Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC)

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.

Integrated HPV genomes tend to integrate in gene desert areas in the CaSki, HeLa, and SiHa cervical cancer cell lines

“…The integration of the HPV genome into the human genome might be one of the important mechanisms that induced related cancers [5,9] and is also the strategy used by many other species of virus for carcinogenesis [3,7,33,34,38]. The integration sites in genomes targeted by viruses have been extensively explored [13,16,26].…”

The Oncogenic Roles of JC Virus T Antigen in Breast Carcinogenesis

“…JCV T antigen was involved in colorectal carcinogenesis and liver metastasis ( Sinagra et al, 2014 ; Shoraka et al, 2020 ; Vilkin and Niv, 2011 ). Reportedly, JCV T antigen stabilized β-catenin for its nuclear translocation to initiate cancer proliferation and development ( Nosho et al, 2009 ).…”

Epigenetic Inheritance From Normal Origin Cells Can Determine the Aggressive Biology of Tumor-Initiating Cells and Tumor Heterogeneity

“…For both TIC and its corresponding NOC, all the biological characteristics are determined by their respective epigenomes, that is, all epigenetic programs that regulate the expression of all genes within the genome. 30 TIC’s epigenome includes not only epigenetic-abnormalities, secondary epigenetic-abnormalities (epigenetic aberrance due to genetic changes), 31 but also the established epigenetic status of genes inherited from NOC. Of which, secondary epigenetic-abnormalities are the most well-known aspect that contributes to the malignant phenotype of tumors.…”