Abstract
Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing β-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp-carcinoma sequence.
Highlights
The association between chronic viral infection and human malignancy is well established: papillomaviruses are involved in the pathogenesis of human cervical cancer (Dell and Gaston 2001), Epstein-Barr virus has been linked to Burkitt's lymphoma, nasopharyngeal carcinoma, post-transplant lymphoma, Hodgkin's disease, and gastric carcinoma (Thompson and Kurzrock 2004); hepatitis viruses B and C are associated with hepatocellular carcinoma (Monto and Wright 2001), Simian virus 40 has been linked to mesothelioma (Rizzo et al 2001), and many more
Incorporation of viral DNA may interfere with the normal sequence of human DNA bases, in a genetic manner, or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation
Diploid Colorectal cancer (CRC) cell lines transfected with JC virus (JCV)-containing plasmids developed Chromosomal instability (CIN) (Niv et al 2004)
Summary
The association between chronic viral infection and human malignancy is well established: papillomaviruses are involved in the pathogenesis of human cervical cancer (Dell and Gaston 2001), Epstein-Barr virus has been linked to Burkitt's lymphoma, nasopharyngeal carcinoma, post-transplant lymphoma, Hodgkin's disease, and gastric carcinoma (Thompson and Kurzrock 2004); hepatitis viruses B and C are associated with hepatocellular carcinoma (Monto and Wright 2001), Simian virus 40 has been linked to mesothelioma (Rizzo et al 2001), and many more. The mechanisms responsible for the malignant transformation in cases of long-lasting viral infection differ according to the particular virus and cancer and have been extensively studied. An established association between viral infection and cancer may lead the way for development of a vaccine which could prevent both the infection as well as the malignant transformation. Incorporation of viral DNA may interfere with the normal sequence of human DNA bases, in a genetic manner, or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Activation of oncogenes or silencing of tumor suppressor genes may be the result of long lasting inflammation. These gene products enhance proliferation and inhibit apoptosis and differentiation, driving the cells towards carcinogenesis. Three main pathways have been described: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylation phenotype (CIMP; Boland and Goel 2010)
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