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1
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Rocchi A, Sariyer IK, Berger JR. Revisiting JC virus and progressive multifocal leukoencephalopathy. J Neurovirol 2023; 29:524-537. [PMID: 37659983 DOI: 10.1007/s13365-023-01164-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/10/2023] [Accepted: 07/27/2023] [Indexed: 09/04/2023]
Abstract
Since its definition 65 years ago, progressive multifocal leukoencephalopathy (PML) has continued to devastate a growing population of immunosuppressed patients despite major advances in our understanding of the causative JC virus (JCV). Unless contained by the immune system, JCV lyses host oligodendrocytes collateral to its life cycle, leading to demyelination, neurodegeneration, and death. Novel treatments have stagnated in the absence of an animal model while current antiviral agents fail to address the now ubiquitous polyomavirus. In this review, we highlight the established pathogenesis by which JCV infection progresses to PML, highlighting major challenges that must be overcome to eliminate the underlying virus and, therefore, the debilitating disease.
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Affiliation(s)
- Angela Rocchi
- Department of Microbiology, Immunology and Inflammation, Center for Neurovirology and Gene Editing, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA
| | - Ilker K Sariyer
- Department of Microbiology, Immunology and Inflammation, Center for Neurovirology and Gene Editing, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.
| | - Joseph R Berger
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Convention Avenue, Philadelphia, PA, 19104, USA.
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2
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Rajendra K, Sharma P. Viral Pathogens in Oesophageal and Gastric Cancer. Pathogens 2022; 11:476. [PMID: 35456151 PMCID: PMC9029269 DOI: 10.3390/pathogens11040476] [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: 03/13/2022] [Revised: 04/10/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022] Open
Abstract
Tumour virology was born with the discovery by Peyton Rous in 1911 of a filterable agent in chicken cellular extracts that caused neoplasia in healthy chickens. Universally, 20% of all human cancers have a viral aetiology. Viruses are involved at various stages of the carcinogenesis pathway, depending on the viral pathogen, and likely require co-factors. Multiple risk factors have been associated with oesophageal and gastric malignancy, including carcinogenic pathogens. These viruses and bacteria include human papillomavirus (HPV) [oesophageal cancer], Epstein-Barr virus (EBV) [proximal stomach cancer], and Helicobacter pylori (HP) [non-cardia stomach cancer]. Viruses such as EBV have been firmly established as causal for up to 10% of gastric cancers. HPV is associated with 13 to 35% of oesophageal adenocarcinoma but its role is unclear in oesophageal squamous cell carcinomas. The causal relationship between hepatitis B (HBV), cytomegalovirus (CMV), HPV, and John Cunningham (JCV) and gastric neoplasia remains indeterminate and warrants further study. The expression of viral antigens by human tumours offers preventive and therapeutic potential (including vaccination) and has already been harnessed with vaccines for HPV and HBV. Future goals include viral protein-based immunotherapy and monoclonal antibodies for the treatment of some of the subset of EBV and HPV-induced gastro-esophageal cancers.
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Affiliation(s)
- Kishen Rajendra
- School of Medicine, The International Medical University, Kuala Lumpur 57000, Malaysia
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO 64128, USA;
- School of Medicine, University of Kansas, Kansas City, MO 66160, USA
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3
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Izi S, Youssefi M, Mohammadian Roshan N, Azimian A, Amel Jamehdar S, Zahedi Avval F. Higher detection of JC polyomavirus in colorectal cancerous tissue after pretreatment with topoisomerase I enzyme; colorectal tissue serves as a JCPyV persistence site. Exp Mol Pathol 2021; 123:104687. [PMID: 34592199 DOI: 10.1016/j.yexmp.2021.104687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/11/2021] [Accepted: 09/22/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND The JC polyomavirus has been blamed to contribute in colorectal cancer (CRC), however, the topic is still controversial. Varying detection rate of JCPyV genome has been reported mainly due to technical reasons. Here, we provide summative data on the topic, with emphasize on technical issues. METHODS Formalin-fixed paraffin-embedded tissue samples from 50 patients with CRC, consisting of tumoral and non-cancerous marginal tissue (totally 100 samples) were included in the study. After DNA extraction, specific JCPyV T-Ag sequences were targeted using Real-time PCR. To unwind the supercoiled JCPyV genome, pretreatment with topoisomerase I, was applied. Immunohistochemical (IHC) staining was performed using an anti-T-Ag monoclonal antibody. RESULTS In the first attempts, no samples were found to be positive in Real-time PCR assays. However, JCPyV sequences were found in 60% of CRC tissues and 38% of non-cancerous colorectal mucosa after application of pre-treatment step with topoisomerase I enzyme (P = 0.028). T-Ag protein was found in the nuclear compartment of the stained cells in IHC assays. CONCLUSIONS The presence of JCPyV in CRC tissues, as well as T-Ag localization in the nucleolus, where its oncogenic effect takes place, may provide supporting evidence for JCPyV involvement in CRC development. The study highlights the importance of using topoisomerase I to enhance JCPyV genome detection. Also, colorectal tissue is one of the permissive human tissue for JC resistance after preliminary infection.
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Affiliation(s)
- Samira Izi
- Department of Clinical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IRAN; Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoud Youssefi
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Antimicrobial resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nema Mohammadian Roshan
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Azimian
- Department of Pathobiology and Laboratory Sciences, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Saeid Amel Jamehdar
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Antimicrobial resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farnaz Zahedi Avval
- Department of Clinical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IRAN.
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4
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Palrasu M, Zaika E, El-Rifai W, Que J, Zaika AI. Role of Bacterial and Viral Pathogens in Gastric Carcinogenesis. Cancers (Basel) 2021; 13:1878. [PMID: 33919876 PMCID: PMC8070847 DOI: 10.3390/cancers13081878] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/02/2021] [Accepted: 04/11/2021] [Indexed: 01/10/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tumor types, gastric carcinogenesis is tightly linked to infectious events. Infections with Helicobacter pylori (H. pylori) bacterium and Epstein-Barr virus (EBV) are the two most investigated risk factors for GC. These pathogens infect more than half of the world's population. Fortunately, only a small fraction of infected individuals develops GC, suggesting high complexity of tumorigenic processes in the human stomach. Recent studies suggest that the multifaceted interplay between microbial, environmental, and host genetic factors underlies gastric tumorigenesis. Many aspects of these interactions still remain unclear. In this review, we update on recent discoveries, focusing on the roles of various gastric pathogens and gastric microbiome in tumorigenesis.
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Affiliation(s)
- Manikandan Palrasu
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Elena Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA;
| | - Alexander I. Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
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Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair. Cancers (Basel) 2021; 13:cancers13040916. [PMID: 33671606 PMCID: PMC7926742 DOI: 10.3390/cancers13040916] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary The p53 family is a complex family of transcription factors with different cellular functions that are involved in several physiological processes. A massive amount of data has been accumulated on their critical role in the tumorigenesis and the aggressiveness of cancers of different origins. If common features are observed, there are numerous specificities that may reflect particularities of the tissues from which the cancers originated. In this regard, gastric cancer tumorigenesis is rather remarkable, as it is induced by bacterial and viral infections, various chemical carcinogens, and familial genetic alterations, which provide an example of the variety of molecular mechanisms responsible for cell transformation and how they impact the p53 family. This review summarizes the knowledge gathered from over 40 years of research on the role of the p53 family in gastric cancer, which still displays one of the most elevated mortality rates amongst all types of cancers. Abstract Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.
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Esmailzadeh N, Ranaee M, Alizadeh A, Khademian A, Saber Amoli S, Sadeghi F. Presence of JC Polyomavirus in Nonneoplastic Inflamed Colon Mucosa and Primary and Metastatic Colorectal Cancer. Gastrointest Tumors 2019; 7:30-40. [PMID: 32399463 DOI: 10.1159/000504293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 10/20/2019] [Indexed: 12/24/2022] Open
Abstract
Background Despite decades of epidemiologic and histopathologic investigations, the association between JC polyomavirus (JCPyV) infection and colorectal cancer (CRC) remains controversial. Objective This study tested the presence of JCPyV sequences and determined the viral load in a series of colorectal samples from Iranian patients. In total, 223 formalin-fixed paraffin-embedded samples from patients diagnosed with primary and metastatic CRC as well as with nonneoplastic inflamed colon mucosa were analyzed by quantitative real-time PCR for the presence of JCPyV large tumor antigen (LT-Ag) sequences. Results JCPyV LT-Ag sequences were detected in 18.6% of the CRC tissues and in 15.5% of the nonneoplastic control group. Viral LT-Ag was quantified in 18/100 primary colon adenocarcinomas, 2/10 metastatic adenocarcinomas, and 1/3 primary adenocarcinomas of the rectum. Two JCPyV-positive metastatic tumors presented a negative test result for JCPyV in the corresponding primary tumor. The median JCPyV LT-Ag copy number was 64 × 10<sup>-2</sup> per cell and 14 × 10<sup>-2</sup> per cell in the CRC cases and the nonneoplastic samples, respectively. There was no statistically significant difference between the two study groups regarding median LT-Ag DNA load (p = 0.059). Among the JCPyV-positive samples, the LT-Ag DNA load was higher in 2 metastatic tumors (from a patient with lung metastasis: 232 × 10<sup>-2</sup> copies per cell; from a patient with liver metastasis: 121 × 10<sup>-2</sup> copies per cell). Conclusions The detection of JCPyV DNA at low copy numbers (lower than 1 viral copy per cell equivalent) and the absence of viral sequences in the corresponding primary tumors of the JCPyV-positive metastatic samples weaken the hypothesis of an etiological role of JCPyV in primary CRC induction.
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Affiliation(s)
- Nadia Esmailzadeh
- Department of Microbiology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Ranaee
- Department of Pathology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ahad Alizadeh
- Metabolic Diseases Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Aynaz Khademian
- Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Saghar Saber Amoli
- Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Haghi Navand A, Teimoori A, Makvandi M, Nisi N, Seyedian SS, Ranjbari N, Ahmadi Angali K, Keyani H, Tabasi M, Pourjabari K. Study on JV Virus in Patients with Colon Cancer Type
Adenocarcinoma. Asian Pac J Cancer Prev 2019; 20:1147-1151. [PMID: 31030488 PMCID: PMC6948910 DOI: 10.31557/apjcp.2019.20.4.1147] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Introduction: Colorectal cancer is the most repetitious malignancies with high mortality worldwide. JC virus (JCV) is ubiquitous Polyomavirus, with seroprevalence rates ranging from 70% to 90% in adult population. Recently the role of JCV have been reported in many malignant tumors worldwide. The association of JCV was reported in patients with colon and rectum cancers. Thus this study was conducted to evaluate the association of JCV DNA in patients with colon cancer type Adenocarcinoma. Material and Methods: A total of 120 formalin-fixed paraffin-embedded tissue blocks samples were collected including 20/40(50%) males, 20/40(50%) females patients with Colorectal Cancer(CRC), and 80 (50% males, 50% females) patients with benign tumor as a control. DNA was extracted for all the samples. Nested PCR was carried out for detection of Vp1/T-Ag junction genome in JCV genome by Nested-PCR assay. Randomly, PCR products of 6 samples were sequenced to analysis the partial JCV DNA. The phylogeny tree was constructed to determine homology identity with other JCV. Results: 4/40(10%) samples of test group and 10/80 (12.5%) of control samples were positive for JCV DNA (P= 0.69). Out of 4 samples positive for JC DNA, 3(7.5%) were males and 1(2.4%) female (P=0.29). The frequency of JCV DNA in age group> 50 years was 4/32(10%), while in age group <50 years was 0/8 (0%) (p= 0.29). Conclusion: prevalence of JCV DNA was among 10% patients with CRC and 12.5% benign tumors (p=0.69). The distribution of JCV DNA was among 7.5% male and 2.5% female (p= 0.29). The frequency of JCV DNA was among 10% cases of age group >50 years and 0% of age group <50 years (P= 0.29). The subsequent T-Ag protein expression might explain the increased risk of colorectal cancer and requires further investigation.
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Affiliation(s)
- Azadeh Haghi Navand
- Infectious and Tropical Diseases Research Center Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. manoochehrmakvandi299@ gmail.com,Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Teimoori
- Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Manoochehr Makvandi
- Infectious and Tropical Diseases Research Center Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. manoochehrmakvandi299@ gmail.com,Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nilofar Nisi
- Infectious and Tropical Diseases Research Center Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. manoochehrmakvandi299@ gmail.com,Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Saeid Seyedian
- Alimentary Tract Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nastarn Ranjbari
- Department of Pathology, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kambiz Ahmadi Angali
- Department of Biostatistic, School of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hadis Keyani
- Infectious and Tropical Diseases Research Center Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. manoochehrmakvandi299@ gmail.com
| | - Maryam Tabasi
- Infectious and Tropical Diseases Research Center Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. manoochehrmakvandi299@ gmail.com
| | - Keyvan Pourjabari
- Infectious and Tropical Diseases Research Center Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. manoochehrmakvandi299@ gmail.com
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8
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Charostad J, Astani A, Goudarzi H, Faghihloo E. DNA methyltransferases in virus-associated cancers. Rev Med Virol 2018; 29:e2022. [PMID: 30511446 DOI: 10.1002/rmv.2022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 10/24/2018] [Accepted: 10/24/2018] [Indexed: 12/19/2022]
Abstract
Human tumor viruses are either casually linked or contribute in the development of human cancers. Viruses can stimulate oncogenesis through affecting diverse biological pathways in human cells. Growing data have demonstrated frequent involvement of one of the most characteristic parts of cellular epigenetic machinery, DNA methylation, in the oncogenesis. DNA methylation of cellular genes is catalyzed by DNA methyltransferases (DNMTs) as a key effector enzyme in this process. Dysregulation of DNMTs can cause aberrant gene methylation in promoter of cancer-related genes including tumor suppressor genes, resulting in gene silencing. In this regard, the role of tumor viruses is remarkable. Here, in this review, we used published information to elucidate whether tumor viruses are able to manipulate DNMT regulation, and if so, what are its consequences in the process of oncogenesis. This essay also aims to shed light on which cellular pathways have been engaged by viruses to induce DNMTs.
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Affiliation(s)
- Javad Charostad
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Akram Astani
- Zoonotic Diseases Research Center, School of Public Health, Sahid Sadoughi University of Medical Sciences, Yazd, Iran.,Department of Microbiology, Shahid Sadoghi University of Medical Science, Yazd, Iran
| | - Hossein Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Fattahi S, Kosari‐Monfared M, Ghadami E, Golpour M, Khodadadi P, Ghasemiyan M, Akhavan‐Niaki H. Infection‐associated epigenetic alterations in gastric cancer: New insight in cancer therapy. J Cell Physiol 2018; 233:9261-9270. [DOI: 10.1002/jcp.27030] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 06/25/2018] [Indexed: 12/11/2022]
Abstract
Gastric cancer risk is higher for malignancies motivated by bacterial and viral infections. Epigenetic abnormalities including DNA methylation, histone modifications, and noncoding RNAs are important regulatory key players in gastric cancer development in infected patients. Epigenetic memory restoration is an extremely interesting phenomenon which should be considered in therapeutic approaches. In vitro and in vivo antiviral treatments in combination with epigenetic therapeutic strategies along with standard chemotherapy revealed promising outcomes in gastric cancer prevention and treatment. This review summarizes our current understanding of the gastric cancer infections and epigenetic alterations caused by these agents. We focus on studies highlighting recent advances in epigenetic restoration by target specific drugs and present also a comprehensive overview of effective antiviral drug treatments against gastric cancer.
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Affiliation(s)
- Sadegh Fattahi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences Babol Iran
- North Research Center, Pasteur Institute Amol Iran
| | | | - Elham Ghadami
- Department of Genetics Faculty of Medicine, Babol University of Medical Sciences Babol Iran
| | - Monireh Golpour
- Molecular and Cell Biology Research Center, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Science Sari Iran
| | - Parastoo Khodadadi
- Department of Genetics Faculty of Medicine, Babol University of Medical Sciences Babol Iran
| | - Mohammad Ghasemiyan
- Department of Genetics Faculty of Medicine, Babol University of Medical Sciences Babol Iran
| | - Haleh Akhavan‐Niaki
- Department of Genetics Faculty of Medicine, Babol University of Medical Sciences Babol Iran
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10
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Yazdani Cherati A, Yahyapour Y, Ranaee M, Rajabnia M, Shokri Shirvani J, Hajiahmadi M, Sadeghi F. No Evidence for an Association between JC Polyomavirus Infection and Gastroduodenal Diseases. Gastrointest Tumors 2018; 5:47-53. [PMID: 30574481 DOI: 10.1159/000489928] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 05/05/2018] [Indexed: 12/20/2022] Open
Abstract
Background Helicobacter pylori (HP) infection is one of the hypothesized infectious etiologies of gastric cancer (GC) and other gastroduodenal diseases. It was suggested that other infectious agents, including oncogenic viruses, may increase the risk of gastroduodenal diseases. A number of reports regarding JC polyomavirus (JCPyV) have shown that JCPyV could be implicated in colorectal cancer and gastrointestinal carcinogenesis. Objective The current investigation aimed to investigate whether JCPyV could have any association with the pathogenesis of gastroduodenal diseases either alone or together with HP. Methods A total of 237 fresh or formalin-fixed and paraffin-embedded gastroduodenal samples were examined by quantitative real-time polymerase chain reaction targeting the JCPyV large tumor antigen (LTag) oncogene, and viral load was determined as viral copy number/cell. Results In total, 2 out of 237 samples (0.8%) were positive for JCPyV LTag DNA. One positive sample derived from diffuse-type gastric adenocarcinoma (6.8 × 10-3 copies/cell) and other JCPyV-positive sample obtained from a patient with gastritis (2.5 × 10-3 copies/cell) were recorded. Both JCPyV-positive samples were negative for HP infection. Conclusion This study suggests no association between JCPyV infection and GC or other gastroduodenal diseases. The very low frequency of JCPyV LTag sequences in GC is an important aspect that weakens the hypothesis of the pathogenic role of JCPyV in gastric tumor induction.
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Affiliation(s)
| | - Yousef Yahyapour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Ranaee
- Department of Pathology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Rajabnia
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Javad Shokri Shirvani
- Department of Internal Medicine, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mahmoud Hajiahmadi
- Department of Community Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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11
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Costa NR, Gil da Costa RM, Medeiros R. A viral map of gastrointestinal cancers. Life Sci 2018; 199:188-200. [PMID: 29476768 DOI: 10.1016/j.lfs.2018.02.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/16/2018] [Indexed: 12/12/2022]
Abstract
Cancers of the gastrointestinal tract (GIT) are expected to account for approximately 20% of all cancers in 2017. Apart from their high incidence, GIT cancers show high mortality rates, placing these malignancies among the most prominent public health issues of our time. Cancers of the GIT are the result of a complex interplay between host genetic factors and environmental factors and frequently arise in the context of a continued active inflammatory response. Several tumor viruses are able to elicit such chronic inflammatory responses. In fact, several viruses have an impact on GIT tumor initiation and progression, as well as on patients' response to therapy and prognosis, through direct and indirect mechanisms. In this review, we have gathered information on different viruses' rates of infection, viral-driven specific carcinogenesis mechanisms and viral-related impact on the prognosis of cancers of the GIT (specifically in organs that have an interface with the environment - esophagus, stomach, intestines and anus). Overall, while some viral infections show a strong causal relation with specific gastrointestinal cancers, these represent a relatively small fraction of GIT malignancies. Other types of cancer, like Esophageal Squamous Cell Carcinoma, require further studies to confirm the carcinogenic role of some viral agents.
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Affiliation(s)
- Natália R Costa
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal.
| | - Rui M Gil da Costa
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; LEPABE, Faculty of Engineering, University of Porto, Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal; CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal; Research Department, Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), Porto, Portugal
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12
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Delbue S, Comar M, Ferrante P. Review on the role of the human Polyomavirus JC in the development of tumors. Infect Agent Cancer 2017; 12:10. [PMID: 28174598 PMCID: PMC5292005 DOI: 10.1186/s13027-017-0122-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 01/24/2017] [Indexed: 12/12/2022] Open
Abstract
Almost one fifth of human cancers worldwide are associated with infectious agents, either bacteria or viruses, and this makes the possible association between infections and tumors a relevant research issue. We focused our attention on the human Polyomavirus JC (JCPyV), that is a small, naked DNA virus, belonging to the Polyomaviridae family. It is the recognized etiological agent of the Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease, occurring in immunosuppressed individuals. JCPyV is able to induce cell transformation in vitro when infecting non-permissive cells, that do not support viral replication and JCPyV inoculation into small animal models and non human primates drives to tumor formation. The molecular mechanisms involved in JCPyV oncogenesis have been extensively studied: the main oncogenic viral protein is the large tumor antigen (T-Ag), that is able to bind, among other cellular factors, both Retinoblastoma protein (pRb) and p53 and to dysregulate the cell cycle, but also the early proteins small tumor antigen (t-Ag) and Agnoprotein appear to cooperate in the process of cell transformation. Consequently, it is not surprising that JCPyV genomic sequences and protein expression have been detected in Central Nervous System (CNS) tumors and colon cancer and an association between this virus and several brain and non CNS-tumors has been proposed. However, the significances of these findings are under debate because there is still insufficient evidence of a casual association between JCPyV and solid cancer development. In this paper we summarized and critically analyzed the published literature, in order to describe the current knowledge on the possible role of JCPyV in the development of human tumors.
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Affiliation(s)
- Serena Delbue
- Department of Biomedical, Surgical and Dental Sciences, University of Milano, Via Pascal, 36-20133 Milan, Italy
| | - Manola Comar
- Department of Medical Sciences, University of Trieste, Trieste, Italy.,Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy
| | - Pasquale Ferrante
- Department of Biomedical, Surgical and Dental Sciences, University of Milano, Via Pascal, 36-20133 Milan, Italy.,Istituto Clinico Città Studi, Milan, Italy
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Mouh FZ, Mzibri ME, Slaoui M, Amrani M. Recent Progress in Triple Negative Breast Cancer Research. Asian Pac J Cancer Prev 2017; 17:1595-608. [PMID: 27221827 DOI: 10.7314/apjcp.2016.17.4.1595] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is defined as a type of breast carcinoma that is negative for expression of oestrogene and progesterone hormone receptors (ER, PR) and HER2. This form of breast cancer is marked by its aggressiveness, low survival rate and lack of specific therapies. Recently, important molecular characteristics of TNBC have been highlighted and led to the identification of some biomarkers that could be used in diagnosis, as therapeutic targets or to assess the prognosis. In this review, we summarize recent progress in TNBC research focusing on the genetic and epigenetic alterations of TNBC and the potential use of these biomarkers in the targeted therapy for better management of TNBC.
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Affiliation(s)
- Fatima Zahra Mouh
- Equipe deRecherche ONCOGYMA, University of Mohamed V, Faculty of Medicine and Pharmacy of Rabat Morocco E-mail :
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Sinagra E, Raimondo D, Gallo E, Stella M, Cottone M, Orlando A, Rossi F, Orlando E, Messina M, Tomasello G, Lo Monte AI, La Rocca E, Rizzo AG. Could JC virus provoke metastasis in colon cancer? World J Gastroenterol 2014; 20:15745-15749. [PMID: 25400458 PMCID: PMC4229539 DOI: 10.3748/wjg.v20.i42.15745] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 05/05/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the prevalence of John Cunningham virus (JC virus) in a small cohort of patients with colon cancer and to assess its presence in hepatic metastasis. METHODS Nineteen consecutive patients with histologically diagnosed colon cancer were included in our study, together with ten subjects affected by histologically and serologically diagnosed hepatitis C virus infection. In the patients included in the colon cancer group, JC virus was searched for in the surgical specimen; in the control group, JC virus was searched for in the hepatic biopsy. The difference in the prevalence of JC virus in the hepatic biopsy between the two groups was assessed through the χ(2) test. RESULTS Four out of 19 patients with colon cancer had a positive polymerase chain reaction (PCR) test for JC virus, and four had liver metastasis. Among the patients with liver metastasis, three out of four had a positive PCR test for JC virus in the surgical specimen and in the liver biopsy; the only patient with liver metastasis with a negative test for JC virus also presented a negative test for JC virus in the surgical specimen. In the control group of patients with hepatitis C infection, none of the ten patients presented JC virus infection in the hepatic biopsy. The difference between the two groups regarding JC virus infection was statistically significant (χ(2) = 9.55, P = 0.002). CONCLUSION JC virus may play a broader role than previously thought, and may be mechanistically involved in the late stages of these tumors.
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Activation of c-Myc and Cyclin D1 by JCV T-Antigen and β-catenin in colon cancer. PLoS One 2014; 9:e106257. [PMID: 25229241 PMCID: PMC4167695 DOI: 10.1371/journal.pone.0106257] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Accepted: 07/30/2014] [Indexed: 12/17/2022] Open
Abstract
During the last decade, mounting evidence has implicated the human neurotropic virus JC virus in the pathology of colon cancer. However, the mechanisms of JC virus-mediated oncogenesis are still not fully determined. One candidate to mediate these effects is the viral early transcriptional product T-Antigen, which has the ability to inactivate cell cycle regulatory proteins such as p53. In medulloblastomas, T-Antigen has been shown to bind the Wnt signaling pathway protein β-catenin; however, the effects of this interaction on downstream cell cycle regulatory proteins remain unknown. In light of these observations, we investigated the association of T-Antigen and nuclear β-catenin in colon cancer cases and the effects of this complex in the activation of the transcription and cell cycle regulators c-Myc and Cyclin D1 in vitro. Gene amplification demonstrated the presence of viral sequences in 82.4% of cases and we detected expression of T-Antigen in 64.6% of cases by immunohistochemistry. Further, we found that T-Antigen and β-catenin co-localized in the nuclei of tumor cells and we confirmed the physical binding between these two proteins in vitro. The nuclear presence of T-Antigen and β-catenin resulted in the significant enhancement of TCF-dependent promoter activity and activation of the β-catenin downstream targets, c-Myc and Cyclin D1. These observations provide further evidence for a role of JCV T-Antigen in the dysregulation of the Wnt signaling pathway and in the pathogenesis of colon cancer.
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Hampras SS, Viscidi RP, Helzlsouer KJ, Lee JH, Fulp WJ, Giuliano AR, Platz EA, Rollison DE. Prospective study of seroreactivity to JC virus T-antigen and risk of colorectal cancers and adenomas. Cancer Epidemiol Biomarkers Prev 2014; 23:2591-6. [PMID: 25128403 DOI: 10.1158/1055-9965.epi-14-0370] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
John Cunningham virus (JCV) is a common polyomavirus classified as a possible carcinogen by the International Agency for Research on Cancer. JCV may play a role in colorectal carcinogenesis, although we previously reported no association between JCV capsid antibodies and colorectal cancer. No studies have examined the role of seroreactivity to JCV T-antigen (T-Ag) oncoprotein in colorectal cancer. A case-control study nested within a community-based prospective cohort (CLUE II) was conducted. In 1989, 25,080 residents of Washington County, Maryland, were enrolled in CLUE II, completing baseline questionnaires and providing blood samples. At follow-up, 257 incident colorectal cancer cases were identified by linkage to population-based cancer registries through 2006 and matched to controls on age, sex, race, and date of blood draw. One hundred and twenty-three colorectal adenoma cases were identified through self-report during follow-up and matched to controls on age, sex, race, date of blood draw, and colorectal cancer screening. Baseline serum samples were tested for seroreactivity to JCV T-Ag. Associations between JCV T-Ag seroreactivity and colorectal cancer/adenomas were evaluated using conditional logistic regression models. Overall, seroreactivity to JCV T-Ag was not statistically significantly associated with the risk of either colorectal cancer [OR, 1.34; 95% confidence interval (CI), 0.89-2.01] or adenoma (OR, 1.30; 95% CI, 0.70-2.42), while a borderline association with colorectal cancer was observed among women (OR, 1.82; 95% CI, 1.00-3.31). Our past evaluation of JCV capsid seropositivity, combined with current findings, does not support a notable etiologic role for JCV infection in colorectal cancer.
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Affiliation(s)
- Shalaka S Hampras
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida
| | - Raphael P Viscidi
- Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Kathy J Helzlsouer
- Center for Prevention and Research, Mercy Medical Center, Baltimore, Maryland
| | - Ji-Hyun Lee
- University of New Mexico Cancer Center, Albuquerque, New Mexico
| | - William J Fulp
- Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida
| | - Anna R Giuliano
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Dana E Rollison
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
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Butcher LD, Garcia M, Arnold M, Ueno H, Goel A, Boland CR. Immune response to JC virus T antigen in patients with and without colorectal neoplasia. Gut Microbes 2014; 5:468-75. [PMID: 25007286 PMCID: PMC5515464 DOI: 10.4161/gmic.29573] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
JC virus (JCV) is a polyomavirus that infects approximately 75% of the population and encodes a T antigen (T-Ag) gene, which is oncogenic and inactivates the p53 and pRb/p107/p130 protein families. Previous work in our lab has identified the presence of T-Ag in colorectal neoplasms. While JCV remains in a latent state for the majority of those infected, we hypothesized that a disturbance in immunological control may permit JCV to reactivate, which may be involved in the development of colorectal neoplasia. Our aim was to determine the cell mediated immune response to JCV T-Ag, and determine if it is altered in patients with colorectal adenomatous polyps (AP) or cancers (CRC). Peripheral blood mononuclear cells (PBMCs) isolated from the blood of patients undergoing colonoscopy or colorectal surgery were stimulated by a peptide library covering the entire T-Ag protein of JCV. Cytokine production and T cell proliferation were evaluated following T-Ag stimulation using Luminex and flow cytometry assays. JCV T-Ag peptides stimulated secretion of IL-2, which induced T cell expansion in all three groups. However, stronger IL-10 and IL-13 production was seen in patients without colorectal neoplasms. IP-10 was produced at very high levels in all groups, but not significantly differently between groups. Most patients exhibited CD4(+) and CD8(+) T cells in response to stimulation by the T-Ag clusters. The combination of IL-2 and IP-10 secretion indicates the presence of T-Ag-specific Th1 cells in all patients, which is higher in patients without carcinoma.
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Affiliation(s)
- Lindsay D Butcher
- Institute of Biomedical Studies; Baylor University; Waco, TX USA,Gastrointestinal Cancer Research Laboratory; Baylor Research Institute and Charles A. Sammons Cancer Center; Baylor University Medical Center; Dallas, TX USA
| | - Melissa Garcia
- Gastrointestinal Cancer Research Laboratory; Baylor Research Institute and Charles A. Sammons Cancer Center; Baylor University Medical Center; Dallas, TX USA
| | - Mildred Arnold
- Gastrointestinal Cancer Research Laboratory; Baylor Research Institute and Charles A. Sammons Cancer Center; Baylor University Medical Center; Dallas, TX USA
| | - Hideki Ueno
- Baylor Institute for Immunology Research; Baylor Research Institute; Baylor University Medical Center; Dallas, TX USA
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory; Baylor Research Institute and Charles A. Sammons Cancer Center; Baylor University Medical Center; Dallas, TX USA
| | - C Richard Boland
- Gastrointestinal Cancer Research Laboratory; Baylor Research Institute and Charles A. Sammons Cancer Center; Baylor University Medical Center; Dallas, TX USA,Correspondence to: C Richard Boland;
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The role of inflammation in gastric cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 816:235-57. [PMID: 24818726 DOI: 10.1007/978-3-0348-0837-8_10] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastric cancer, despite its declining incidence rate, is still the second cause of cancer-related death worldwide, killing 750,000 people each year and remaining the second common type of cancer. The best examples of inflammation-associated cancer in human beings may be gastric cancer. Understanding the molecular mechanism of the inflammation in gastric carcinogenesis is important for developing new strategies against gastric cancer.
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Souza DSM, Piazza RS, Pilotto MR, Nascimento MDAD, Moresco V, Taniguchi S, Leal DAG, Schmidt ÉC, Cargin-Ferreira E, Bícego MC, Sasaki ST, Montone RC, de Araujo RA, Franco RMB, Bouzon ZL, Bainy ACD, Barardi CRM. Virus, protozoa and organic compounds decay in depurated oysters. Int J Food Microbiol 2013; 167:337-45. [DOI: 10.1016/j.ijfoodmicro.2013.09.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 09/24/2013] [Accepted: 09/26/2013] [Indexed: 11/17/2022]
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Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 2012; 25:471-506. [PMID: 22763635 DOI: 10.1128/cmr.05031-11] [Citation(s) in RCA: 299] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.
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Chiaravalli AM, Longhi E, Vigetti D, De Stefano FI, Deleonibus S, Capella C, Solcia E, Parravicini C. Gastrointestinal cancers reactive for the PAb416 antibody against JCV/SV40 T-Ag lack JCV DNA sequences while showing a distinctive pathologic profile. J Clin Pathol 2012; 66:44-9. [PMID: 23012397 DOI: 10.1136/jclinpath-2012-200963] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIM Immunohistochemical and molecular studies have suggested an oncogenic role for JCV in gastrointestinal carcinomas, but at least in colorectal cancers, the data are far from being unambiguous. METHODS Two large series of formalin-fixed paraffin-embedded gastric and colorectal cancers were analysed for the expression of JCV large T Antigen (T-Ag) with a panel of five antibodies, and for the presence of T-Ag DNA sequences using two PCR systems. RESULTS Intense nuclear staining was observed in 54/116 (46%) colorectal, and in 92/234 (39%) gastric cancers, using the PAb416 monoclonal antibody against large T-Ag. In colorectal cancers, PAb416-positivity was directly related to the presence of chromosomal instability, lymph node metastases and a more advanced tumour stage, and inversely related to proximal tumour site and the presence of microsatellite instability (MSI). In gastric cancers, the glandular histotype, the presence of lymph node metastases, a low frequency of MSI and EBV infection, and a worse prognosis were significantly associated with PAb416 immunoreactivity. Moreover, at both these sites, PAb416 expression was significantly associated with p53 nuclear accumulation. No positivity was obtained with all the other four anti-T-Ag-antibodies, and molecular analysis failed to demonstrate the presence of JCV DNA sequences in tested cases. CONCLUSIONS Our immunohistochemical and molecular results do not support the idea that JCV T-Ag has a role in gastrointestinal carcinogenesis. It is possible that PAb416, besides binding the viral protein, may cross-react with a hitherto undefined protein whose expression is associated with a distinct pathological profile and, at least in gastric cancers, with worse prognosis.
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Aituov B, Duisembekova A, Bulenova A, Alibek K. Pathogen-driven gastrointestinal cancers: Time for a change in treatment paradigm? Infect Agent Cancer 2012; 7:18. [PMID: 22873119 PMCID: PMC3508868 DOI: 10.1186/1750-9378-7-18] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 07/27/2012] [Indexed: 02/06/2023] Open
Abstract
The regulation of cancerous tumor development is converged upon by multiple pathways and factors. Besides environmental factors, gastrointestinal (GI) tract cancer can be caused by chronic inflammation, which is generally induced by bacteria, viruses, and parasites. The role of these inducers in cancer development, cell differentiation and transformation, cell cycle deregulation, and in the expression of tumor-associated genes cannot be ignored. Although Helicobacter pylori activates many oncogenic pathways, particularly those in gastric and colorectal cancers, the role of viruses in tumor development is also significant. Viruses possess significant oncogenic potential to interfere with normal cell cycle control and genome stability, stimulating the growth of deregulated cells. An increasing amount of recent data also implies the association of GI cancers with bacterial colonization and viruses. This review focuses on host-cell interactions that facilitate primary mechanisms of tumorigenesis and provides new insights into novel GI cancer treatments.
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Affiliation(s)
- Bauyrzhan Aituov
- Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana 010000, Kazakhstan
| | - Assem Duisembekova
- Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana 010000, Kazakhstan
| | - Assel Bulenova
- Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana 010000, Kazakhstan
| | - Kenneth Alibek
- Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana 010000, Kazakhstan
- Republican Scientific Center for Emergency Care, 3 Kerey and Zhanibek Khan Street, Astana 010000, Kazakhstan
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Hachana M, Amara K, Ziadi S, Gacem RB, Korbi S, Trimeche M. Investigation of human JC and BK polyomaviruses in breast carcinomas. Breast Cancer Res Treat 2012; 133:969-77. [PMID: 22108781 DOI: 10.1007/s10549-011-1876-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 11/04/2011] [Indexed: 11/30/2022]
Abstract
We have previously showed the presence of the simian virus 40 (SV40) and the mouse mammary tumor virus (MMTV)-like in a significant proportions of Tunisian breast carcinomas. However, to date there are no published studies concerning evaluation of the possible implication of the human polyomaviruses JC (JCV) and BK (BKV) in breast carcinomas. The presence of JCV and BKV DNA was investigated by PCR in a 123 primary breast carcinomas and matched adjacent non-tumor breast tissues. The results were correlated to clinicopathological and virological parameters. JCV T-antigen DNA was detected in 23% of breast carcinoma cases; however, all cases were negative for BKV. JCV T antigen PCR products were further confirmed as authentic JCV genome by direct sequencing. JCV was found in invasive ductal carcinomas (28/112 cases) but not in invasive lobular carcinomas (0/5) or medullary carcinomas (0/6). JCV DNA presence correlates inversely with the expression of estrogen (P = 0.022) and progesterone (P = 0.008) receptors. JCV DNA presence correlates also with "triple negative" phenotype (P = 0.021). With regard to virological data, a trend toward an inverse correlation was noted between the presence of JCV and SV40 (P = 0.06). Moreover, significant correlation was found between multiple viral infection (JCV, and/or SV40, and/or MMTV-like in the same tumor) and "triple negative" phenotype (P = 0.001) and also with p53 accumulation (P = 0.028). To the best of our knowledge, this is the first study demonstrating the presence of JCV in a subset of breast carcinomas. Also our results suggest that "triple negative" breast carcinomas are viral-related tumors.
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Affiliation(s)
- Mohamed Hachana
- Department of Pathology, Farhat Hached Hospital, 4000 Sousse, Tunisia
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Lucchese G. A peptide talk between JC virus and the human host: from silent infection to autoimmunity. Immunopharmacol Immunotoxicol 2012; 34:1067-74. [PMID: 22594935 DOI: 10.3109/08923973.2012.686510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Analysis of JC virus (JCV) polyprotein for peptide sharing with the human proteome reveals that the virus has hundreds of pentapeptide sequences in common with the human proteins. The datum is interesting in light of the fundamental role exerted by short amino acid sequences in protein-protein interactions and, consequently, in biochemical reactions and immune recognition. Searching for new approaches to understand the JCV infection scenarios, from the immunoevasion phenomenon underlying the viral asymptomatic stay in the human host to the (re)activation phase and associated pathogenic sequelae, the present study describes the diffuse pentapeptide communication network between JCV and the human host.
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Affiliation(s)
- Guglielmo Lucchese
- Department of Biochemistry and Molecular Biology, University of Bari, Italy.
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Wang JP, Wang ZZ, Zheng YS, Xia P, Yang XH, Liu YP, Takano Y, Zheng HC. JC virus existence in Chinese gastrointestinal carcinomas. Oncol Lett 2012; 3:1073-1078. [PMID: 22783394 DOI: 10.3892/ol.2012.627] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 12/16/2011] [Indexed: 11/05/2022] Open
Abstract
The John Cunningham virus (JCV) infects a large proportion of the population worldwide and may cause progressive multifocal leukoencephalopathy upon immunodeficiency. Recent reports provided evidence of its oncogenetic role in malignancies. In this study, JCV was examined by targeting T antigen, viral protein and agnoprotein in paraffin-embedded or frozen gastrointestinal carcinomas and paired non-neoplastic mucosa (NNM) samples by nested-PCR followed by Southern blot analysis. In addition, the expression of JCV T antigen, ki-67, caspase-3, p53, Rb and β-catenin was studied by immunohistochemistry on tissue microarrays. The positive rate of JCV T antigen was higher in paraffin-embedded gastrointestinal carcinomas compared to adjacent NNM by nested-PCR followed by Southern blot analysis (36.9 vs. 16.9%, P<0.05), while there was no difference in other viral oncogenes regardless of whether they were paraffin-embedded or frozen samples. Immunohistochemically, T antigen was detectable in 9.6% (13/135) of carcinoma cases, which was higher than its positive rate in NNM (0.8%, 1/126, P<0.01). However, the genomic JCV DNA existence or its T antigen expression was not correlated with age, gender, tumor size, histological types, lymph node metastasis, expression of ki-67, caspase-3, p53, Rb and β-catenin of gastric carcinomas (P>0.05). In conlusion, JCV T antigen may be involved in gastrointestinal carcinogenesis as an oncogene in China.
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Affiliation(s)
- Jian-Ping Wang
- Department of Biochemistry and Molecular Biology, Institute of Pathology and Physiology, College of Basic Medicine, China Medical University, Shenyang 110001, P.R. China
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Lee SS, Jung WT, Kim CY, Ha CY, Min HJ, Kim HJ, Kim TH. The synchronous prevalence of colorectal neoplasms in patients with stomach cancer. JOURNAL OF THE KOREAN SOCIETY OF COLOPROCTOLOGY 2011; 27:246-51. [PMID: 22102975 PMCID: PMC3218129 DOI: 10.3393/jksc.2011.27.5.246] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2011] [Accepted: 08/05/2011] [Indexed: 12/21/2022]
Abstract
Purpose The association between stomach cancer and colorectal cancer is controversial. The purpose of this study was to determine the synchronous prevalence of colorectal neoplasms in patients with stomach cancer. Methods A total of 123 patients with stomach cancer (86 male) and 246 consecutive, age- and sex-matched persons without stomach cancer were analyzed from July 2005 to June 2010. All of them underwent colonoscopy within 6 months after undergoing gastroscopy. Results The prevalence of colorectal neoplasms was significantly higher in the stomach cancer group (35.8%) than in the control group (17.9%) (P < 0.001). Colorectal neoplasms were more prevalent in the patients with stomach cancer (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.71 to 5.63). In particular, the difference in the prevalence of colorectal neoplasms was more prominent in the patients above 50 years old (OR, 3.54; 95% CI, 1.80 to 6.98). Conclusion The results showed that the synchronous prevalence of colorectal neoplasms was higher in patients with stomach cancer than in those without stomach cancer. Therefore, patients with stomach cancer should be regarded as a high-risk group for colorectal neoplasms, and colonoscopy should be recommended for screening.
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Affiliation(s)
- Sang Su Lee
- Department of Internal Medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea
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Shen CH, Wu JD, Hsu CD, Jou YC, Lin CT, Wang M, Wu SF, Chan MW, Chiang MK, Fang CY, Chang D. The high incidence of JC virus infection in urothelial carcinoma tissue in Taiwan. J Med Virol 2011; 83:2191-9. [DOI: 10.1002/jmv.22240] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Chang CF, Wang M, Ou WC, Chen PL, Shen CH, Lin PY, Fang CY, Chang D. Human JC virus-like particles as a gene delivery vector. Expert Opin Biol Ther 2011; 11:1169-75. [DOI: 10.1517/14712598.2011.583914] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Ramamoorthy S, Devaraj B, Miyai K, Luo L, Liu YT, Boland CR, Goel A, Carethers JM. John Cunningham virus T-antigen expression in anal carcinoma. Cancer 2010; 117:2379-85. [PMID: 24048785 DOI: 10.1002/cncr.25793] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Revised: 10/07/2010] [Accepted: 10/11/2010] [Indexed: 12/29/2022]
Abstract
BACKGROUND Anal carcinoma is thought to be driven by human papillomavirus (HPV) infection through interrupting function of cell regulatory proteins such as p53 and pRb. John Cunningham virus (JCV) expresses a T-antigen that causes malignant transformation through development of aneuploidy and interaction with some of the same regulatory proteins as HPV. JCV T-antigen is present in brain, gastric, and colon malignancies, but has not been evaluated in anal cancers. The authors examined a cohort of anal cancers for JCV T-antigen and correlated this with clinicopathologic data. METHODS Archived anal carcinomas were analyzed for JCV T-antigen expression. DNA from tumor and normal tissue was sequenced for JCV with viral copies determined by quantitative polymerase chain reaction and Southern blotting. HPV and microsatellite instability (MSI) status was correlated with JCV T-antigen expression. RESULTS Of 21 cases of anal cancer (mean age 49 years, 38% female), 12 (57%) were in human immunodeficiency virus (HIV)-positive individuals. All 21 cancers expressed JCV T-antigen, including 9 HPV-negative specimens. More JCV copies were present in cancer versus surrounding normal tissue (mean 32.54 copies/μg DNA vs 2.98 copies/μg DNA, P = .0267). There was no correlation between disease stage and viral copies, nor between viral copies and HIV-positive or -negative status (28.7 vs 36.34 copies/μg DNA, respectively, P = .7804). In subset analysis, no association was found between JCV T-antigen expression and HPV or MSI status. CONCLUSIONS Anal carcinomas uniformly express JCV T-antigen and contain more viral copies compared with surrounding normal tissue. JCV and its T-antigen oncogenic protein, presumably through interruption of cell regulatory proteins, may play a role in anal cancer pathogenesis.
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Affiliation(s)
- Sonia Ramamoorthy
- Department of Surgery, University of California, San Diego, California; Moores Comprehensive Cancer Center, University of California, San Diego, California
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Bellizzi A, Barucca V, Di Nardo G, Fioriti F, Iebba V, Schippa S, Conte M, Checchi MP, Colosimo M, Cucchiara S, Oliva S, Chiarini F, Pietropaolo V. JC Viral Reactivation in a Pediatric Patient with Crohn's Disease. Int J Immunopathol Pharmacol 2010; 23:955-959. [DOI: 10.1177/039463201002300333] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023] Open
Abstract
This is a report concerning human polyomavirus JC (JCV) reactivation in a pediatric patient with Crohn's disease (CD) during the treatment with 5-aminosalicylic acid (5-ASA), a non-steroidal anti-inflammatory drug (NSAID). We examined 9 bioptic samples from three different bowel districts (ileum, cecum, rectum) of this child. These samples were analyzed by Quantitative PCR (Q-PCR) to investigate the presence of JCV DNA. JCV DNA was detected in one rectum biopsy taken two months after 5-ASA treatment. Although our result must be validated in a larger group of subjects and with a longer follow-up period, it underlines the importance of JCV monitoring in CD patients.
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Affiliation(s)
| | | | - G. Di Nardo
- Department of Pediatrics, “Sapienza” University, Rome
| | - F. Fioriti
- National Institute for Infectious Diseases “Lazzaro Spallanzani”, Rome, Italy
| | | | | | | | | | | | - S. Cucchiara
- Department of Pediatrics, “Sapienza” University, Rome
| | - S. Oliva
- Department of Pediatrics, “Sapienza” University, Rome
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31
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Efficient gene transfer using the human JC virus-like particle that inhibits human colon adenocarcinoma growth in a nude mouse model. Gene Ther 2010; 17:1033-41. [PMID: 20410928 DOI: 10.1038/gt.2010.50] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The JC virus (JCV) may infect human oligodendrocytes and consequently cause progressive multifocal leukoencephalopathy (PML) in patients with immune deficiency. In addition, the virus has also been detected in other human tissues, including kidney, B lymphocytes, and gastrointestinal tissue. The recombinant major structural protein, VP1, of JCV is able to self-assemble to form a virus-like particle (VLP). It has been shown that the VLP is capable of packaging and delivering exogenous DNA into human cells for gene expression. However, gene transfer is not efficient when using in vitro DNA packaging methods with VLPs. In this study, a novel in vivo DNA packaging method using the JCV VLP was used to obtain high efficiency gene transfer. A reporter gene, the green fluorescence protein, and a suicide gene, the herpes simplex virus thymidine kinase (tk), were encapsidated into VLPs in Escherichia coli. The VLP was used to specifically target human colon carcinoma (COLO-320 HSR) cells in a nude mouse model. Intraperitoneal administration of ganciclovir in the tk-VLP-treated mice greatly reduced tumor volume. These findings suggest that it will be possible to develop the JCV VLP as a gene delivery vector for human colon cancer therapy in the future.
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32
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The presence of JC virus in gastric carcinomas correlates with patient's age, intestinal histological type and aberrant methylation of tumor suppressor genes. Mod Pathol 2010; 23:522-30. [PMID: 20081806 DOI: 10.1038/modpathol.2009.184] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
JC virus (JCV) is a neurotropic polyomavirus and the causative agent of progressive multifocal leukoencephalopathy. A role for JCV in gastrointestinal malignancies has been recently suggested. This study was carried out to determine the prevalence of polyomaviruses including JCV, BKV and SV40 in gastric cancers in Tunisia and to determine the clinicopathological characteristics of virus-associated gastric carcinomas. The presence of polyomaviruses DNA sequences was surveyed in 61 cases of primary gastric carcinomas and in 53 paired non-tumor gastric mucosa by PCR. Findings were correlated to clinicopathological parameters, p53 expression and methylation status of 11 tumor-related genes. Using PCR assays, JCV T-antigen sequence was more frequently detected in gastric carcinomas than in non-tumor gastric mucosa (26 vs 6%, P=0.03), while those of SV40 and BKV were not detected in any cases. Correlation analysis showed that JCV had higher frequency in patients older than 55 years (P=0.034) and in the intestinal histological type (P=0.04). With regard to methylation status, P16 and P14 showed significantly higher methylation frequencies in JCV-positive gastric carcinomas than in JCV-negative cases (P=0.007 and P=0.003, respectively). Moreover, the mean of the methylation index was significantly higher in JCV-positive than in JCV-negative cases (P=0.024). In multivariate logistic regression analysis, age of patients and the methylation index are only the two independent factors associated with JCV infection. Kaplan-Meier survival analysis showed a trend toward better survival for JCV-associated gastric carcinomas patients (log-rank, P=0.11). Our study suggests a role of JCV as cofactor in the pathogenesis of the intestinal type of gastric carcinomas in older persons.
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De Giorgio R, Ricciardiello L, Naponelli V, Selgrad M, Piazzi G, Felicani C, Serra M, Fronzoni L, Antonucci A, Cogliandro R, Barbara G, Corinaldesi R, Tonini M, Knowles C, Stanghellini V. Chronic Intestinal Pseudo-Obstruction Related to Viral Infections. Transplant Proc 2010; 42:9-14. [DOI: 10.1016/j.transproceed.2009.12.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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34
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Jang EJ, Jang JS, Kim JH, Bae HI, Suh IS. Detection of JC Virus T-Ag in Early Gastric Cancer. KOREAN JOURNAL OF PATHOLOGY 2010. [DOI: 10.4132/koreanjpathol.2010.44.5.456] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Eun Jeong Jang
- Department of Pathology, Kyungpook National University Hospital, Daegu, Korea
| | - Jung Sik Jang
- Department of Pathology, Kyungpook National University Hospital, Daegu, Korea
| | - Jae Hoon Kim
- Department of Pathology, Kyungpook National University Hospital, Daegu, Korea
| | - Han Ik Bae
- Department of Pathology, Kyungpook National University Hospital, Daegu, Korea
| | - In Soo Suh
- Department of Pathology, Kyungpook National University Hospital, Daegu, Korea
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35
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Yamaoka S, Yamamoto H, Nosho K, Taniguchi H, Adachi Y, Sasaki S, Arimura Y, Imai K, Shinomura Y. Genetic and epigenetic characteristics of gastric cancers with JC virus T-antigen. World J Gastroenterol 2009; 15:5579-5585. [PMID: 19938198 PMCID: PMC2785062 DOI: 10.3748/wjg.15.5579] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2009] [Revised: 09/18/2009] [Accepted: 09/25/2009] [Indexed: 02/06/2023] Open
Abstract
AIM To clarify the significance of JC virus (JCV) T-antigen (T-Ag) expression in human gastric cancer. METHODS We investigated the relationship between T-Ag detected by immunohistochemistry and Epstein-Barr virus (EBV) infection, microsatellite instability (MSI), and genetic and epigenetic alterations in gastric cancers. Mutations in the p53, beta-catenin, KRAS, BRAF, PIK3CA genes were analyzed by polymerase chain reaction (PCR)-single strand conformation polymorphism and DNA sequencing. Allelic losses were determined by PCR at 7 microsatellite loci. Aberrant DNA methylation was analyzed by MethyLight assay. RESULTS JCV T-Ag protein expression was found in 49% of 90 gastric cancer tissues. T-Ag positivity was not correlated with clinicopathological characteristics. T-Ag expression was detected in a similar percentage of EBV positive cancers (4 of 9, 44%) and EBV negative cancers (35 of 73, 48%). T-Ag expression was detected in a significantly lower percentage of MSI-H cancers (14%) than in non MSI-H cancers (55%, P = 0.005). T-Ag expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of beta-catenin (15 of 21, 71%) than in cancers without (42%, P = 0.018). p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers (32%) than in T-Ag negative cancers (57%, P = 0.018). T-Ag positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers (P = 0.008 and P = 0.003). CONCLUSION The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations.
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Abstract
We recently reported the frequent detection of polyomaviruses (BK virus [BKV] or simian virus 40 [SV40]) in 46% of stool samples from hospitalized children. In order to determine if adults exhibit fecal shedding of polyomavirus, single stool specimens from healthy adults were evaluated by PCR. Overall, 20 (18.2%) of 110 specimens were positive for human polyomaviruses: 9 with BKV, 9 with JC virus (JCV), 1 with SV40, and 1 with both JCV and SV40. Among the 94 subjects without immune compromise, 17 (18.1%) were excreting polyomaviruses. This shedding frequency in adults was significantly lower than that observed in children (P < 0.001). These findings support the hypothesis that the gastrointestinal tract may be a site of polyomavirus persistence, and they suggest a fecal-oral route of viral transmission.
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37
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JC virus T-antigen in colorectal cancer is associated with p53 expression and chromosomal instability, independent of CpG island methylator phenotype. Neoplasia 2009; 11:87-95. [PMID: 19107235 DOI: 10.1593/neo.81188] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Revised: 10/16/2008] [Accepted: 10/16/2008] [Indexed: 12/25/2022] Open
Abstract
JC virus has a transforming gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize beta-catenin. A link between JCVT and CpG island methylator phenotype (CIMP) has been suggested. However, no large-scale study has examined the relations of JCVT with molecular alterations, clinical outcome, or prognosis in colon cancer. We detected JCVT expression (by immunohistochemistry) in 271 (35%) of 766 colorectal cancers. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other loci (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight. We examined loss of heterozygosity in 2p, 5q, 17q, and 18q. JCVT was significantly associated with p53 expression (P < .0001), p21 loss (P < .0001), CIN (>/=2 chromosomal segments with LOH; P < .0001), nuclear beta-catenin (P = .006), LINE-1 hypomethylation (P = .002), and inversely with CIMP-high (P = .0005) and microsatellite instability (MSI) (P < .0001), but not with PIK3CA mutation. In multivariate logistic regression analysis, the associations of JCVT with p53 [adjusted odds ratio (OR), 8.45; P < .0001], CIN (adjusted OR, 2.53; P = .003), cyclin D1 (adjusted OR, 1.57; P = .02), LINE-1 hypomethylation (adjusted OR, 1.97 for a 30% decline as a unit; P = .03), BRAF mutation (adjusted OR, 2.20; P = .04), and family history of colorectal cancer (adjusted OR, 0.64; P = .04) remained statistically significant. However, JCVT was no longer significantly associated with CIMP, MSI, beta-catenin, or cyclooxygenase-2 expression in multivariate analysis. JCVT was unrelated with patient survival. In conclusion, JCVT expression in colorectal cancer is independently associated with p53 expression and CIN, which may lead to uncontrolled cell proliferation.
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38
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Maginnis MS, Atwood WJ. JC virus: an oncogenic virus in animals and humans? Semin Cancer Biol 2009; 19:261-9. [PMID: 19505654 DOI: 10.1016/j.semcancer.2009.02.013] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2008] [Revised: 02/09/2009] [Accepted: 02/12/2009] [Indexed: 12/12/2022]
Abstract
JC virus (JCV) is a human polyomavirus of the Polyomaviridae family, which also includes BK virus and simian vacuolating virus 40 (SV40). JC virus was first isolated in 1971 from the brain of a patient with Progressive Multifocal Leukoencephalopathy (PML). Like other polyomaviruses, JCV has a restricted host range. The virus infects the majority of the human population with seroconversion occurring during adolescence. JCV has a limited and specific tissue tropism infecting the kidney and oligodendrocytes and astrocytes in the central nervous system (CNS). Initial JCV infection is generally asymptomatic in immunocompetent hosts, and it establishes a persistent infection in the kidney and possibly bone marrow. In immunocompromised individuals JCV can cause a lytic infection in the CNS and lead to development of the fatal, demyelinating disease PML. The name polyoma is derived from the Greek terms: poly, meaning many, and oma, meaning tumors, owing to the capacity of this group of viruses to cause tumors. JCV inoculation of small animal models and non-human primates, which are not permissive to a productive JCV infection, leads to tumor formation. Given the ubiquitous nature of the virus and its strong association with cancer in animal models, it is hypothesized that JCV plays a role in human cancers. However, the role for JCV in human cancers and tumor formation is not clear. Some researchers have reported an association of JCV with human cancers including brain tumors, colorectal cancers, and cancers of the gastrointestinal tract, while other groups report no correlation. Here, we review the role of JCV in cancers in animal models and present the findings on JCV in human cancers.
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Affiliation(s)
- Melissa S Maginnis
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA
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39
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Lin PY, Fung CY, Chang FP, Huang WS, Chen WC, Wang JY, Chang D. Prevalence and genotype identification of human JC virus in colon cancer in Taiwan. J Med Virol 2008; 80:1828-34. [PMID: 18712832 DOI: 10.1002/jmv.21296] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Although JC virus (JCV), a human polyomavirus, has been detected in colon cancers, the association between JCV and colon cancer remains controversial. In Taiwan, the prevalence of JCV infection in colon cancer patients has not been reported. Thus, the purpose of this study was to investigate JCV infection in colon cancers in Taiwan. Formalin-fixed, paraffin-embedded tissues from 22 colon cancer patients were examined in this study. Nested PCR was performed to detect viral genomic DNA. The product of the nested PCR flanking the JCV regulatory region was sequenced further. Viral large tumor protein, LT, and late capsid protein, VP1, were examined by immunohistochemistry (IHC). Nested PCR revealed JCV genomic DNA in 86.4% (19/22) of the colon cancer tissue samples. Both rearranged and archetypal genotypes of JCV were identified. Expression of JCV LT was positive in 63.6% (14/22) of the examined colon cancer tissue samples but not in any adjacent normal region. Expression of viral capsid protein VP1 was not detected in any of the tissues examined. The current study demonstrates that JCV genomic DNA was present in the examined colon cancer tissues. The genotypes of JCV in colon cancer tissues were also identified. Expression of viral early protein but not structural capsid protein was detected in the examined colon cancer tissues. Furthermore, a high prevalence of JCV infection in colon cancer tissues in Taiwan was also demonstrated.
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Affiliation(s)
- Paul Yann Lin
- Department of Pathology, Chang Gung Memorial Hospital at Chia-Yi, Chang Gung University, Chia-Yi, Taiwan
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40
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Li J, Wagner JL, Mookerjee B. Characterization of Non-Conserved HLA-A *0201 Binding T cell Epitopes of JC Virus T Antigen. Virology (Auckl) 2008. [DOI: 10.4137/vrt.s957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
JC virus-specific CD8+ cytotoxic T lymphocytes are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy. However, very few JC virus T cell epitopes restricted to MHC class I have been defined. Of the two HLA-A*0201-restricted JCV epitopes, VP1p36 and VP1p100, studies have shown that they are conserved T cell epitopes of polyomaviruses. The cross-recognition associated to these epitopes has complicated the efforts of understanding the dynamics of immune response to JC virus. Based on the previously identified HLA-A*0201 binding T cell epitope of Simian virus 40 T antigen P281–289 (KCDDVLLLL) and BK virus T antigen P558–566 (SLQNSEFLL), T cell epitopes of JC Virus T antigen P282–290 (KCEDVFLLM) and P557–565 (SLSCSEYLL) were identified. In this report, we demonstrated that JC Virus P282–290 and P557–565 were able to stimulate T cell responses in healthy donors’ PBMCs and CD8+ cytotoxic T lymphocytes raised with both peptides could recognize and lyse their targets. Most importantly, there were no T cell cross-recognitions between JC Virus, BK Virus and SV40 virus. Therefore, JCV T-ag epitopes P282–290 and P557–565 could be better antigen epitopes compared to VP1p36 and VP1p100 to study the dynamics of cellular immune response to JCV in PML patients. In addition, as a HLA-A*0201 binding T cell epitope, both peptides could be a valuable component of immunotherapies aiming at increasing the cellular immune response against JCV for the treatment of progressive multifocal leukoencephalopathy.
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Affiliation(s)
- Jongming Li
- Department of Medical Oncology, 1024 Curtis Building, Thomas Jefferson University, 1015 Walnut St., Philadelphia, PA 19107
| | - John L. Wagner
- Department of Medical Oncology, 1024 Curtis Building, Thomas Jefferson University, 1015 Walnut St., Philadelphia, PA 19107
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41
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Emerson LL, Carney HM, Layfield LJ, Sherbotie JR. Collecting duct carcinoma arising in association with BK nephropathy post-transplantation in a pediatric patient. A case report with immunohistochemical and in situ hybridization study. Pediatr Transplant 2008; 12:600-5. [PMID: 18652620 DOI: 10.1111/j.1399-3046.2007.00855.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The development of malignancy in a renal transplant graft is an uncommon phenomenon. A renal neoplasm developing in the adult donor kidney of a pediatric transplant recipient has only rarely been reported. We report a case of collecting duct carcinoma arising in association with BK virus nephropathy in an adult living-related donor renal allograft to a pediatric recipient. Our case is the second report of neoplasia occurring in association with BK virus nephropathy post-transplantation, suggesting that BK virus may play a role in oncogenesis. It has been proposed that the T-Ag protein encoded by the polyomavirus family of viruses disrupts chromosomal integrity, creating oncogenes, and inactivating tumor suppressor genes. In our study, immunohistochemical staining with antibody directed against BK virus large T antigen showed nuclear staining within urothelium, tubular epithelium, tubular intraepithelial neoplasia, and invasive carcinoma. In situ hybridization did not identify BK virus DNA within neoplastic cells. T-Ag protein expression has been shown to be tumor-specific in bladder, gastric, and colorectal cancers. The finding of T-Ag protein expression in both intraepithelial and invasive neoplastic tissues in our case raises the possibility of BK virus as a causative agent in oncogenesis.
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Affiliation(s)
- Lyska L Emerson
- Department of Pathology, University of Utah School of Medicine and Associated Regional and University Pathologists (ARUP) Laboratories, Salt Lake City, UT, USA.
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42
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Del Valle L, White MK, Khalili K. Potential mechanisms of the human polyomavirus JC in neural oncogenesis. J Neuropathol Exp Neurol 2008; 67:729-40. [PMID: 18648329 PMCID: PMC2771681 DOI: 10.1097/nen.0b013e318180e631] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The human polyomavirus JC (JCV) is a small DNA tumor virus and the etiologic agent of the progressive multifocal leukoencephalopathy. In progressive multifocal leukoencephalopathy, active JCV replication causes the lytic destruction of oligodendrocytes. The normal immune system prevents JCV replication and suppresses the virus into a state of latency so that expression of viral proteins cannot be detected. In a cellular context that is nonpermissive for viral replication, JCV can affect oncogenic transformation. For example, JCV is highly tumorigenic when inoculated into experimental animals, including rodents and monkeys. In these animal tumors, there is expression of early T-antigen but not of late capsid proteins, nor is there viral replication. Moreover, mice transgenic for JCV T-antigen alone develop tumors of neural tube origin. Detection of JCV genomic sequences and expression of viral T-antigen and agnoprotein suggest a possible association of this virus with a variety of human brain and non-CNS tumors. Here, we discuss the mechanisms involved in JCV oncogenesis, briefly review studies that do and do not support a causative role for this virus in human CNS tumors, and identify key issues for future research.
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Affiliation(s)
- Luis Del Valle
- Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122, USA
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43
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Selgrad M, Malfertheiner P, Fini L, Goel A, Boland CR, Ricciardiello L. The role of viral and bacterial pathogens in gastrointestinal cancer. J Cell Physiol 2008; 216:378-88. [PMID: 18338378 DOI: 10.1002/jcp.21427] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The association of Helicobacter pylori (H. pylori) with gastric cancer is thus far the best understood model to comprehend the causal relationship between a microbial pathogen and cancer in the human gastrointestinal tract. Besides H. pylori, a variety of other pathogens are now being recognized as potential carcinogens in different settings of human cancer. In this context, viral causes of human cancers are central to the issue since these account for 10-20% of cancers worldwide. In the case of H. pylori and gastric cancer, as well as the human papillomavirus and anal cancer, the causal relationship between the infectious agent and the related cancer in the gastrointestinal tract has been clearly confirmed by epidemiological and experimental studies. Similarly, Epstein-Barr virus and the oncogenic JC virus are being suggested as possible causative agents for cancers in the upper and lower gastrointestinal tract. This review discusses various viral and microbial pathogens and their oncogenic properties in the evolution of gastrointestinal carcinogenesis and summarizes the available experimental data make a convincing agreement favoring the associations between infectious agents and specific human cancers.
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Affiliation(s)
- Michael Selgrad
- Department of Internal Medicine, Gastroenterology, Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas 75246, USA
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44
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Boland CR. The molecular biology of gastrointestinal cancer: implications for diagnosis and therapy. Gastrointest Endosc Clin N Am 2008; 18:401-13, vii. [PMID: 18674693 PMCID: PMC2561895 DOI: 10.1016/j.giec.2008.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancers are caused by the sequential accumulation of alterations in genes that control the growth, differentiation, and other behaviors of cells. It has long been recognized that cancers are very heterogeneous pathologically, which is a reflection of the variable genetic lesions that give rise to the variety of lesions present in the gastrointestinal tract. Despite this complexity, certain types of genetic alterations are linked to specific pathologic lesions. This review summarizes the current understanding of the molecular pathogenesis of gastrointestinal neoplasia and provides explanations for some of the pathologic variability of lesions encountered by the endoscopist.
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Affiliation(s)
- C. Richard Boland
- Chief, Gastroenterology, Baylor University Medical Center (H-250), 3500 Gaston Avenue, Dallas, TX 75246,
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45
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Nosho K, Yamamoto H, Takahashi T, Mikami M, Hizaki K, Maehata T, Taniguchi H, Yamaoka S, Adachi Y, Itoh F, Imai K, Shinomura Y. Correlation of laterally spreading type and JC virus with methylator phenotype status in colorectal adenoma. Hum Pathol 2008; 39:767-775. [PMID: 18284934 DOI: 10.1016/j.humpath.2007.10.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 09/24/2007] [Accepted: 10/04/2007] [Indexed: 12/13/2022]
Abstract
Accurate frequencies of CpG island methylator phenotype (CIMP) have not been determined for laterally spreading tumors (LSTs) and other flat-type colorectal adenomas, and the role of JC virus T-antigen (T-Ag) in these tumors is unclear. We used MethyLight assay to analyze the relationship between CIMP status and clinicopathologic characteristics in tissue from 72 LST of granular-type (LST-G), 35 LST of nongranular-type (LST-NG), 54 protruded-type adenomas, and 89 colorectal cancers. We also investigated the relationship between CIMP status and T-Ag by immunohistochemistry. With the use of 5 markers for CIMP status, tumors were classified as CIMP-high (> or = 4/5 methylated promoters), CIMP-low (1/5 to 3/5 methylated promoters), or CIMP-0 (no methylated promoters). The proportion classified as CIMP-0 status was 5.6% for protruded-type adenoma, 17.1% for LST-NG, and 29.2% for LST-G (LST-G versus protruded-type adenoma, P = .001). CIMP-low status was established for 62.5% of LST-G, 74.3% of LST-NG, and 81.5% of protruded-type adenomas. CIMP-high status was established for 8.3% of LST-G, 8.6% of LST-NG, and 12.9% of protruded-type adenomas. The proportions of CIMP-low and CIMP-high status were not significantly different between the 3 groups. Multiple logistic analysis showed that LST-G appearance was the only significant factor for identifying CIMP-0 status. BRAF mutation was the only significant factor for identifying CIMP-high status. T-Ag expression increased with CIMP status and was not associated with macroscopic appearance. In conclusion, among colorectal adenomas, CIMP-high status was determined by BRAF mutation and not by macroscopic type, unlike CIMP-0. JC virus T-Ag may be important in determining methylator phenotype.
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Affiliation(s)
- Katsuhiko Nosho
- First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
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Jung WT, Li MS, Goel A, Boland CR. JC virus T-antigen expression in sporadic adenomatous polyps of the colon. Cancer 2008; 112:1028-36. [PMID: 18205186 DOI: 10.1002/cncr.23266] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND JC virus (JCV) has been implicated in the pathogenesis of colorectal cancer; however, its role in premalignant lesions is unknown. The hypothesis that JCV DNA sequences and T-antigen (T-Ag) expression may be present in adenomatous polyps of the colon was tested. Furthermore, an association between JCV and microsatellite instability (MSI) was also sought in these lesions. METHODS DNA was extracted from 74 paraffin-embedded adenomatous polyps. JCV gene sequences were amplified by polymerase chain reaction (PCR), and the specificity confirmed by DNA sequencing. Immunohistochemical staining was performed to localize T-Ag expression in the adenomas using a monoclonal antibody. For microsatellite instability analysis, 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24, and NR-27) were coamplified in a pentaplex PCR and analyzed for deletion mutations. RESULTS JCV T-Ag sequences were found in 82% (61 of 74) of adenomas, and T-Ag protein was expressed in 16% (12 of 74) of these polyps. The T-Ag staining was localized exclusively in the nuclei of adenoma cells, but never in the cytoplasm or the adjacent nonneoplastic cells. The prevalence of MSI-H and non-MSI-H (MSI-L/MSS) in adenomatous polyps was 9.5% (7 of 74) and 90.5% (67 of 74), respectively. Among the 61 adenomas that harbored JCV sequences, 8% (5 of 61) were MSI-H, and similarly among 12 adenomatous polyps expressing T-Ag protein 8% (1 of 12) of the adenomatous polyps were MSI-H. CONCLUSIONS JCV T-Ag DNA sequences are frequently present in adenomatous polyps of the colon, and T-Ag is expressed specifically in the nuclei of these premalignant lesions. This study indicates that JCV T-Ag is present in the early stage of colonic carcinogenesis. Future studies will be required to determine the molecular mechanism of carcinogenesis in these JCV-infected lesions.
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Affiliation(s)
- Woon-Tae Jung
- Division of Gastroenterology, Department of Internal Medicine, The Charles A Sammons Cancer Center, and the Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75246, USA
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Kutsuna T, Zheng H, Abdel-Aziz HO, Murai Y, Tsuneyama K, Furuta I, Takano Y. High JC virus load in tongue carcinomas may be a risk factor for tongue tumorigenesis. Virchows Arch 2008; 452:405-10. [PMID: 18283491 PMCID: PMC2668633 DOI: 10.1007/s00428-007-0534-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 10/17/2007] [Accepted: 10/21/2007] [Indexed: 11/26/2022]
Abstract
The John Cunningham virus (JCV) asymptomatically infects a large proportion (approximately 90%) of the population worldwide but may be activated in immunodeficient patients, resulting in progressive multifocal leukoencephalopathy. Recent reports demonstrated its oncogenic role in malignancies. In this paper, the presence of JCV-targeting T antigen was investigated in tongue carcinoma (TC, n = 39), dysplastic tongue epithelium (DTE, n = 15) and glossitis (n = 15) using real-time polymerase chain reaction (PCR) and in situ PCR and immunohistochemistry, and JCV copies were analyzed with the clinicopathological parameters of TCs. The results demonstrated that glossitis and DTEs had significantly lower copies of JCV (410.5 +/- 44.3 and 658.3 +/- 53.3 copies/mug DNA respectively) than TCs (981.5 +/- 14.0, p < 0.05). When they were divided into three groups with 0-200 copies/mug DNA (low), 201-1,000 (moderate) and more than 1001 (high), TCs showed 3 (7.6%) in the low group, 21 (53.8%) in the moderate group and 15 (38.4%) in the high group and glossitis showed 11 (73.3%) in the low group, 0 (0%) in the moderate group and 4 (26.6%) in the high group. The DTEs occupied an intermediate position between them (p < 0.001). In situ PCR demonstrated that the nuclei of TC and DTE cells are sporadically T-antigen positive but not in nasal turbinate epithelial cells. Immunohistochemistry for T-antigen protein revealed four positive cases only in TCs. The existence of JCV T-antigen DNA was not associated with the clinicopathological variables of TCs. In conclusion, the presence of JCV may be a risk factor of tongue carcinogenesis.
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Affiliation(s)
- Tomohiko Kutsuna
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194 Japan
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Huachuan Zheng
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194 Japan
- Department of Biochemistry, College of Basic Medicine, China Medical University, Shenyang, China
| | - Hekmat Osman Abdel-Aziz
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194 Japan
| | - Yoshihiro Murai
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194 Japan
| | - Koichi Tsuneyama
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194 Japan
| | - Isao Furuta
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Yasuo Takano
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194 Japan
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Murai Y, Zheng HC, Abdel Aziz HO, Mei H, Kutsuna T, Nakanishi Y, Tsuneyama K, Takano Y. High JC virus load in gastric cancer and adjacent non-cancerous mucosa. Cancer Sci 2007; 98:25-31. [PMID: 17083566 PMCID: PMC11159151 DOI: 10.1111/j.1349-7006.2006.00354.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The JC virus (JCV) infects a large proportion of the worldwide population and approximately 90% of adults are seropositive. Recent reports have described the possibility of its oncogenetic role in several malignancies. The aim of the present study was to assess the oncogenetic significance of JCV for gastric cancer. Twenty-two sample pairs of fresh tumor and adjacent non-cancerous tissue (ANCT) as well as 10 normal gastric mucosa specimens were investigated on the basis of nested polymerase chain reaction (PCR) followed by Southern blotting, DNA direct sequencing, real-time PCR, in situ PCR and immunohistochemistry. The T antigen sequence was detected in 86.4% of gastric cancers and ANCT, and in 100% of the normal mucosa samples, as for virus capsid protein, 54.1%, 68.1% and 70%, respectively. A generally low incidence was noted for agnoprotein. The JCV DNA load was approximately 10-fold higher in both gastric cancers and paired ANCT (4784 +/- 759 and 5394 +/- 1466 copies/microg DNA, respectively) than in normal gastric tissue (542.4 +/- 476.0 copies/microg DNA, P < 0.0001). In situ PCR revealed sporadic JCV genome-positive cancer cells and foveolar epithelial cells. T antigen protein expression assessed by immunohistochemistry was detected only in one case (1/22; 4.5%), probably because the half life of T antigen might be short. It was concluded that the gastric epithelium in most Japanese people is infected with JCV at a low rate but levels of infection are increased markedly in both cancer cells and ANCT, indicating that multiplication of JCV copies might be a risk factor and a background for gastric carcinogenesis.
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Affiliation(s)
- Yoshihiro Murai
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama 430-0194, Japan.
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Zheng H, Abdel Aziz HO, Nakanishi Y, Masuda S, Saito H, Tsuneyama K, Takano Y. Oncogenic role of JC virus in lung cancer. J Pathol 2007; 212:306-15. [PMID: 17534844 DOI: 10.1002/path.2188] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The JC virus (JCV) infects a large proportion of the population world wide and can cause progressive multifocal leucoencephalopathy in the context of immunodeficiency. Recent reports provide evidence that it may also be oncogenic. Here, JCV was examined by targeting its T-antigen in lung carcinomas (n=103) and normal lung tissues (n=18) by nested-PCR followed by Southern blot, real-time PCR, immunohistochemistry, in situ hybridization and in situ PCR. Additionally, expression of Ki-67, caspase-3, beta-catenin, p53, and Rb was analysed by immunohistochemistry on tissue microarrays of lung carcinomas. Copy numbers of JCV were compared with clinicopathological features. Normal lung tissue was positive significantly less frequently, and contained a lower copy number of JCV than lung carcinomas (p<0.05), and copies were lower in lung adenocarcinomas than in squamous, small or large cell carcinomas (p<0.05). In situ PCR and immunolabelling revealed JCV positivity in the nuclei of lung carcinoma cells. The JCV copy number correlated closely with sex, and expression of Ki-67 and membrane beta-catenin (p<0.05), but not with age, tumour size, pleural invasion, lymph node metastasis, expression of caspase-3, cytoplasmic beta-catenin, p53 or Rb, prognosis, smoking or cancer family history (p>0.05). Age and UICC staging were independent prognostic factors for lung carcinoma patients. These data suggest that JCV may be involved in lung carcinogenesis, especially in tumour types other than adenocarcinoma. Lung carcinomas with higher JCV copy numbers display high proliferation and down-regulation of cell adhesion mediated by membrane beta-catenin.
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MESH Headings
- Aged
- Aged, 80 and over
- Antigens, Viral, Tumor/genetics
- Blotting, Southern/methods
- Carcinoma/pathology
- Carcinoma/virology
- Carcinoma, Large Cell/pathology
- Carcinoma, Large Cell/virology
- Carcinoma, Small Cell/pathology
- Carcinoma, Small Cell/virology
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/virology
- DNA, Viral/analysis
- Female
- Gene Expression Profiling
- Humans
- In Situ Hybridization
- JC Virus/genetics
- JC Virus/immunology
- JC Virus/pathogenicity
- Lung Neoplasms/pathology
- Lung Neoplasms/virology
- Male
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- Oncogenic Viruses
- RNA, Messenger/analysis
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Analysis, DNA
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Affiliation(s)
- H Zheng
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan
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