Oxidative stress indicated by elevated expression of Nrf2 and 8-OHdG promotes hepatocellular carcinoma progression

Abstract

Reactive oxygen species (ROS) is excessively generated in tumors creating an oxidative stress in tumor microenvironment. We investigated hepatic expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and 8-hydroxydeoxyguanosine (8-OHdG) in hepatocellular carcinoma (HCC) patients, and asked if ROS epigenetically upregulated Nrf2 and enhanced aggressiveness in HCC cells. Expression of Nrf2 (n = 100) and 8-OHdG (n = 53) was remarkably increased in HCC tissues compared with the noncancerous hepatic tissues. Elevated expression of 8-OHdG was associated with poor survival in HCC patients. HO, as ROS representative, provoked oxidative stress in HepG2 cells, indicated by increased protein carbonyl content and decreased total antioxidant capacity. Nrf2 expression and 8-OHdG formation were markedly increased in the HO-treated cells compared with the untreated control. Co-treatment with antioxidants, tocopheryl acetate (TA) and S-adenosylmethionine (SAM) effectively attenuated expression of Nrf2 and 8-OHdG in HO-treated cells. HepG2 cells treated with HO had significantly higher migration and invasion capabilities than the untreated control cells, and this aggressiveness was significantly inhibited by TA and SAM. Bisulfite sequencing revealed that CpG dinucleotides in Nrf2 promoter were unmethylated in the HO-treated cells similar to the untreated control. In conclusion, robust histological evidence of increased antioxidative response and oxidative DNA damage in human HCC tissues was demonstrated. Elevated oxidative DNA lesion 8-OHdG was associated with shorter survival. Experimentally, ROS enhanced Nrf2 expression, 8-OHdG formation and tumor progression in HCC cells. These effects were inhibited by antioxidants. Therefore, oxidative stress-reducing regimens might be beneficial to diminish the ROS-induced HCC progression.

Apple phlorizin supplementation attenuates oxidative stress in hamsters fed a high-fat diet

“…Nrf2, as an antioxidative transcription factor responding to ROS, controls the antioxidant response element (ARE)‐dependent gene regulation under oxidative stress conditions (Lee & Johnson, ; Ma‐On et al, ). On activation, Nrf2 mediates the induction of a spectrum of cytoprotective proteins including phase II enzymes, such as NAD(P)H: quinone oxidoreductase (NQO1), and antioxidant proteins, such as HO‐1 and GSH, by ARE‐dependent pathway (He, Chen, Lin, & Ma, ; Itoh et al, ; Jia et al, ; Ma, Kinneer, Bi, Chan, & Kan, ; Nguyen, Sherratt, & Pickett, ).…”

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

“…OS is associated with the excessive generation of free radicals, such as reactive oxygen species (ROS), and/or decreased efficacy of antioxidant defenses. In humans, the pervasive impact of OS has been linked to the development of a variety of diseases as diverse as Alzheimer's disease [3], cancer [4], heart failure [5] and obesity [6]. OS is also a prevalent biomarker associated with the semen of approximately 35% of infertile men [7] and the presence of elevated levels of seminal ROS has been reported arising from male reproductive tract pathologies such as varicocele [8], inflammatory [9] and prostate cancer [10].…”

Effects of chlorogenic acid on the liver cell metabolism under high glucose conditions

“…Previously, it was demonstrated that the Nrf2 pathway protects mice podocytes exposed to hyperglycemia partly through regulation of sirtuin 1 (Sirt1) activity (Q. ZHANG & al [29]). Another study reported that the expression of Nrf2 is enhanced by ROS formation and inhibited by antioxidants in hepatic cells (C. MA-ON& al [30]).…”