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Ding YD, Shu LZ, He RS, Chen KY, Deng YJ, Zhou ZB, Xiong Y, Deng H. Listeria monocytogenes: a promising vector for tumor immunotherapy. Front Immunol 2023; 14:1278011. [PMID: 37868979 PMCID: PMC10587691 DOI: 10.3389/fimmu.2023.1278011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 09/25/2023] [Indexed: 10/24/2023] Open
Abstract
Cancer receives enduring international attention due to its extremely high morbidity and mortality. Immunotherapy, which is generally expected to overcome the limits of traditional treatments, serves as a promising direction for patients with recurrent or metastatic malignancies. Bacteria-based vectors such as Listeria monocytogenes take advantage of their unique characteristics, including preferential infection of host antigen presenting cells, intracellular growth within immune cells, and intercellular dissemination, to further improve the efficacy and minimize off-target effects of tailed immune treatments. Listeria monocytogenes can reshape the tumor microenvironment to bolster the anti-tumor effects both through the enhancement of T cells activity and a decrease in the frequency and population of immunosuppressive cells. Modified Listeria monocytogenes has been employed as a tool to elicit immune responses against different tumor cells. Currently, Listeria monocytogenes vaccine alone is insufficient to treat all patients effectively, which can be addressed if combined with other treatments, such as immune checkpoint inhibitors, reactivated adoptive cell therapy, and radiotherapy. This review summarizes the recent advances in the molecular mechanisms underlying the involvement of Listeria monocytogenes vaccine in anti-tumor immunity, and discusses the most concerned issues for future research.
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Affiliation(s)
- Yi-Dan Ding
- Medical College, Nanchang University, Nanchang, China
| | - Lin-Zhen Shu
- Medical College, Nanchang University, Nanchang, China
| | - Rui-Shan He
- Medical College, Nanchang University, Nanchang, China
| | - Kai-Yun Chen
- Office of Clinical Trials Administration, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yan-Juan Deng
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
- Tumor Immunology Institute, Nanchang University, Nanchang, China
| | - Zhi-Bin Zhou
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
- Tumor Immunology Institute, Nanchang University, Nanchang, China
| | - Ying Xiong
- Department of General Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Huan Deng
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
- Tumor Immunology Institute, Nanchang University, Nanchang, China
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Liu Y, Zheng P, Jiao T, Zhang M, Wu Y, Zhang X, Wang S, Zhao Z. Paiteling induces apoptosis of cervical cancer cells by down-regulation of the E6/E7-Pi3k/Akt pathway: A network pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2023; 305:116062. [PMID: 36535331 DOI: 10.1016/j.jep.2022.116062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/29/2022] [Accepted: 12/14/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Human papillomavirus (HPV) infection is considered to be the main pathogen causing intraepithelial neoplasia. Paiteling (PTL) has been used to treat intraepithelial neoplasia caused by human papillomavirus (HPV) infection for more than 20 years in China, but its specific mechanism of action is not very clear, and further research is still needed. OBJECTIVE This study designed a comprehensive strategy to study the pharmacological mechanism of paiteling in regulating cervical cancer cell apoptosis by integrating LC-MS/MS, network pharmacology and pharmacological experiments. METHODS We used liquid chromatography-tandem mass spectrometry to detect the active substances in PTL and performed protein-protein interaction analysis on the intersection of the targets of these key compounds and the targets of intraepithelial neoplasia. Additionally, by using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG), the potential pathway of PTL against HPV-induced intraepithelial neoplasia was predicted. Finally, we used HeLa and Ect1/E6E7 cells for experimental verification. RESULTS The protein-protein interaction network predicted that AKT1, TP53, MYC, STAT3, MTOR, and MAPK were pivotal targets for PTL to inhibit epithelial neoplasia. KEGG enrichment analysis showed that the Pi3k/Akt pathway and HPV infection had scientific significance. Compared to the control group, after PTL diluent stimulated HeLa and Ect1/E6E7 cells for 24 h, cell viability, migration, and invasion capabilities were significantly reduced, and cell apoptosis was significantly increased, conforming to a dose-effect relationship and time-effect relationship. PCR, cellular immunohistochemistry, and western blot experiments showed that PTL reduced the expression of E6, Pi3k, E7, Akt, Bcl-xl, while increasing the expression of Bad in HeLa and Ect1/E6E7 cells. CONCLUSION PTL can induce cervical cancer cell apoptosis by inhibiting the E6/E7-Pi3k/Akt signaling pathway. It may provide an effective alternative strategy of traditional Chinese medicine for the treatment of epithelial neoplasia caused by HPV infection.
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Affiliation(s)
- Yunhua Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Pengfei Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Tingting Jiao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Mengmeng Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yingjie Wu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xinjiang Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shuyue Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zongjiang Zhao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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3
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Gameiro SF, Evans AM, Mymryk JS. The tumor immune microenvironments of HPV + and HPV - head and neck cancers. WIREs Mech Dis 2022; 14:e1539. [PMID: 35030304 DOI: 10.1002/wsbm.1539] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/24/2022]
Abstract
Human papillomaviruses (HPVs) are the etiological agent of a significant, and increasing, fraction of head and neck squamous cell carcinomas (HNSCC)-a heterogenous group of malignancies in the head and neck region. HPV infection accounts for approximately 25% of all cases, with the remainder typically caused by smoking and excessive alcohol consumption. These distinct etiologies lead to profound clinical and immunological differences between HPV-positive (HPV+ ) and HPV-negative (HPV- ) HNSCC, likely related to the expression of exogenous viral antigens in the HPV+ subtype. Specifically, HPV+ HNSCC patients generally exhibit better treatment response compared to those with HPV- disease, leading to a more favorable prognosis, with lower recurrence rate, and longer overall survival time. Importantly, a plethora of studies have illustrated that the tumor immune microenvironment (TIME) of HPV+ HNSCC has a strikingly distinct immune composition to that of its HPV- counterpart. The HPV+ TIME is characterized as being immunologically "hot," with more immune infiltration, higher levels of T-cell activation, and higher levels of immunoregulation compared to the more immunologically "cold" HPV- TIME. In general, cancers with an immune "hot" TIME exhibit better treatment response and superior clinical outcomes in comparison to their immune "cold" counterparts. Indeed, this phenomenon has also been observed in HPV+ HNSCC patients, highlighting the critical role of the TIME in influencing prognosis, and further validating the use of cancer therapies that capitalize on the mobilization and/or modulation of the TIME. This article is categorized under: Cancer > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Steven F Gameiro
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Andris M Evans
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.,Department of Otolaryngology, The University of Western Ontario, London, Ontario, Canada.,Department of Oncology, The University of Western Ontario, London, Ontario, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada
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4
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Chen Z, Utro F, Platt D, DeSalle R, Parida L, Chan PKS, Burk RD. K-Mer Analyses Reveal Different Evolutionary Histories of Alpha, Beta, and Gamma Papillomaviruses. Int J Mol Sci 2021; 22:9657. [PMID: 34502564 PMCID: PMC8432194 DOI: 10.3390/ijms22179657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/04/2021] [Accepted: 09/05/2021] [Indexed: 12/31/2022] Open
Abstract
Papillomaviruses (PVs) are a heterogeneous group of DNA viruses that can infect fish, birds, reptiles, and mammals. PVs infecting humans (HPVs) phylogenetically cluster into five genera (Alpha-, Beta-, Gamma-, Mu- and Nu-PV), with differences in tissue tropism and carcinogenicity. The evolutionary features associated with the divergence of Papillomaviridae are not well understood. Using a combination of k-mer distributions, genetic metrics, and phylogenetic algorithms, we sought to evaluate the characteristics and differences of Alpha-, Beta- and Gamma-PVs constituting the majority of HPV genomes. A total of 640 PVs including 442 HPV types, 27 non-human primate PV types, and 171 non-primate animal PV types were evaluated. Our analyses revealed the highest genetic diversity amongst Gamma-PVs compared to the Alpha and Beta PVs, suggesting reduced selective pressures on Gamma-PVs. Using a sequence alignment-free trimer (k = 3) phylogeny algorithm, we reconstructed a phylogeny that grouped most HPV types into a monophyletic clade that was further split into three branches similar to alignment-based classifications. Interestingly, a subset of low-risk Alpha HPVs (the species Alpha-2, 3, 4, and 14) split from other HPVs and were clustered with non-human primate PVs. Surprisingly, the trimer-constructed phylogeny grouped the Gamma-6 species types originally isolated from the cervicovaginal region with the main Alpha-HPV clade. These data indicate that characterization of papillomavirus heterogeneity via orthogonal approaches reveals novel insights into the biological understanding of HPV genomes.
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Affiliation(s)
- Zigui Chen
- Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
- Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Filippo Utro
- Computational Genomics, IBM T. J. Watson Research, Yorktown Heights, NY 10598, USA; (F.U.); (D.P.); (L.P.)
| | - Daniel Platt
- Computational Genomics, IBM T. J. Watson Research, Yorktown Heights, NY 10598, USA; (F.U.); (D.P.); (L.P.)
| | - Rob DeSalle
- Sackler Institute of Comparative Genomics, American Museum of Natural History, New York, NY 10024, USA;
| | - Laxmi Parida
- Computational Genomics, IBM T. J. Watson Research, Yorktown Heights, NY 10598, USA; (F.U.); (D.P.); (L.P.)
| | - Paul K. S. Chan
- Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
- Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Robert D. Burk
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Obstetrics, Gynecology and Woman’s Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Duan F, Chen J, Yao H, Wang Y, Jia Y, Ling Z, Feng Y, Pan Z, Yin Y, Jiao X. Enhanced therapeutic efficacy of Listeria-based cancer vaccine with codon-optimized HPV16 E7. Hum Vaccin Immunother 2021; 17:1568-1577. [PMID: 33449866 DOI: 10.1080/21645515.2020.1839291] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Cervical cancer is a leading cause of high mortality in women in developing countries and has a serious impact on women's health. Human papilloma virus (HPV) prophylactic vaccines have been produced and may hold promise for reducing the incidence of cervical cancer. However, the limitations of current HPV vaccine strategies make the development of HPV therapeutic vaccines particularly important for the treatment of HPV related lesions. Our previous work has demonstrated that LM4Δhly::E7 was safe and effective in inducing antitumor effect by antigen-specific cellular immune responses and direct killing of tumor cell on a cervical cancer model. In this study, the codon usage effect of a novel Listeria-based cervical cancer vaccine LM4Δhly::E7-1, was evaluated for effects of codon-optimized E7 expression, cellular immune response and therapeutic efficacy in a tumor-bearing murine model. Our data demonstrated that up-regulated expression of E7 was strikingly elevated by codon usage optimization, and thus induced significantly higher Th1-biased immunity, lymphocyte proliferation, and strong specific CTL activity ex-vivo compared with LM4Δhly::E7-treated mice. Furthermore, LM4Δhly::E7-1 enhanced a remarkable therapeutic effect in establishing tumors. Taken together, our results suggest that codon usage optimization is an important consideration in constructing live bacterial-vectored vaccines and is required for promoting effective T cell responses.
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Affiliation(s)
- Feifei Duan
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Jiaqi Chen
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Hao Yao
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Yuting Wang
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Yanyan Jia
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Zhiting Ling
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Youwei Feng
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Zhiming Pan
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Yuelan Yin
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Xin'An Jiao
- Jiangsu Key Laboratory of Zoonosis, Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, MOA of China, Joint International Research Laboratory of Agriculture and Agri-Product Safety, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou, Jiangsu Province, China
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6
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Cho M, Kim H, Je M, Son HS. Analysis of Codon Usage Patterns in the Human Papillomavirus Oncogenes. Curr Bioinform 2021. [DOI: 10.2174/1574893615999200614173136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Background:
Persistent high-risk genital human papillomavirus (HPV) infection is a major cause of cervical
cancer in women. The products of the viral transforming genes E6 and E7 in the high-risk HPVs are known to be similar
in their amino acid composition and structure. We performed a comparative analysis of codon usage patterns in the E6
and E7 genes of HPVs.
Methods:
The E6 and E7 gene sequences of eight HPV subtypes were analyzed to determine their nucleotide
composition, relative synonymous codon usage (RSCU), effective number of codons (ENC), neutrality, genetic
variability, selection pressure, and codon adaptation index (CAI). Additionally, a correspondence analysis (CoA) was
performed.
Results:
The analysis to determine the effects of differences in composition on the codon usage patterns revealed that
there may be usage bias for ‘A’ nucleotides. This was consistent with the results of the RSCU analysis, which
demonstrated that the selection of A/T-rich patterns and the preference for A/T-ended codons in HPVs are influenced by
compositional constraints. Moreover, the results reveal that selection pressure plays an important role in the CoA results
for the RSCU values, Tajima’s D tests, and neutrality tests.
Conclusion:
The results of this study are consistent with previous findings that most papillomavirus genes are under
purifying selection pressure, which limits changes to the encoded proteins. Natural selection and mutation pressures
resulting in changes in the nucleotide composition and codon usage bias in the two tumor genes of HPV act differently
during the evolution of the HPV subtype; thus, throughout the viral life cycle, HPV can constantly evolve to adapt to a
new environment.
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Affiliation(s)
- Myeongji Cho
- Laboratory of Computational Biology & Bioinformatics, Graduate School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826,Korea
| | - Hayeon Kim
- Department of Biomedical Laboratory Science, Kyungdong University, 815 Gyeonhwon-ro, Munmak, Wonju, Gangwondo, 24695,Korea
| | - Mikyeong Je
- Laboratory of Computational Biology & Bioinformatics, Graduate School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826,Korea
| | - Hyeon S. Son
- Laboratory of Computational Biology & Bioinformatics, Graduate School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826,Korea
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7
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Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway. Sci Rep 2020; 10:22166. [PMID: 33335127 PMCID: PMC7746698 DOI: 10.1038/s41598-020-78453-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 11/23/2020] [Indexed: 11/10/2022] Open
Abstract
The ability to translate three nucleotide sequences, or codons, into amino acids to form proteins is conserved across all organisms. All but two amino acids have multiple codons, and the frequency that such synonymous codons occur in genomes ranges from rare to common. Transcripts enriched in rare codons are typically associated with poor translation, but in certain settings can be robustly expressed, suggestive of codon-dependent regulation. Given this, we screened a gain-of-function library for human genes that increase the expression of a GFPrare reporter encoded by rare codons. This screen identified multiple components of the mitogen activated protein kinase (MAPK) pathway enhancing GFPrare expression. This effect was reversed with inhibitors of this pathway and confirmed to be both codon-dependent and occur with ectopic transcripts naturally coded with rare codons. Finally, this effect was associated, at least in part, with enhanced translation. We thus identify a potential regulatory module that takes advantage of the redundancy in the genetic code to modulate protein expression.
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8
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Chen Z, Boon SS, Wang MH, Chan RWY, Chan PKS. Genomic and evolutionary comparison between SARS-CoV-2 and other human coronaviruses. J Virol Methods 2020; 289:114032. [PMID: 33290786 PMCID: PMC7718587 DOI: 10.1016/j.jviromet.2020.114032] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/15/2020] [Accepted: 12/02/2020] [Indexed: 11/28/2022]
Abstract
Three highly pathogenic human coronaviruses can cause severe acute respiratory syndrome (SARS-CoV, SARS-CoV-2 and MERS-CoV). Although phylogenetic analyses have indicated ancient origin of human coronaviruses from animal relatives, their evolutionary history remains to be established. Using phylogenetics and “high order genomic structures” including trimer spectrums, codon usage and dinucleotide suppression, we observed distinct clustering of all human coronaviruses that formed phylogenetic clades with their closest animal relatives, indicating they have encompassed long evolutionary histories within specific ecological niches before jumping species barrier to infect humans. The close relationships between SARS-CoV and SARS-CoV-2 imply similar evolutionary origin. However, a lower Effective Codon Number (ENC) pattern and CpG dinucleotide suppression in SARS-CoV-2 genomes compared to SARS-CoV and MERS-CoV may imply a better host fitness, and thus their success in sustaining a pandemic. Characterization of coronavirus heterogeneity via complementary approaches enriches our understanding on the evolution and virus-host interaction of these emerging human pathogens while the underlying mechanistic basis in pathogenicity warrants further investigation.
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Affiliation(s)
- Zigui Chen
- Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
| | - Siaw S Boon
- Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Maggie H Wang
- Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Renee W Y Chan
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Paul K S Chan
- Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
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9
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Deb B, Uddin A, Chakraborty S. Genome-wide analysis of codon usage pattern in herpesviruses and its relation to evolution. Virus Res 2020; 292:198248. [PMID: 33253719 DOI: 10.1016/j.virusres.2020.198248] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/11/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022]
Abstract
The preferential use of a specific codon, out of a group of synonymous codons encoding the same amino acid, in a gene transcript results from the bias in codon choice. Various evolutionary forces namely mutation pressure and natural selection influence the pattern of codon usage i.e. distinct for each gene/genome. We investigated the pattern of codon usage of eight human herpesvirus genomes and compared them with two other herpesvirus genomes namely murine herpesvirus 68 and bovine herpesvirus type 1.1 to elucidate its compositional features, pattern of codon usage across the genomes and report the differences of codon usage pattern of human herpesviruses from that of other two other viruses. We also identified the similarity of the codon usage of human herpesviruses with its host (human). The genes were found to be CG rich in HHV2, HHV3, HHV4, HHV6, HHV7 and BH genomes while TA rich in HHV1, HHV5, HHV8 and MH genomes. The codon usage bias (CUB) of genes was low. A highly significant correlation was found among compositional contents depicting the role of mutational pressure along with natural selection in framing CUB. Several more frequently used codons as well as less frequently used codons were identified to be similar between each human virus and its host (human), while murine herpesvirus 68 and bovine herpesvirus type 1.1 genomes did not possess similar adaptation strategy as human herpesviruses to human (host), thus we could conclude that viral CUB might have been shaped as per their host's nature for better surveillance. Neutrality plot revealed mutational pressure mostly influenced the CUB of HHV1, HHV8 and MH viruses, while natural selection had a major impact in the CUB of HHV2, HHV3, HHV4, HHV5, HHV6, HHV7 and BH genomes.
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Affiliation(s)
- Bornali Deb
- Department of Biotechnology, Assam University, Silchar, 788011, Assam, India
| | - Arif Uddin
- Department of Zoology, Moinul Hoque Choudhury Memorial Science College, Algapur, Hailakandi, 788150, Assam, India
| | - Supriyo Chakraborty
- Department of Biotechnology, Assam University, Silchar, 788011, Assam, India.
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10
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Van Leuven JT, Ederer MM, Burleigh K, Scott L, Hughes RA, Codrea V, Ellington AD, Wichman HA, Miller CR. ΦX174 Attenuation by Whole-Genome Codon Deoptimization. Genome Biol Evol 2020; 13:5921183. [PMID: 33045052 PMCID: PMC7881332 DOI: 10.1093/gbe/evaa214] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 12/11/2022] Open
Abstract
Natural selection acting on synonymous mutations in protein-coding genes influences genome composition and evolution. In viruses, introducing synonymous mutations in genes encoding structural proteins can drastically reduce viral growth, providing a means to generate potent, live-attenuated vaccine candidates. However, an improved understanding of what compositional features are under selection and how combinations of synonymous mutations affect viral growth is needed to predictably attenuate viruses and make them resistant to reversion. We systematically recoded all nonoverlapping genes of the bacteriophage ΦX174 with codons rarely used in its Escherichia coli host. The fitness of recombinant viruses decreases as additional deoptimizing mutations are made to the genome, although not always linearly, and not consistently across genes. Combining deoptimizing mutations may reduce viral fitness more or less than expected from the effect size of the constituent mutations and we point out difficulties in untangling correlated compositional features. We test our model by optimizing the same genes and find that the relationship between codon usage and fitness does not hold for optimization, suggesting that wild-type ΦX174 is at a fitness optimum. This work highlights the need to better understand how selection acts on patterns of synonymous codon usage across the genome and provides a convenient system to investigate the genetic determinants of virulence.
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Affiliation(s)
- James T Van Leuven
- Department of Biological Science, University of Idaho.,Institute for Modeling Collaboration and Innovation, University of Idaho
| | | | - Katelyn Burleigh
- Department of Biological Science, University of Idaho.,Present address: Seattle Children's Research Institute, Seattle, WA
| | - LuAnn Scott
- Department of Biological Science, University of Idaho
| | - Randall A Hughes
- Applied Research Laboratories, University of Texas, Austin.,Present address: Biotechnology Branch, CCDC US Army Research Laboratory, Adelphi, MD
| | - Vlad Codrea
- Institute for Cellular and Molecular Biology, University of Texas, Austin
| | - Andrew D Ellington
- Applied Research Laboratories, University of Texas, Austin.,Institute for Cellular and Molecular Biology, University of Texas, Austin
| | - Holly A Wichman
- Department of Biological Science, University of Idaho.,Institute for Modeling Collaboration and Innovation, University of Idaho
| | - Craig R Miller
- Department of Biological Science, University of Idaho.,Institute for Modeling Collaboration and Innovation, University of Idaho
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11
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Abstract
The simian polyomavirus SV40 was reported to express Vp4, an N-terminally truncated form of the minor capsid proteins Vp2 and Vp3. Since a missense mutation of the putative Vp4 start codon (Vp2M228I) was found to give reduced progeny release and delayed lysis, Vp4 was claimed to be a viroporin. However, two independent research groups, including our own, were unable to replicate these findings. In contrast, we found no Vp4 expression in SV40-infected cells and no reduction in progeny release for Vp4-deficient virus, and finally, we found that the single amino acid substitution unavoidably introduced into the overlapping Vp2/Vp3 genes during Vp4 mutagenesis reduced early steps but not virus release. Remarkably, the existence of the viroporin Vp4 still seems to be widely accepted, which presumably is preventing important research on polyomavirus release. With this perspective, we will review and comment on the most important experiments that led to the disputed announcement of the viroporin Vp4.
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Luo W, Tian L, Gan Y, Chen E, Shen X, Pan J, Irwin DM, Chen RA, Shen Y. The fit of codon usage of human-isolated avian influenza A viruses to human. INFECTION GENETICS AND EVOLUTION 2020; 81:104181. [PMID: 31918040 DOI: 10.1016/j.meegid.2020.104181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 12/14/2019] [Accepted: 01/05/2020] [Indexed: 01/06/2023]
Abstract
Avian influenza A viruses (AIVs) classify into 18 hemagglutinin (HA) and 11 neuraminidase (NA) subtypes. Even though H1N1 and H3N2 subtypes usually circulate among humans leading to infection, occasionally, H5, H6, H7, H9, and H10 that circulate in poultry also infect humans, and especially H5N1 and H7N9. Efficient virus replication is a critical factor that influences infection. Codon usage of a virus must coevolve with its host for efficient viral replication, therefore, we conduct a comprehensive analysis of codon usage bias in human-isolated AIVs to test their adaptation to host expression system. The relative synonymous codon usage (RSCU) pattern, and the codon adaptation index (CAI) are calculated for this purpose. We find that all human-isolated AIVs tend to eliminate GC and CpG compositions, which may prevent activation of the host innate immune system. Although codon usage differs between AIV subtypes, our data support the conclusion that natural selection has played a major role and mutation pressure a minor role in shaping codon usage bias in all AIVs. Our efforts discover that codon usage of genes encoding surface proteins of H5N1, and the polymerase genes of H7N9 has better fit to the human expression system. This may associate with their better replication and infection in human.
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Affiliation(s)
- Wen Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Lin Tian
- Guangdong Provincial Hospital of Chinese Medicine, Zhuhai 519015, China
| | - Yingde Gan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Enlong Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Xuejuan Shen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Junbin Pan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - David M Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto M5S 1A8, Canada
| | - Rui-Ai Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Zhaoqing Institute of Biotechnology, Zhaoqing 526238, China.
| | - Yongyi Shen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Zhaoqing Institute of Biotechnology, Zhaoqing 526238, China.
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13
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Liu Y, Li H, Pi R, Yang Y, Zhao X, Qi X. Current strategies against persistent human papillomavirus infection (Review). Int J Oncol 2019; 55:570-584. [PMID: 31364734 DOI: 10.3892/ijo.2019.4847] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/16/2019] [Indexed: 11/06/2022] Open
Abstract
Human papillomavirus (HPV) is the most common sexually transmitted infection, exhibiting a tropism for the epidermis and mucosae. The link between persistent HPV infection and malignancies involving the anogenital tract as well as the head and neck has been well‑established, and it is estimated that HPV‑related cancers involving various anatomical sites account for 4.5% of all human cancers. Current prophylactic vaccines against HPV have enabled the prevention of associated malignancies. However, the sizeable population base of current infection in whom prophylactic vaccines are not applicable, certain high‑risk HPV types not included in vaccines, and the vast susceptible population in developing countries who do not have access to the costly prophylactic vaccines, put forward an imperative need for effective therapies targeting persistent infection. In this article, the life cycle of HPV, the mechanisms facilitating HPV evasion of recognition and clearance by the host immune system, and the promising therapeutic strategies currently under investigation, particularly antiviral drugs and therapeutic vaccines, are reviewed.
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Affiliation(s)
- Yu Liu
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hongyi Li
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ruyu Pi
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yang Yang
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaorong Qi
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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14
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Singh P, Venkatesan A, Padmanabhan P, Gulyas B, Dass J FP. Codon usage of human hepatitis C virus clearance genes in relation to its expression. J Cell Biochem 2019; 121:534-544. [PMID: 31310376 DOI: 10.1002/jcb.29290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 03/15/2019] [Indexed: 11/08/2022]
Abstract
Hepatitis C virus (HCV) infection is among the leading causes of hepatocellular carcinoma and liver cirrhosis globally, with a high economic burden. The disease progression is well established, but less is known about the spontaneous HCV infection clearance. This study tries to establish the relationship between codon biasness and expression of HCV clearance candidate genes in normal and HCV infected liver tissues. A total of 112 coding sequences comprising 151 679 codons were subjected to the computation of codon indices, namely relative synonymous codon usage, an effective number of codon (Nc), frequency of optimal codon, codon adaptation index, codon bias index, and base compositions. Codon indices report of GC3s, GC12, hydropathicity, and aromaticity implicates both mutational and translational selection in the candidate gene set. This was further correlated with the differentially expressed genes among the selected genes using BioGPS. A significant correlation is observed between the gene expression of normal liver and cancerous liver tissues with codon bias (Nc). Gene expression is also correlated with relative codon bias values, indicating that CCL5, APOA2, CD28, IFITM1, and TNFSF4 genes have higher expression. These results are quite encouraging in selecting the high responsive genes in HCV clearance. However, there could be additional genes which could also orchestrate the clearance role with the above mentioned first line of defensive genes.
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Affiliation(s)
- Pratichi Singh
- Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Arthi Venkatesan
- Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Parasuraman Padmanabhan
- Centre for Neuroimaging Research at NTU (CeNReN), Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Balazs Gulyas
- Centre for Neuroimaging Research at NTU (CeNReN), Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Febin Prabhu Dass J
- Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
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15
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Takaaki K, Tatsuo S. Analysis of factors affecting codon usage bias in human papillomavirus. ACTA ACUST UNITED AC 2018. [DOI: 10.5897/jbsa2017.0106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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16
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Analysis of Class I Major Histocompatibility Complex Gene Transcription in Human Tumors Caused by Human Papillomavirus Infection. Viruses 2017; 9:v9090252. [PMID: 28891951 PMCID: PMC5618018 DOI: 10.3390/v9090252] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 08/31/2017] [Accepted: 09/02/2017] [Indexed: 12/25/2022] Open
Abstract
Oncoproteins from high-risk human papillomaviruses (HPV) downregulate the transcription of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus in tissue culture model systems. This could allow infected or transformed cells to evade the adaptive immune response. Using data from over 800 human cervical and head & neck tumors from The Cancer Genome Atlas (TCGA), we determined the impact of HPV status on the mRNA expression of all six MHC-I heavy chain genes, and the β2 microglobulin light chain. Unexpectedly, these genes were all expressed at high levels in HPV positive (HPV+) cancers compared with normal control tissues. Indeed, many of these genes were expressed at significantly enhanced levels in HPV+ tumors. Similarly, the transcript levels of several other components of the MHC-I peptide-loading complex were also high in HPV+ cancers. The coordinated expression of high mRNA levels of the MHC-I antigen presentation apparatus could be a consequence of the higher intratumoral levels of interferon γ in HPV+ carcinomas, which correlate with signatures of increased infiltration by T- and NK-cells. These data, which were obtained from both cervical and oral tumors in large human cohorts, indicates that HPV oncoproteins do not efficiently suppress the transcription of the antigen presentation apparatus in human tumors.
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Chen J, Zhao KN. HPV-p53-miR-34a axis in HPV-associated cancers. ANNALS OF TRANSLATIONAL MEDICINE 2016; 3:331. [PMID: 26734641 DOI: 10.3978/j.issn.2305-5839.2015.09.39] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Human papillomaviruses (HPVs) are known to cause many cancers by altering multiple signalling pathways through their oncogene integration into host genome and expression. Studies have shown that many microRNAs (miRs) may function as oncogenes (called as oncomiRs) to promote an oncogenic effect. MiR-34a among the reported oncomiRs is a key player in the carcinogenesis caused by infection with HPVs. In this mini-review, we summarise the roles of miR-34a in HPV-caused cancers. MiR-34a is transcriptionally regulated by tumour suppressor p53. HPV oncogene E6 inhibits expression of p53 to decrease the levels of miR-34a, leading to the increased expression of multiple genes which are targeted by miR-34a. The upregulation of these genes increases cancer cell proliferation, survival and migration in HPV-associated cancers.
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Affiliation(s)
- Jiezhong Chen
- 1 School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia ; 2 Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou 325000, China ; 3 Centre for Kidney Disease Research-Venomics Research, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, Australia
| | - Kong-Nan Zhao
- 1 School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia ; 2 Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou 325000, China ; 3 Centre for Kidney Disease Research-Venomics Research, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, Australia
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18
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Upadhyay M, Vivekanandan P. Depletion of CpG Dinucleotides in Papillomaviruses and Polyomaviruses: A Role for Divergent Evolutionary Pressures. PLoS One 2015; 10:e0142368. [PMID: 26544572 PMCID: PMC4636234 DOI: 10.1371/journal.pone.0142368] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 10/21/2015] [Indexed: 12/31/2022] Open
Abstract
Background Papillomaviruses and polyomaviruses are small ds-DNA viruses infecting a wide-range of vertebrate hosts. Evidence supporting co-evolution of the virus with the host does not fully explain the evolutionary path of papillomaviruses and polyomaviruses. Studies analyzing CpG dinucleotide frequencies in virus genomes have provided interesting insights on virus evolution. CpG dinucleotide depletion has not been extensively studied among papillomaviruses and polyomaviruses. We sought to analyze the relative abundance of dinucleotides and the relative roles of evolutionary pressures in papillomaviruses and polyomaviruses. Methods We studied 127 full-length sequences from papillomaviruses and 56 full-length sequences from polyomaviruses. We analyzed the relative abundance of dinucleotides, effective codon number (ENC), differences in synonymous codon usage. We examined the association, if any, between the extent of CpG dinucleotide depletion and the evolutionary lineage of the infected host. We also investigated the contribution of mutational pressure and translational selection to the evolution of papillomaviruses and polyomaviruses. Results All papillomaviruses and polyomaviruses are CpG depleted. Interestingly, the evolutionary lineage of the infected host determines the extent of CpG depletion among papillomaviruses and polyomaviruses. CpG dinucleotide depletion was more pronounced among papillomaviruses and polyomaviruses infecting human and other mammals as compared to those infecting birds. Our findings demonstrate that CpG depletion among papillomaviruses is linked to mutational pressure; while CpG depletion among polyomaviruses is linked to translational selection. We also present evidence that suggests methylation of CpG dinucleotides may explain, at least in part, the depletion of CpG dinucleotides among papillomaviruses but not polyomaviruses. Conclusions The extent of CpG depletion among papillomaviruses and polyomaviruses is linked to the evolutionary lineage of the infected host. Our results highlight the existence of divergent evolutionary pressures leading to CpG dinucleotide depletion among small ds-DNA viruses infecting vertebrate hosts.
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Affiliation(s)
- Mohita Upadhyay
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, 006, India
| | - Perumal Vivekanandan
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, 006, India
- * E-mail:
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19
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Zhang L, Wu J, Ling MT, Zhao L, Zhao KN. The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses. Mol Cancer 2015; 14:87. [PMID: 26022660 PMCID: PMC4498560 DOI: 10.1186/s12943-015-0361-x] [Citation(s) in RCA: 162] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 04/06/2015] [Indexed: 01/08/2023] Open
Abstract
Infection with Human papillomaviruses (HPVs) leads to the development of a wide-range of cancers, accounting for 5% of all human cancers. A prominent example is cervical cancer, one of the leading causes of cancer death in women worldwide. It has been well established that tumor development and progression induced by HPV infection is driven by the sustained expression of two oncogenes E6 and E7. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways that may be equally important for transformation. Among these pathways, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling cascade plays a very important role in HPV-induced carcinogenesis by acting through multiple cellular and molecular events. In this review, we summarize the frequent amplification of PI3K/Akt/mTOR signals in HPV-induced cancers and discuss how HPV oncogenes E6/E7/E5 activate the PI3K/Akt/mTOR signalling pathway to modulate tumor initiation and progression and affect patient outcome. Improvement of our understanding of the mechanism by which the PI3K/Akt/mTOR signalling pathway contributes to the immortalization and carcinogenesis of HPV-transduced cells will assist in devising novel strategies for preventing and treating HPV-induced cancers.
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Affiliation(s)
- Lifang Zhang
- Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, 325035 , Zhejiang, PR China.
| | - Jianhong Wu
- Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, 4102, QLD, Australia.
- Current address: Department of Gastric Cancer and Soft Tissue Sarcomas Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, PR China.
| | - Ming Tat Ling
- Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, 4102, QLD, Australia.
| | - Liang Zhao
- The University of Queensland, Brisbane, 4072, QLD, Australia.
| | - Kong-Nan Zhao
- Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, 325035 , Zhejiang, PR China.
- Centre for Kidney Disease Research-Venomics Research, The University of Queensland School of Medicine, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, QLD, Australia.
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20
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Liu GB, Chen J, Wu ZH, Zhao KN. Association of human papillomavirus with Fanconi anemia promotes carcinogenesis in Fanconi anemia patients. Rev Med Virol 2015; 25:345-53. [PMID: 25776992 DOI: 10.1002/rmv.1834] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/13/2015] [Accepted: 02/15/2015] [Indexed: 12/22/2022]
Abstract
Fanconi anemia (FA) is a rare recessive disorder associated with chromosomal fragility. FA patients are at very high risk of cancers, especially head and neck squamous cell carcinomas and squamous cell carcinomas caused by infection of human papillomaviruses (HPVs). By integrating into the host genome, HPV oncogenes E6 and E7 drive the genomic instability to promote DNA damage and gene mutations necessary for carcinogenesis in FA patients. Furthermore, E6 and E7 oncoproteins not only inhibit p53 and retinoblastoma but also impair the FANC/BRCA signaling pathway to prevent DNA damage repair and alter multiple signals including cell-cycle checkpoints, telomere function, cell proliferation, and interference of the host immune system leading to cancer development in FA patients. In this review, we summarize recent advances in unraveling the molecular mechanisms of FA susceptibility to HPV-induced cancers, which facilitate rational preventive and therapeutic strategies.
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Affiliation(s)
- Guang Bin Liu
- School of Health and Wellbeing, Faculty of Health, Engineering and Sciences, The University of Southern Queensland, Toowoomba, Australia
| | - Jiezhong Chen
- School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.,Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia
| | - Zhan He Wu
- Western Sydney Genomic Diagnosis, The Children's Hospital at Westmead, Sydney, Australia
| | - Kong-Nan Zhao
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, China.,Centre for Kidney Disease Research-Venomics Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Australia
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21
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Chen J. Signaling pathways in HPV-associated cancers and therapeutic implications. Rev Med Virol 2015; 25 Suppl 1:24-53. [PMID: 25752815 DOI: 10.1002/rmv.1823] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Revised: 10/15/2014] [Accepted: 12/27/2014] [Indexed: 12/19/2022]
Affiliation(s)
- Jiezhong Chen
- School of Biomedical Sciences and Australian Institute for Bioengineering and Nanotechnology; The University of Queensland; Brisbane Queensland Australia
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22
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Jebali A, Kalantar SM, Hekmatimoghaddam S, Saffarzadeh N, Sheikha MH, Ghasemi N. Surface modification of tri-calcium phosphate nanoparticles by DOPE and/or anti-E6 antibody to enhance uptake of antisense of E6 mRNA. Colloids Surf B Biointerfaces 2015; 126:297-302. [PMID: 25601794 DOI: 10.1016/j.colsurfb.2014.12.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 12/18/2014] [Accepted: 12/22/2014] [Indexed: 10/24/2022]
Abstract
The main aim of this study was to evaluate the uptake of E6 mRNA antisense into cervical cancer cells, induced by human papilloma virus (HPV). In this study, the carrier of the antisense was tri-calcium phosphate nanoparticles (TCP NPs) conjugated with dioleoyl phosphatidyl ethanolamine (DOPE) and/or anti-E6 antibody. At first, TCP NPs were synthesized, coated with carboxy-polyethylene glycol, and then conjugated with anti-E6 antibody and/or DOPE by carbodiimide cross-linker. Then, a single stranded DNA, which was complementary (antisense) of E6 mRNA, was attached to each one. Finally, the uptake of conjugated and unconjugated TCP NPs into HelaS3 cells was separately evaluated by Fourier transform infrared spectroscopy, optical microscopy, and fluorescent microscopy. Also, the cytotoxicity of these carriers was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Overall, 4 types of TCP NPs were used in this study, including 1) TCP NPs conjugated with DOPE (TCP NPs/DOPE), 2) TCP NPs conjugated with DOPE and antibody (TCP NPs/DOPE/Anti-E6 Ab), 3) TCP NPs conjugated with antibody (TCP NPs/Anti-E6 Ab), and 4) TCP NPs which not conjugated with DOPE and antibody (unconjugated TCP NPs). Uptake tests showed that although all types of TCP NPs could transfer antisense of E6 mRNA into HelaS3 cells, TCP NPs/DOPE and TCP NPs/DOPE/Anti-E6 Ab had more uptake than TCP NPs/Anti-E6 Ab and unconjugated TCP NPs. Moreover, MTT assay showed that TCP NPs/DOPE was more toxic than TCP NPs/DOPE/Anti-E6 Ab, TCP NPs/Anti-E6 Ab, and unconjugated TCP NPs. It can be concluded that TCP NPs/DOPE/Anti-E6 Ab is a good choice for oligonucleotide delivery, because of higher uptake and less toxicity, compared with other formulations.
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Affiliation(s)
- Ali Jebali
- Department of Laboratory Sciences, School of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Seyed Mehdi Kalantar
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Research and Clinical Centre for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyedhossein Hekmatimoghaddam
- Department of Laboratory Sciences, School of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Negin Saffarzadeh
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | | | - Nasrin Ghasemi
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Hu C, Chen J, Ye L, Chen R, Zhang L, Xue X. Codon usage bias in human cytomegalovirus and its biological implication. Gene 2014; 545:5-14. [PMID: 24814188 DOI: 10.1016/j.gene.2014.05.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 05/02/2014] [Accepted: 05/06/2014] [Indexed: 10/25/2022]
Abstract
Human cytomegalovirus (HCMV) infection, a worldwide contagion, causes a serious disorder in infected individuals. Analysis of codon usage can reveal much molecular information about this virus. The effective number of codon (ENC) values, relative synonymous codon usage (RSCU) values, codon adaptation index (CAI), and nucleotide contents was investigated in approximately 160 coding sequences (CDS) among 17 human cytomegalovirus genomes using the software CodonW. Linear regression analysis and logistic regression were performed to explore the preliminary data. The results showed that, overall, HCMV genomes had low codon usage bias (mean ENC=47.619). However, the ENC of individual CDS varied widely and was distributed unevenly between host-related genes and viral-self-function genes (P=0.002, odds ratio (OR)=3.194), as did the GC content (P=0.016, OR=2.178). The ENC values correlated with CAI, GC content, and the nucleotide composing at the 3rd codon position (GC3s) (P<0.001). There was a significant variation in the codon preference that depended on the RSCU data. The predicted ENC curve suggested that mutational pressure, rather than natural selection, was one of the main factors that determined the codon usage bias in HCMV. Among 123 genes with known function, the genes related to viral self-replication and viral-host interaction showed different ENC and CAI values, and GC and GC3s contents. In conclusion, the detailed codon usage bias theoretically revealed information concerning HCMV evolution and could be a valuable additional parameter for HCMV gene function research.
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Affiliation(s)
- Changyuan Hu
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District 325035, Wenzhou City, Zhejiang Province, China
| | - Jing Chen
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District 325035, Wenzhou City, Zhejiang Province, China
| | - Lulu Ye
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Ouhai District 325035, Wenzhou City, Zhejiang Province, China
| | - Renpin Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District 325035, Wenzhou City, Zhejiang Province, China
| | - Lifang Zhang
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Ouhai District 325035, Wenzhou City, Zhejiang Province, China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Ouhai District 325035, Wenzhou City, Zhejiang Province, China.
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24
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Hepatitis A virus adaptation to cellular shutoff is driven by dynamic adjustments of codon usage and results in the selection of populations with altered capsids. J Virol 2014; 88:5029-41. [PMID: 24554668 DOI: 10.1128/jvi.00087-14] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED Hepatitis A virus (HAV) has a highly biased and deoptimized codon usage compared to the host cell and fails to inhibit host protein synthesis. It has been proposed that an optimal combination of abundant and rare codons controls the translation speed required for the correct capsid folding. The artificial shutoff host protein synthesis results in the selection of variants containing mutations in the HAV capsid coding region critical for folding, stability, and function. Here, we show that these capsid mutations resulted in changes in their antigenicity; in a reduced stability to high temperature, low pH, and biliary salts; and in an increased efficacy of cell entry. In conclusion, the adaptation to cellular shutoff resulted in the selection of large-plaque-producing virus populations. IMPORTANCE HAV has a naturally deoptimized codon usage with respect to that of its cell host and is unable to shut down the cellular translation. This fact contributes to the low replication rate of the virus, in addition to other factors such as the highly inefficient internal ribosome entry site (IRES), and explains the outstanding physical stability of this pathogen in the environment mediated by a folding-dependent highly cohesive capsid. Adaptation to artificially induced cellular transcription shutoff resulted in a redeoptimization of its capsid codon usage, instead of an optimization. These genomic changes are related to an overall change of capsid folding, which in turn induces changes in the cell entry process. Remarkably, the adaptation to cellular shutoff allowed the virus to significantly increase its RNA uncoating efficiency, resulting in the selection of large-plaque-producing populations. However, these populations produced much-debilitated virions.
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de Matos RPA, Sichero L, Mansur IM, do Bonfim CM, Bittar C, Nogueira RL, Küpper DS, Valera FCP, Nogueira ML, Villa LL, Calmon MF, Rahal P. Nucleotide and phylogenetic analysis of human papillomavirus types 6 and 11 isolated from recurrent respiratory papillomatosis in Brazil. INFECTION GENETICS AND EVOLUTION 2013; 16:282-9. [PMID: 23466889 DOI: 10.1016/j.meegid.2012.12.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 12/28/2012] [Accepted: 12/29/2012] [Indexed: 01/21/2023]
Abstract
There are few studies about the distribution of natural molecular variants of low-risk HPVs. Our aim was to evaluate the E6 early gene variability among HPV-6 and HPV-11 isolates detected in recurrent respiratory papillomatosis (RRP) samples obtained in a cohort of Brazilian patients. We also performed a phylogenetic analysis in order to compare nucleotide sequences identified in our study with previously reported isolates from different anatomic sites (laryngeal papillomas, genital warts, cervical cancer and anal swabs) obtained from other parts of the world to determine the phylogenetic relationships of variants detected in Brazil. The complete coding region of the E6 gene of 25 samples was cloned and sequenced: 18 isolates of HPV-6 (72%) and 7 isolates of HPV-11 (28%). A total of four different HPV-6 genomic variants and two HPV-11 genomic variants was identified. It was not possible to correlate specific variants with disease severity. Phylogenetic trees for both HPV types were constructed enclosing both E6 sequences detected in our study and formerly published sequences. In both phylogenetic trees, the sequences from Brazil did not group together. We could not establish a geographical association between HPV-6 or HPV-11 variants, unlike HPV-16 and HPV-18.
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Affiliation(s)
- Renata Prandini Adum de Matos
- UNESP - São Paulo State University, IBILCE, Institute of Bioscience, Language & Literature and Exact Science, Department of Biology, Rua Cristóvão Colombo 2265, Bairro Jardim Nazareth, CEP 15054-010, São José do Rio Preto, São Paulo, Brazil.
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Grabowska AK, Riemer AB. The invisible enemy - how human papillomaviruses avoid recognition and clearance by the host immune system. Open Virol J 2012; 6:249-56. [PMID: 23341860 PMCID: PMC3547646 DOI: 10.2174/1874357901206010249] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 06/06/2012] [Accepted: 06/15/2012] [Indexed: 12/20/2022] Open
Abstract
Human papillomavirus (HPV) needs to persist in squamous epithelia for a certain amount of time to complete its reproductive cycle. Therefore, the virus has evolved multiple immune evasion strategies. The interplay of these immune evasion mechanisms with the host immune system decides whether a HPV infection is cleared or becomes persistent. Clearance of HPV-induced lesions is mediated by a cellular immune response, consisting of both cytotoxic T lymphocyte and T helper cell responses. Persistent HPV infection, on the other hand, is the single most important risk factor for the development of HPV-associated premalignant lesions and HPV-driven cancers. This article reviews the immune evasion mechanisms employed by high-risk HPVs to escape host immune recognition and attack.
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Affiliation(s)
- Agnieszka K Grabowska
- Immunotherapy and -prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Pavon-Eternod M, David A, Dittmar K, Berglund P, Pan T, Bennink JR, Yewdell JW. Vaccinia and influenza A viruses select rather than adjust tRNAs to optimize translation. Nucleic Acids Res 2012; 41:1914-21. [PMID: 23254333 PMCID: PMC3561966 DOI: 10.1093/nar/gks986] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Transfer RNAs (tRNAs) are central to protein synthesis and impact translational speed and
fidelity by their abundance. Here we examine the extent to which viruses manipulate tRNA
populations to favor translation of their own genes. We study two very different viruses:
influenza A virus (IAV), a medium-sized (13 kB genome) RNA virus; and vaccinia virus (VV),
a large (200 kB genome) DNA virus. We show that the total cellular tRNA population remains
unchanged following viral infection, whereas the polysome-associated tRNA population
changes dramatically in a virus-specific manner. The changes in polysome-associated tRNA
levels reflect the codon usage of viral genes, suggesting the existence of local tRNA
pools optimized for viral translation.
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Affiliation(s)
- Mariana Pavon-Eternod
- Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
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Lampson BL, Pershing NLK, Prinz JA, Lacsina JR, Marzluff WF, Nicchitta CV, MacAlpine DM, Counter CM. Rare codons regulate KRas oncogenesis. Curr Biol 2012; 23:70-5. [PMID: 23246410 DOI: 10.1016/j.cub.2012.11.031] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Revised: 10/30/2012] [Accepted: 11/13/2012] [Indexed: 11/19/2022]
Abstract
Oncogenic mutations in the small Ras GTPases KRas, HRas, and NRas render the proteins constitutively GTP bound and active, a state that promotes cancer. Ras proteins share ~85% amino acid identity, are activated by and signal through the same proteins, and can exhibit functional redundancy. Nevertheless, manipulating expression or activation of each isoform yields different cellular responses and tumorigenic phenotypes, even when different ras genes are expressed from the same locus. We now report a novel regulatory mechanism hardwired into the very sequence of RAS genes that underlies how such similar proteins impact tumorigenesis differently. Specifically, despite their high sequence similarity, KRAS is poorly translated compared to HRAS due to enrichment in genomically underrepresented or rare codons. Converting rare to common codons increases KRas expression and tumorigenicity to mirror that of HRas. Furthermore, in a genome-wide survey, similar gene pairs with opposing codon bias were identified that not only manifest dichotomous protein expression but also are enriched in key signaling protein classes and pathways. Thus, synonymous nucleotide differences affecting codon usage account for differences between HRas and KRas expression and function and may represent a broader regulation strategy in cell signaling.
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Affiliation(s)
- Benjamin L Lampson
- Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
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Chen J. Roles of the PI3K/Akt pathway in Epstein-Barr virus-induced cancers and therapeutic implications. World J Virol 2012; 1:154-61. [PMID: 24175221 PMCID: PMC3782276 DOI: 10.5501/wjv.v1.i6.154] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Revised: 10/16/2012] [Accepted: 11/07/2012] [Indexed: 02/05/2023] Open
Abstract
Viruses have been shown to be responsible for 10%-15% of cancer cases. Epstein-Barr virus (EBV) is the first virus to be associated with human malignancies. EBV can cause many cancers, including Burkett's lymphoma, Hodgkin's lymphoma, post-transplant lymphoproliferative disorders, nasopharyngeal carcinoma and gastric cancer. Evidence shows that phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) plays a key role in EBV-induced malignancies. The main EBV oncoproteins latent membrane proteins (LMP) 1 and LMP2A can activate the PI3K/Akt pathway, which, in turn, affects cell survival, apoptosis, proliferation and genomic instability via its downstream target proteins to cause cancer. It has also been demonstrated that the activation of the PI3K/Akt pathway can result in drug resistance to chemotherapy. Thus, the inhibition of this pathway can increase the therapeutic efficacy of EBV-associated cancers. For example, PI3K inhibitor Ly294002 has been shown to increase the effect of 5-fluorouracil in an EBV-associated gastric cancer cell line. At present, dual inhibitors of PI3K and its downstream target mammalian target of rapamycin have been used in clinical trials and may be included in treatment regimens for EBV-associated cancers.
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Affiliation(s)
- Jiezhong Chen
- Jiezhong Chen, Illawarra Health and Medical Research Institute, University of Wollongong, Northfields Avenue, NSW 2522, Australia
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Shi SL, Jiang YR, Liu YQ, Xia RX, Qin L. Selective pressure dominates the synonymous codon usage in parvoviridae. Virus Genes 2012; 46:10-9. [PMID: 22996735 DOI: 10.1007/s11262-012-0818-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Accepted: 09/05/2012] [Indexed: 12/16/2022]
Abstract
Parvoviridae is a family of small non-enveloped viruses and divided into two subfamilies. The family members infect a wide range of organisms from insects to humans and some of the members (e.g., nonpathogenic adeno-associated viruses) are effective gene therapy delivery vectors. We detailed the synonymous codon usage pattern of Parvoviridae family from the available 58 sequenced genomes through multivariate statistical methods. Our results revealed that nine viruses showed some degree of strong codon bias, and the others possessed a general weak trend of codon bias. ENc-plot and neutrality plot results showed that selective pressure dominated over mutation in shapes coding sequence's composition. The overall GC content and GC content at the third synonymous codon position were the principal determinants behind the variations within the codon usage patterns, as they both significantly correlated with the first axis of correspondence analysis. In addition, gene length had no direct influence on the codon usage pattern. Densovirinae subfamily and Parvovirinae subfamily possessed nine identical preferred codons, though most of the two subfamilies codon usage frequencies were significantly different. The result of cluster analysis based on synonymous codon usage was discordant with that of taxonomic classification. Adeno-associated viruses formed a separated clade far from other Parvoviridae members in the dendrogram. Thus, we concluded that natural selection rather than mutation pressure accounts for the main factor that affects the codon bias in Parvoviridae family.
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Affiliation(s)
- Sheng-Lin Shi
- Postdoctoral Station of Plant Protection, Shenyang Agricultural University, No.120 Dongling Road, Shenyang, P.R.China.
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Sabol I, Matovina M, Si-Mohamed A, Grce M. Characterization and whole genome analysis of human papillomavirus type 16 e1-1374^63nt variants. PLoS One 2012; 7:e41045. [PMID: 22911739 PMCID: PMC3404080 DOI: 10.1371/journal.pone.0041045] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 06/20/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The variation of the most common Human papillomavirus (HPV) type found in cervical cancer, the HPV16, has been extensively investigated in almost all viral genes. The E1 gene variation, however, has been rarely studied. The main objective of the present investigation was to analyze the variability of the E6 and E1 genes, focusing on the recently identified E1-1374^63nt variant. METHODOLOGY/PRINCIPAL FINDINGS Variation within the E6 of 786 HPV16 positive cervical samples was analyzed using high-resolution melting, while the E1-1374^63nt duplication was assayed by PCR. Both techniques were supplemented with sequencing. The E1-1374^63nt duplication was linked with the E-G350 and the E-C109/G350 variants. In comparison to the referent HPV16, the E1-1374^63nt E-G350 variant was significantly associated with lower grade cervical lesions (p = 0.029), while the E1-1374^63nt E-C109/G350 variant was equally distributed between high and low grade lesions. The E1-1374^63nt variants were phylogenetically closest to E-G350 variant lineage (A2 sub-lineage based on full genome classification). The major differences between E1-1374^63nt variants were within the LCR and the E6 region. On the other hand, changes within the E1 region were the major differences from the A2 sub-lineage, which has been historically but inconclusively associated with high grade cervical disease. Thus, the shared variations cannot explain the particular association of the E1-1374^63nt variant with lower grade cervical lesions. CONCLUSIONS/SIGNIFICANCE The E1 region has been thus far considered to be well conserved among all HPVs and therefore uninteresting for variability studies. However, this study shows that the variations within the E1 region could possibly affect cervical disease, since the E1-1374^63nt E-G350 variant is significantly associated with lower grade cervical lesions, in comparison to the A1 and A2 sub-lineage variants. Furthermore, it appears that the silent variation 109T>C of the E-C109/G350 variant might have a significant role in the viral life cycle and warrants further study.
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Affiliation(s)
- Ivan Sabol
- Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Mihaela Matovina
- Department of Microbiology and Parasitology, School of Medicine, University of Rijeka, Rijeka, Croatia
| | - Ali Si-Mohamed
- Laboratoire de Virologie, Hôpital Européen Georges Pompidou, Paris, France
| | - Magdalena Grce
- Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
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Human papillomavirus gene expression is controlled by host cell splicing factors. Biochem Soc Trans 2012; 40:773-7. [DOI: 10.1042/bst20120079] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
HPVs (human papillomaviruses) infect stratified epithelia and cause a variety of lesions ranging from benign warts to invasive tumours. The virus life cycle is tightly linked to differentiation of the keratinocyte it infects: papillomaviruses modulate host gene expression to ensure efficient virus replication. For example, the viral transcription factor E2 can directly up-regulate, in an epithelial differentiation-dependent manner, cellular SRSFs [SR (serine/arginine-rich) splicing factors] that control constitutive and alternative splicing. Changes in alternative splicing and the mechanisms controlling this for viral mRNAs have been the subject of intense exploration. However, to date experiments have only been carried out in model systems because the genetic systems suitable for studying alternative splicing of viral RNAs in the context of the virus life cycle are relatively recent and technically challenging. Now using these life cycle-supporting systems, our laboratory has identified SR proteins as important players in differentiation-dependent regulation of HPV gene expression. Better understanding of the role of cellular factors in regulating the virus life cycle is needed as it may help development of novel diagnostic approaches and antiviral therapies in the future.
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