Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

Abstract

Carcinogenesis is an important chronic toxicity of metals and metalloids, although their mechanisms of action are still unclear. Comparison of gene expression patterns induced by carcinogenic metals, metalloids, and model carcinogens would give an insight into understanding of their carcinogenic mechanisms. In this study, we examined the gene expression alteration in human hepatoma cell line, HepG2, after exposing to two metals (cadmium and nickel), a metalloid (arsenic), and three model carcinogenic chemicals N-dimethylnitrosoamine (DMN), 12-O-tetradecanoylphorbol-13-acetate (TPA), and tetrachloroethylene (TCE) using DNA microarrays with 8,795 human genes. Of the genes altered by As, Cd, and Ni exposures, 31-55% were overlapped with those altered by three model carcinogenic chemical exposures in our experiments. In particular, the metals and metalloid shared certain characteristics with TPA and TCE in remarkable upregulations of the genes associated with progression of cell cycle, which might play a central role in As, Cd, and Ni carcinogenesis. This characteristic of gene expression alteration was partially counteracted by intracellular accumulation of vitamin C in Asexposed cells, whereas the number of cell-cycle associated genes was increased in Cd-and Niexposed cells. In our experimental conditions, ROS might have an accelerative effect on the cell proliferation mechanisms of As, but have an inhibitory effect on those of other two heavy metals. Furthermore, based on the results of Q-PCR, the oncogene PTTG1, which was upregulated by all carcinogenic chemical exposures in the array experiments, might be a useful biomarker for evaluation of the carcinogenesis of inorganic carcinogens. Environ. Mol. Mutagen. 50:46-59, 2009.

Sex-specific effects of early life cadmium exposure on DNA methylation and implications for birth weight

“…One exception is the PTTG1, which was more expressed in liver cancer cells in response to Cd exposure in vitro 27 . In contrast, in the present study on healthy newborns PTTG1 was more methylated with increasing Cd exposure.…”

The NRF2-KEAP1 Pathway Is an Early Responsive Gene Network in Arsenic Exposed Lymphoblastoid Cells

“…Our study is the first using microarrays to report the induction of SQSTM1 and ABCB6 genes, which are regulated by Nrf2, after iAs exposure. Similarly, other known Nrf2-regulated genes such as ALDH2 , GPX2 , GSR , AKR and SLC that have been previously reported to be induced by acute exposure to iAs in different cell types were not detected within our study [19], [20], [28]. This once again highlights the importance of the need to characterize both the early time points and acute vs. chronic exposures for identifying molecular signatures of response.…”

Cadmium stress: an oxidative challenge

“…A disturbed redox balance can, however, also induce uncontrolled cell proliferation and Cd carcinogenicity seems to be crucially mediated by the production of ROS (Waisberg et al 2003). Overall, different opinions exist regarding the accelerating and/or inhibitory effect of ROS on cell proliferation mechanisms (Kawata et al 2009). …”