Oxidative stress-induced TET1 upregulation mediates active DNA demethylation in human gastric epithelial cells.

The gastrointestinal (GI) tract is more vulnerable to effects by the outside environment, and experiences oxidative stress. A wide diversity of GI disorders can be partially attributed to oxidative stress. However, the mechanism of oxidative stress-caused GI pathological changes is not clear. In the present study, human gastric epithelial cells (hGECs) were treated with hydrogen peroxide (H2O2), and oxidative stress was determined. The effect of oxidative stress on the levels of some antioxidative enzymes, proliferation, nuclear DNA damage, apoptosis, expression of ten-eleven translocation (TET), and level of DNA methylation was determined in these cells. The results showed that H2O2 treatment caused oxidative stress, increased the levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA), decreased the level of glutathione (GSH), inhibited proliferation, caused nuclear DNA damage and apoptosis, upregulated the expression of TET1 gene, and ultimately led to active DNA demethylation in hGECs. The present study presents a mechanism by which oxidative stress induces active DNA demethylation in hGECs. We propose that TET inhibitors can be used to restore the oxidative stress-induced DNA demethylation, and thus inhibit possible malignant transformation of GI cells.

FOXO signaling pathway participates in oxidative stress-induced histone deacetylation.

High concentrations of antioxidants can exert pro-oxidative effects, elevate the level of intracellular reactive oxygen species (ROS), and cause oxidative stress in cells. We previously found that high concentrations of curcumin, a natural polyphenol antioxidant, elevated ROS levels and upregulated the expression of histone deacetylase 1 (HDAC1) in human gastric cancer cells (hGCCs); however, its potential mechanisms and subsequent functions have not been elucidated. In the present study, we treated hGCCs with high concentrations of curcumin, detected several indicators of oxidative stress, and investigated the mechanism of curcumin-treatment-mediated HDAC1 upregulation and its effect on histone acetylation. The results showed that curcumin treatment caused oxidative stress in hGCCs and upregulated HDAC1/2 expression via the forkhead box O (FOXO) signaling pathway, ultimately leading to the deacetylation of histones in hGCCs. Moreover, HDAC1/2 mediates the deacetylation of FOXOs and promotes their transcription activities, implying a positive feedback loop between FOXOs and HDAC1/2. These findings present a mechanism by which oxidative stress induces histone deacetylation in hGCCs.

c-Met/MAPK pathway promotes the malignant progression of residual hepatocellular carcinoma cells after insufficient radiofrequency ablation.

Radiofrequency ablation (RFA) is popularly used in the treatment of hepatocellular carcinoma (HCC). However, the accelerated malignant progression of residual HCC cells after RFA is the main obstacle for the application of this technology in HCC treatment. In the present study, HepG2 cells, an established human HCC cell line, experienced repeatedly with heat treatment, survived cells, HepG2-H cells, were used to simulate residual HCC cells after RFA. The abilities of proliferation, colony formation, and migration were compared between HepG2 and HepG2-H cells. Then, RNA sequencing was used to explore the difference in genes expression between two groups of cells. Subsequently, the level of c-Met, one of membranous receptors of MAPK signal pathway, was measured by RT-qPCR and western blot; the effect of c-Met inhibition on the malignant progression of HepG2-H cells was evaluated. The results showed that HepG2-H cells exhibited higher abilities in the proliferation, colony formation, and migration than that of HepG2 cells. Moreover, differentially expressed genes between two groups of cells were prominently enriched in MAPK signal pathway. The level of c-Met in HepG2-H cells was significantly higher than that in HepG2 cells, and the inhibition in the activity of c-Met could repress the malignant behaviors of HepG2-H cells. These results indicated that the accelerated malignant progression of residual HCC cells after RFA can be partly attributed to the overexpression of c-Met and the activation of MAPK signal pathway. Therefore, we proposed that RFA followed by c-Met inhibitor intake maybe is a better treatment protocol for HCC.