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Induction of Chromosomal Instability in Colonic Cells by the Human Polyomavirus JC Virus¹

Departments of Internal Medicine and Gastroenterology [L. R., E. R., F. B.], Cytology and Histopathology [G. C.], and Microbiology and Virology [A. R., M. P. L.], University of Bologna, 40138 Bologna, Italy; Center for Applied Biomedical Research (CRBA) S. Orsola-Malpighi Hospital, Bologna, Italy [L. R., M. B., C. G., M. P., E. R., F. B.]; Laboratory of Molecular and Cellular Pathology Hokkaido University, Japan [H. S., K. N.]; Department of Biochemistry and Molecular Biology, The Pennsylvania State University [R. J. F.]; Comprehensive Cancer Center and Department of Medicine University of California at San Diego, San Diego, California [A. G., C. R. B.]; and Department of Morphology and Embryology, University of Ferrara, Italy [M. T.]

Most colorectal cancers display chromosomal instability, which is characterized by gross chromosomal rearrangements, loss of heterozygosity and aneuploidy. We have previously demonstrated a link between JC virus strains Mad-1 and 98 and colorectal cancer. Others have also associated the virus to the induction of colon cancer and aneuploid brain tumors by producing a highly tumorigenic protein named T antigen (TAg), which binds to ß-catenin and inactivates key proteins such as p53. The aim is to demonstrate that JC virus is capable of inducing chromosomal instability in colonic cells. We used the human colon cancer cell line RKO as a model. The cell line has wild-type p53, wild-type ß-catenin and APC and is diploid. Neuroblastoma JCI cells, which are infected with the virus, VA13 fibroblasts, which are transformed by the SV40 TAg, were used as positive controls. HCT116, which has mutated ß-catenin, and SW480, which is a model of CIN, were also used as controls. The genomes of the Mad-1 and 98 strains were transfected into cells. As negative controls we used pUC or no plasmids. Cells were collected at 0, 7, 14, and 21 days after transfection. PCR was used for the detection of TAg and the regulatory region DNA sequences at different time frames and Southern blot of whole genomic extracts for viral DNA integration into the host genome. Immunofluorescence and Western blot were performed for TAg, viral capsid proteins, and nuclear ß-catenin expressions, whereas coimmunoprecipitation was used to detect protein interactions. Karyotype analysis and electron microscopy were performed to seek chromosomal instability and cell abnormalities, respectively. Retention of viral sequences was observed for Mad-1- and 98-transfected RKO cells at all time frames with PCR only, whereas Southern blot analysis showed nonintegrated sequences at T7 alone. TAg and capsid protein expressions, as well as increased p53 and nuclear ß-catenin, were observed between T0 and T7 for Mad-1 and 98 alone. Also, interaction between TAg and both p53 and ß-catenin was also observed between T0 and T7. Chromosomal instability, characterized by chromosomal breakage, dicentric chromosomes, and increasing ploidy, was observed at all time frames for Mad-1 and 98, as well as cell abnormalities. In conclusion, we demonstrate that JC virus Mad-1 and 98 are able to induce chromosomal instability in colonic cells with a hit and run mechanism that involves an early interaction with ß-catenin and p53.

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