JCV is a polyomavirus that essentially infects all human populations. Polyomaviruses are characterized by virtue of a T-antigen (T-Ag) gene, which encodes a potent transforming protein. In spite of the fact that all of us have been exposed to and most chronically carry this virus, it usually remains dormant or latent. Polyomaviruses (which include BK Virus and SV40) have complex life cycles in which they can be lytic (replicate virions and kill the host cell), become oncogenic (with or without integration, and induce cancer), or remain latent. Moreover, JCV can induce cancer when injected into the brains of rodents or monkeys. We hypothesize that JCV has the capability of inducing colorectal cancer (CRC) in humans, and we have found that nearly 90% of human CRCs harbor this virus, half of which express the T-Ag. Importantly, we can induce chromosomal instability (CIN) in several in vitro colonic epithelial cell modes, which permit us to study these transformation-associated processes in detail. This application proposes immunological studies to determine whether specific cell-mediated immune responses keep JCV in a latent state. We will test the hypothesis that a defect in cell mediated immunity is associated with the emergence of JCV as an oncogenic virus by studying individuals who have developed colorectal adenomas and carcinomas. We will also test the hypothesis that exposure to JCV in childhood is associated with the appearance of adenomatous polyps in children with familial adenomatous polyposis. Second, we can induce CIN in two diploid CRC cell models by transfecting either the full JCV genome or just the JCV T-Ag gene. By transfecting the JCV T-Ag gene into near-normal colon epithelial cells, we have transformed them into a cell line that forms tumors in nude mice. This provides us with a model to study the molecular biology of early transformation, and the development of CIN in vitro. Similarly, we have found that we can induce CIMP in some non-CIMP CRC cell lines by transfecting JCV T-Ag. Therefore, we can induce the two most fundamental events in CRC using JCV, and can recapitulate the evolution of these earliest aberrations to study the steps by which CIN and CIMP emerge. It is the broad, long-term aim of this research to determine whether vaccination against JCV is a reasonable approach to the prevention of CRC.
This project tests the hypothesis that the common human polyomavirus, JC virus can induce the fundamental changes that are required for colorectal neoplasia to develop. It is the long-term aim of this project to determine whether we should develop a vaccine that will prevent primary infection by JC virus, and prevent the occurrence of colorectal cancer.
|Butcher, Lindsay D; Garcia, Melissa; Arnold, Mildred et al. (2014) Immune response to JC virus T antigen in patients with and without colorectal neoplasia. Gut Microbes 5:468-75|
|Link, Alexander; Balaguer, Francesc; Nagasaka, Takeshi et al. (2014) MicroRNA miR-J1-5p as a potential biomarker for JC virus infection in the gastrointestinal tract. PLoS One 9:e100036|
|Koi, Minoru; Boland, Clement R (2011) Tumor hypoxia and genetic alterations in sporadic cancers. J Obstet Gynaecol Res 37:85-98|
|Goel, Ajay; Boland, Clement Richard (2010) Recent insights into the pathogenesis of colorectal cancer. Curr Opin Gastroenterol 26:47-52|
|Boland, Clement Richard; Shin, Sung Kwan; Goel, Ajay (2009) Promoter methylation in the genesis of gastrointestinal cancer. Yonsei Med J 50:309-21|
|Selgrad, M; De Giorgio, R; Fini, L et al. (2009) JC virus infects the enteric glia of patients with chronic idiopathic intestinal pseudo-obstruction. Gut 58:25-32|
|Link, Alexander; Shin, Sung Kwan; Nagasaka, Takeshi et al. (2009) JC virus mediates invasion and migration in colorectal metastasis. PLoS One 4:e8146|
|Boland, C Richard; Komarova, Natalia L; Goel, Ajay (2009) Chromosomal instability and cancer: not just one CINgle mechanism. Gut 58:163-4|
|Nagasaka, Takeshi; Goel, Ajay; Notohara, Kenji et al. (2008) Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. Int J Cancer 122:2429-36|
|Selgrad, Michael; Koornstra, Jan Jacob; Fini, Lucia et al. (2008) JC virus infection in colorectal neoplasia that develops after liver transplantation. Clin Cancer Res 14:6717-21|
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