The role of JC virus in colorectal carcinogenesis.

CS01-02

We have hypothesized that infection of the gastrointestinal tract with the polyomavirus JC virus (JCV) may be involved in the causation of colorectal cancer (CRC). It has been established that one can immortalize cells and induce aneuploidy by infecting them with the polyomavirus SV-40, which encodes the transforming oncogene, T-antigen. JCV is closely related to SV-40, encodes a T-antigen gene, and 80-90% of the population has antibody titers to the virus. We have demonstrated that 89% of CRCs harbor DNA sequences of the T-antigen from JC virus; this was determined by PCR, and confirmed with Southern blotting, cloning, and sequencing DNA from human tumor specimens. The viral copy number is low, but there are 10-100 fold more copies of the virus in cancers than in the adjacent normal mucosa from patients with CRC. We were also able to detect JCV sequences in xenografts generated from primary human colon cancers. We demonstrated that normal healthy adults carry JCV in the esophagus, stomach, colon, and rectum, and every patient who had a prior history of cancer or a colorectal adenoma had JCV DNA in mucosal biopsies from the upper or lower GI tract. Because of the ubiquitous carriage of this virus by humans, we looked for a mechanism that would account for a dormant state of the virus in most individuals, and its activation in cancer. Viral gene expression is regulated by the transcription control region (TCR) or promoter region of JCV. We found rearranged forms of the TCR, which could not be found in the normal colon, in all CRCs that had JCV. We have subsequently developed several laboratory models to test the hypothesis that primary colonic cells can be infected by JCV. Transfection of the diploid CRC cell line HCT116 with a cloned JCV T-antigen gene induces CIN. Transfection of the diploid CRC cell line RKO with a full-length JCV genome leads to stabilization of β-catenin in the nucleus, an interaction between T-antigen and p53 protein, and leads to aneuploidy within a week. We have also shown that T-antigen expression in human CRCs is significantly associated with promoter methylation, and the CpG island methylator phenotype (CIMP). CIMP is the most common cause of microsatellite instability (MSI) in CRCs. Thus, JCV can be linked to all of the known causes of genetic or epigenetic instability found in CRCs. We have recently found JCV DNA in human gastric and pancreatic cancers as well. These data demonstrate that JCV is ubiquitously present in the human gastrointestinal tract, is present in a variety of human GI cancers, and can be mechanistically linked to CIN, CIMP, and MSI in CRCs. This virus is a candidate as the trigger of neoplasia in the gastrointestinal tract. References: Laghi L, Randolph AE, Chauhan DP, Marra G, Major EO, Neel JV, Boland CR. JC virus DNA is present in the human colon and in colorectal cancers. Proc Natl Acad Sci 96:7484-7489, 1999. Ricciardiello L, Laghi L, Ramamirtham P, Chang CL, Chang DK, Randolph AE, Boland CR. JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract. Gastroenterology 119:1228-1235, 2000. Ricciardiello L, Chang DK, Laghi L, Goel A, Chang CL, Boland CR. Mad-1 is the exclusive JC virus strain present in the human colon, and its transcriptional control region has a deleted 98-bp sequence in colon cancer tissues. J. Virology 75:1996-01, 2001. Ricciardiello L, Baglioni M, Giovannini C, Pariali M, Cenacchi G, Ripalti A, Landini MP, Sawa H, Nagashima K, Frisque RJ, Goel A, Boland CR, Tognon M, Roda E, and Bazzoli F. Induction of chromosomal instability in colonic cells by the human polyomavirus JC through a hit and run mechanism. Cancer Research 63:7256-62, 2003 Laghi L, Randolph AE, Malesci A, Boland CR. Constraints imposed by supercoiling upon in vitro amplification of polyomavirus DNA. J Gen Virol 85(Pt 11):3383-8, 2004. Niv Y, Goel A, and Boland CR. JC virus and colorectal cancer - a possible trigger in the chromosomal instability pathway. Curr Opin Gastroenterol 21:85-9, 2005. Goel A, Li M-S, Nagasaka T, Shin SK, Fuerst F, Ricciardiello L, Wasserman L, and Boland CR. Association of JC virus T-antigen expression with the methylator phenotype in sporadic colorectal cancers. Gastroenterology 130:1950-61, 2006. Shin SK, Boland CR and Goel A. Oncogenic T-antigen of JC virus is present in human gastric cancer. Cancer 107:481-488, 2006, 2006.