Epigenetic dysregulation during chemical carcinogenesis

Abstract

Analysis of the changes in different stage of human cell transformation may yield insights into the multiple events involved in acquisition of the tumorigenic phenotype induced by chemical carcinogens. In this study, we treated human cell lines with known carcinogens and obtained malignant phenotype of cell transformation confirmed by injection subcutaneously in immunodeficient mouse. We then screened differentially methylated genes or miRNAs at different stages of cell transformation using CpG island and miRNA microarray. As a result, we identified that 83 hypermethylated promoters were differentially modified in transformed cells. Among which 17 genes mRNA levels were decreased significantly and methylation at CpG islands of promoters. Particularly, we examined the methylation status of p16INK4α promoter in peripheral blood lymphocytes (PBLs) of 69 polycyclic aromatic hydrocarbons (PAHs) exposed workers. Among the 35 CpG sites we analyzed, 22 were highly hypermethylated in PAHs-exposed group. These 22 hypermethylated CpG sites were positively correlated to levels of urinary 1-hydroxypyrene (1-OHP) and the cytokinesis-block micronucleus (CBMN) in PBLs. In addition, miRNA expression profiles of B(a)P-transformed HBE cells revealed that 12 miRNAs differentially expressed at both pre-transformed and transformed stages. Among these miRNAs, down-regulation of miR-638 was found in 68% (34/50) of human NSCLC tissues. The average expression level of miR-638 in PBLs from 86 PAHs exposed workers increased by 72% compared with control group. Moreover, we demonstrate that miR-638 is involved in the BaP-induced carcinogenesis by targeting BRCA1. Taken together, our findings suggest that aberrant epigenetic regulation can be potentially used as biomarkers for risk assessment.