Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium

Abstract

Cadmium (Cd) is a toxic and carcinogenic metal naturally occurring in the earth’s crust. A common route of human exposure is via diet and cadmium accumulates in the liver. The effects of Cd exposure on gene expression in human hepatocellular carcinoma (HepG2) cells were examined in this study. HepG2 cells were acutely-treated with 0.1, 0.5, or 1.0 μM Cd for 24 hours; or chronically-treated with 0.01, 0.05, or 0.1 μM Cd for three weeks and gene expression analysis was performed using Affymetrix GeneChip® Human Gene 1.0 ST Arrays. Acute and chronic exposures significantly altered the expression of 333 and 181 genes, respectively. The genes most upregulated by acute exposure included several metallothioneins. Downregulated genes included the monooxygenase CYP3A7, involved in drug and lipid metabolism. In contrast, CYP3A7 was upregulated by chronic Cd exposure, as was DNAJB9, an anti-apoptotic J protein. Genes downregulated following chronic exposure included the transcriptional regulator early growth response protein 1. Ingenuity Pathway Analysis revealed that the top networks altered by acute exposure were lipid metabolism, small molecule biosynthesis, and cell morphology, organization, and development; while top networks altered by chronic exposure were organ morphology, cell cycle, cell signaling, and renal and urological diseases/cancer. Many of the dysregulated genes play important roles in cellular growth, proliferation, and apoptosis, and may be involved in carcinogenesis. In addition to gene expression changes, HepG2 cells treated with cadmium for 24 hours indicated a reduction in global levels of histone methylation and acetylation that persisted 72 hours post-treatment.

Heavy Metals and Cancer

“…Another source of environmental contamination is landfills, which have been observed to contain levels of cadmium exceeding safety standards in certain cases [43]. Additionally, ingesting this metal from contaminated food has been noted as a typical source of exposure [14,44].…”

“…Although a causal link involving cadmium was not observed, it does suggest a potential role in malignant growth of the bladder [47]. Cadmium has also demonstrated carcinogenic activity on liver cells in a laboratory setting [44]. Additionally, increased concentrations of cadmium were detected in patients with malignant gliomas, suggesting a potential role of carcinogenesis in the brain [48].…”

“…Similar to other heavy metals, carcinogenic mechanisms associated with cadmium include generation of ROS, epigenetic alterations, inhibiting DNA repair processes and apoptosis [41,46,52,53]. It has been demonstrated that both chronic and acute cadmium exposure has the ability to induce changes in gene regulation, which generates an increased risk for malignant growth [44]. Key proteins that displayed upregulated expression include DNAJB9, a protein involved in regulating cell destruction, and metallothioneins [44].…”

“…It has been demonstrated that both chronic and acute cadmium exposure has the ability to induce changes in gene regulation, which generates an increased risk for malignant growth [44]. Key proteins that displayed upregulated expression include DNAJB9, a protein involved in regulating cell destruction, and metallothioneins [44]. Important regulatory proteins also displayed downregulated expression, such as EGR-1, a protein involved in regulating transcription [44].…”

“…Key proteins that displayed upregulated expression include DNAJB9, a protein involved in regulating cell destruction, and metallothioneins [44]. Important regulatory proteins also displayed downregulated expression, such as EGR-1, a protein involved in regulating transcription [44]. There are not currently any standard therapeutic measures for the treatment of cadmium poisoning [54].…”