Detection of JC Polyomavirus tumor antigen in gastric carcinoma: a report from Iran
Background and Objectives: Factors contributing to development of gastric cancer are still under investigation. The JC Virus (JCV), as an oncogenic virus, has been indicated to play a possible role in gastric carcinogenesis. Theoretically, tumor antigen (T-Ag), the viral transforming protein, is capable of binding and inactivating tumor suppressor proteins p53 and pRb, there by promoting cancer development although such a role in gastric cancer is still controversial and additional data is needed to reach a definite conclusion. The prevalence of the virus varies in different geographic regions, therefore, we aimed to investigate JCV presence in cancerous gastric tissues of Iranian patients.
Materials and Methods: Thirty-one paired samples were included in this study (total of 62 samples). T-Ag sequences were investigated using real-time PCR in formalin fixed paraffin embedded (FFPE) tissue samples from the tumor site and relevant adjacent non-cancerous tissues (ANCT). In positive samples, JCV copy number (viral load) was also measured using real-time PCR. To evaluate T-Ag protein expression, immunohistochemistry examination was performed using an anti-T-Ag specific antibody.
Results: JCV sequences were detected in 17 out of 31 gastric cancer tissue samples (54.84%) and in 10 out of 31 of the non-cancerous adjacent gastric mucosa (32.25%) (Odds ratio of 2.4). Viral load in tumoral and adjacent tissue samples was not statistically different (p=0.88). Immunohistochemical study confirmed presence of JC T-Ag in the nuclear compartment.
Conclusion: We showed the presence of the JC virus in gastric carcinoma tissue samples in our geographic region. This finding provides supportive data for a possible contribution of JCV in gastric cell transformation to malignancy. However, we highly recommend additional investigations to further explore JC virus and gastric cancer in order to reach a conclusion.
Rugge M, Fassan M, Graham DY. Epidemiology of gastric cancer. Gastric Cancer;Springer 2015; 23-34. doi:10.1007/978-3-319-15826-6_2
Malekzadeh R, Derakhshan MH, Malekzadeh Z. Gastric cancer in Iran: epidemiology and risk factors. Arch Iran Med 2009; 12:576-583.
Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res 1992; 52:6735-6740.
Plummer M, Franceschi S, Muñoz N. Epidemiology of gastriccancer. IARC Sci Publ 2004; (157):311-326.
Takano Y, Kato Y, Saegusa M, et al. The role of the Epstein-Barr virus in the oncogenesis of EBV (+) gastric carcinomas. Virchows Arch 1990; 434:17-22.
Shin SK, Li MS, Fuerst F, et al. Oncogenic T‐antigen of JC virus is present frequently in human gastric cancers. Cancer 2006; 107:481-488.
Khalili K, Del Valle L, Otte J, Weaver M, Gordon J. Human neurotropic polyomavirus, JCV, and its role in carcinogenesis. Oncogene 2003; 22:5181-5191.
Haggerty S, Walker D, Frisque R. JC virus-simian virus 40 genomes containing heterologous regulatory signals and chimeric early regions: identification of regions restricting transformation by JC virus. J. Virol 1989; 63:2180-2190.
Khalili K, Sariyer IK, Safak M. Small tumor antigen of polyomaviruses: role in viral life cycle and cell transformation. J Cell Physiol 2008; 215:309-319.
Chang H, Wang M, Tsai R-T, et al. High incidence of JC viruria in JC-seropositive older individuals. J Neurovirol 2002; 8:447-451.
Ling PD, Lednicky JA, Keitel WA, et al. The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study. J Infect Dis 2003; 187:1571-1580.
Shah KV, Daniel RW, Strickler HD, Goedert JJ. Investigation of human urine for genomic sequences of the primate polyomaviruses simian virus 40, BK virus, and JC virus. J Infect Dis 1997; 176:1618-1621.
Del Valle L, Gordon J, Assimakopoulou M, et al. Detection of JC virus DNA sequences and expression of the viral regulatory protein T-antigen in tumors of the central nervous system. Cancer Res 2001; 61:4287-4293.
Del Valle L, White MK, Enam S, et al. Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma. Cancer 2005; 103:516-527.
Laghi L, Randolph AE, Chauhan D, et al. JC virus DNA is present in the mucosa of the human colon and in colorectal cancers. Proc. Natl. Acad. Sci. U.S.A 1999; 96:7484-7489.
Sullivan CS, Tremblay JD, Fewell SW, et al. Species-specific elements in the large T-antigen J domain are required for cellular transformation and DNA replication by simian virus 40. Mol cell biol 2000; 20:5749-5757.
Radhakrishnan S, Otte J, Enam S, et al. JCvirus-induced changes in cellular gene expression in primary human astrocytes. J. Virol 2003; 77:10638-10644.
Dörries K. New aspects in the pathogenesis of polyomavirus-induced disease. Adv Virus Res 1997; 48:205-261.
Dyson N, Bernards R, Friend S, et al. Large T antigens of many polyomaviruses are able to form complexes with the retinoblastoma protein. J. Virol 1990; 64:1353-1356.
Bollag B, Chuke W, Frisque RJ. Hybrid genomes of the polyomaviruses JC virus, BK virus, and simian virus 40: identification of sequences important for efficient transformation. J. Virol 1989; 63:863-872.
Staib C, Pesch J, Gerwig R, et al. p53 Inhibits JC Virus DNA Replicationin Vivoand Interacts with JC Virus Large T-Antigen. Virol. J 1996; 219:237-246.
Niv Y, Goel A, Boland CR. JC virus and colorectal cancer: a possible trigger in the chromosomal instability pathways. Curr Opin Gastroenterol 2005; 21:85-89.
Nosho K, Shima K, Kure S, et al. 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.
Khalili K, Del Valle L, Wang J, et al. T-antigen of human polyomavirus JC cooperates withIGF-IR signaling system in cerebellar tumors of the childhood-medulloblastomas. Anticancer Res 2003; 23:2035-2041.
Neel JV. JC virus and its possible role in oncogenesis. Am J Med Genet 1999; 83:152-156.
Yustein AS, Harper JC, Petroni GR, et al. Allelotype of gastric adenocarcinoma. Cancer Res 1999; 59:1437-1441.
Ricciardiello L, Laghi L, Ramamirtham P, et al. JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract. Gastroenterology 2000; 119:1228-1235.
Ricciardiello L, Baglioni M, Giovannini C, et al. Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus. Cancer Res 2003; 63:7256-7262.
Martini F, Iaccheri L, Lazzarin L, et al. SV40 early region and large T antigen in human brain tumors, peripheral blood cells, and sperm fluids from healthy individuals. Cancer Res 1996; 56:4820-4825.
Murai Y, Zheng HC, Aziz HOA, et al. High JC virus load in gastric cancer and adjacent non‐cancerous mucosa. Cancer Sci 2007; 98:25-31.
Khopde S, Simmons DT. Simian virus 40 DNA replication is dependent on an interaction between topoisomerase I and the C-terminal end of T antigen. J. Virol 2008; 82:1136-1145.
Matos A, Duque V, Luxo C. Topoisomerase I improve JC virus DNA detection. Mol Biol 2016; 5(155):2.
Ricciardiello L, Chang DK, Laghi L, et al. Mad-1 is the exclusive JC virus strain present in the human colon, and its transcriptional control region has a deleted 98-base-pair sequence in colon cancer tissues. J. Virol 2001; 75:1996-2001.
Mou X, Chen L, Liu F, et al. Prevalence of JC virus in Chinese patients with colorectal cancer. PloS one 2012; 7(5):e35900.