FIV associated neoplasms--a mini-review. Vet Immunol Immunopathol 2011; 143:227-34. [PMID: 21722968 DOI: 10.1016/j.vetimm.2011.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Retroviral induced neoplasms have been key to understanding oncogenesis and are important etiologic agents associated with cancer formation. Cats infected with feline immunodeficiency virus (FIV), the feline analogue to human immunodeficiency virus (HIV), are reported to be at increased incidence of neoplasia. This review highlights reported risk factors and tumor cell phenotypes associated with neoplasias arising in FIV-infected animals, differences in oncogenic disease in natural versus experimental FIV infections, and similarities between FIV- and HIV-related malignancies. The most common type of FIV-associated neoplasm reported in the literature is lymphoma, specifically of B-cell origin, with experimentally infected cats developing neoplastic lesions at an earlier age than their naturally infected cohorts. The mechanism of FIV-induced lymphoma has not been completely ascertained, though the majority of published studies addressing this issue suggest oncogenesis arises via indirect mechanisms. HIV-infected individuals have increased risk of neoplasia, specifically B cell lymphoma, in comparison with uninfected individuals. Additional similarities between FIV- and HIV-associated neoplasms include the presence of extranodal lymphoma, a synergism with other oncogenic viruses, and an apparent indirect mechanism of induced oncogenesis. This literature supports study of FIV-associated neoplasms to further characterize this lentiviral-neoplasia association for the benefit of both human and animal disease, and to advance our general knowledge of mechanisms for viral-induced oncogenesis.
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Affiliation(s)
- Elizabeth Magden
- Colorado State University, Department of Microbiology, Immunology, and Pathology, 1619 Campus Delivery, Fort Collins, CO 80523, USA
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44
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Rhea JM, Diwan CA, Molinaro RJ. Mass spectrometry-coupled techniques for viral-related disease biomarker identification. Biomark Med 2011; 4:859-70. [PMID: 21133707 DOI: 10.2217/bmm.10.110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The advent of high-resolution mass spectrometers coupled with proteomic techniques has facilitated the discovery and characterization of novel viral proteins and the detection of virus-induced changes in the cellular proteome. These advances have enabled a more comprehensive characterization of viral interactions involved in infection and pathogenesis, and allowed the discovery of viral biomarkers. This article focuses on the role of mass spectrometry proteomic techniques to identify and characterize both prospective and verified viral biomarkers, and their implications on the diagnosis of disease.
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Affiliation(s)
- Jeanne M Rhea
- Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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45
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Sudol M. From Rous sarcoma virus to plasminogen activator, src oncogene and cancer management. Oncogene 2011; 30:3003-10. [PMID: 21383693 DOI: 10.1038/onc.2011.38] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Plasminogen activator (PLAU) is a serine protease that converts plasminogen to plasmin, a general protease, which promotes fibrinolysis and degradation of extracellular matrix. PLAU was reported in 1970s as one of the robustly induced enzymatic activities in Rous sarcoma virus (RSV)-transformed chicken cells. More than three decades later, with the completion of the sequencing of the chicken genome and the subsequent availability of Affymetrix GeneChip genome arrays, several laboratories have surveyed the transcriptional program affected by the RSV transformation. Interestingly, the PLAU gene was shown to be the most highly upregulated transcript. The induction of PLAU was a transformation-dependent process because viruses with deleted Src gene did not induce the transcription of the PLAU gene. Both Src and PLAU genes are associated with and contribute to the complex phenotype of human cancer. Although the activity and structures of these two enzymes are well characterized, the precise molecular function of these gene products in signaling networks is still not fully understood. Yet, the knowledge of their association with cancer is already translated into the clinical setting. Src kinase inhibitors are being tested in clinical trials of cancer therapy, and PLAU gene and its inhibitor have been included as biomarkers with strong prognostic and therapeutic predictive values. This vignette reviews the history of PLAU and Src discovery, and illuminates the complexity of their relationship, but also points to their emerging impact on public health.
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Affiliation(s)
- M Sudol
- Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger Clinic, Danville, PA 17822-2608, USA.
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Menéndez-Arias L. Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome. Rev Med Virol 2010; 21:3-17. [PMID: 21294212 DOI: 10.1002/rmv.673] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Revised: 10/13/2010] [Accepted: 10/13/2010] [Indexed: 12/11/2022]
Abstract
The recent discovery of xenotropic murine leukaemia virus-related virus (XMRV) in prostate cancer tissues and in the blood of individuals suffering from chronic fatigue syndrome has attracted considerable interest. However, the relevance and significance of XMRV to human disease remain unclear, since the association has not been confirmed in other studies. XMRV is the first gammaretrovirus to be found in humans. XMRV and murine leukaemia viruses share similar structures and genomic organisation. Human restriction factors such as APOBEC3 or tetherin inhibit XMRV replication. Although XMRV induces low rates of transformation in cell culture, it might be able to induce cancer by low-frequency insertional activation of oncogenes or through the generation of highly active transforming viruses. A preference for regulatory regions of transcriptional active genes has been observed after a genomic-wide analysis of XMRV integration sites. Genes related to carcinogenesis and androgen signalling have been identified in the vicinity of integration sites. The XMRV genome contains a glucocorticoid responsive element, and androgens could modulate viral replication in the prostate. Evidence supporting the involvement of XMRV in chronic fatigue syndrome is still very weak, and needs further confirmation and validation. Currently approved anti-retroviral drugs such as zidovudine, tenofovir and raltegravir are efficient inhibitors of XMRV replication in vitro. These drugs might be useful to treat XMRV infection in humans. The identification of XMRV has potentially serious health implications for the implementation of novel techniques including gene therapy or xenotransplantation, while raising concerns on the need for screening donated blood to prevent transmission through transfusion.
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Affiliation(s)
- Luis Menéndez-Arias
- Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.
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Abstract
Phosphorylation represents one the most abundant and important posttranslational modifications of proteins, including viral proteins. Virus-encoded serine/threonine protein kinases appear to be a feature that is unique to large DNA viruses. Although the importance of these kinases for virus replication in cell culture is variable, they invariably play important roles in virus virulence. The current review provides an overview of the different viral serine/threonine protein kinases of several large DNA viruses and discusses their function, importance, and potential as antiviral drug targets.
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48
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Chitra E, Lin YW, Davamani F, Hsiao KN, Sia C, Hsieh SY, Wei OL, Chen JH, Chow YH. Functional interaction between Env oncogene from Jaagsiekte sheep retrovirus and tumor suppressor Sprouty2. Retrovirology 2010; 7:62. [PMID: 20678191 PMCID: PMC2922082 DOI: 10.1186/1742-4690-7-62] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 08/02/2010] [Indexed: 11/10/2022] Open
Abstract
Background Jaagsiekte sheep retrovirus (JSRV) is a type D retrovirus capable of transforming target cells in vitro and in vivo. The Envelope (Env) gene from JSRV and from related retroviruses can induce oncogenic transformation, although the detailed mechanism is yet to be clearly understood. Host cell factors are envisaged to play a critical determining role in the regulation of Env-mediated cell transformation. Results JSRV Env-mediated transformation of a lung adenocarcinoma cell line induced rapid proliferation, anchorage-independent growth and tumor formation, but completely abrogated the migration ability. An analysis of the signaling scenario in the transformed cells suggested the involvement of the ERK pathway regulated by Sprouty2 in cell migration, and the PI3K-Akt and STAT3 pathways in proliferation and anchorage-independence. On the other hand, in a normal lung epithelial cell line, Env-mediated transformation only decreased the migration potential while the other functions remained unaltered. We observed that Env induced the expression of a tumor suppressor, Sprouty2, suggesting a correlation between Env-effect and Sprouty2 expression. Overexpression of Sprouty2 per se not only decreased the migratory potential and tumor formation potential of the target cells but also made them resistant to subsequent Env-mediated transformation. On the other hand, over expression of the functional mutants of Sprouty2 had no inhibitory effect, confirming the role of Sprouty2 as a tumor suppressor. Conclusions Our studies demonstrate that Env and Sprouty2 have a functional relationship, probably through shared signaling network. Sprouty2 functions as a tumor suppressor regulating oncogenic transformation of cells, and it therefore has the potential to be exploited as a therapeutic anti-cancer agent.
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Affiliation(s)
- Ebenezer Chitra
- Vaccine R&D Center, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 350, Taiwan
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Griffiths D, Martineau H, Cousens C. Pathology and Pathogenesis of Ovine Pulmonary Adenocarcinoma. J Comp Pathol 2010; 142:260-83. [DOI: 10.1016/j.jcpa.2009.12.013] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Revised: 11/28/2009] [Accepted: 12/29/2009] [Indexed: 11/30/2022]
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50
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Mougel M, Cimarelli A, Darlix JL. Implications of the nucleocapsid and the microenvironment in retroviral reverse transcription. Viruses 2010; 2:939-960. [PMID: 21994662 PMCID: PMC3185662 DOI: 10.3390/v2040939] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2010] [Revised: 03/03/2010] [Accepted: 04/01/2010] [Indexed: 01/21/2023] Open
Abstract
This mini-review summarizes the process of reverse-transcription, an obligatory step in retrovirus replication during which the retroviral RNA/DNA-dependent DNA polymerase (RT) copies the single-stranded genomic RNA to generate the double-stranded viral DNA while degrading the genomic RNA via its associated RNase H activity. The hybridization of complementary viral sequences by the nucleocapsid protein (NC) receives a special focus, since it acts to chaperone the strand transfers obligatory for synthesis of the complete viral DNA and flanking long terminal repeats (LTR). Since the physiological microenvironment can impact on reverse-transcription, this mini-review also focuses on factors present in the intra-cellular or extra-cellular milieu that can drastically influence both the timing and the activity of reverse-transcription and hence virus infectivity.
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Affiliation(s)
- Marylène Mougel
- CPBS, UMR5236 CNRS, UMI, 4 bd Henri IV, 34965 Montpellier, France; E-Mail:
| | - Andrea Cimarelli
- LaboRetro Unité de Virologie humaine INSERM #758, IFR128, ENS Lyon, 46 Allée d’Italie, 69364 Lyon, France; E-Mail:
| | - Jean-Luc Darlix
- LaboRetro Unité de Virologie humaine INSERM #758, IFR128, ENS Lyon, 46 Allée d’Italie, 69364 Lyon, France; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +33 472728169; Fax: +33 472728137
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