Abstract
Promoter hypermethylation of the runt-related transcription factor 3 (RUNX3) gene is associated with increased risk of hepatocellular carcinoma (HCC). Oxidative stress plays a vital role in both carcinogenesis and progression of HCC. However, whether oxidative stress and RUNX3 hypermethylation in HCC have a cause- and-effect relationship is not known. In this study, plasma protein carbonyl and total antioxidant capacity (TAC) in patients with hepatitis B virus (HBV)-associated HCC (n=60) and age-matched healthy subjects (n=80) was determined. RUNX3 methylation in peripheral blood mononuclear cells (PBMC) of subjects was measured by methylation-specific PCR. Effect of reactive oxygen species (ROS) on induction of RUNX3 hypermethylation in HCC cells was investigated. Plasma protein carbonyl content was significantly higher, whereas plasma TAC was significantly lower, in HCC patients than healthy controls. Based on logistic regression, increased plasma protein carbonyl and decreased plasma TAC were independently associated with increased risk for HCC. PBMC RUNX3 methylation in the patient group was significantly greater than in the healthy group. RUNX3 methylation in hydrogen peroxide (H2O2)-treated HepG2 cells was significantly higher than in untreated control cells. In conclusion, increase in oxidative stress in Thai patients with HBV-associated HCC was demonstrated. This oxidative increment was independently associated with an increased risk for HCC development. RUNX3 in PBMC was found to be hypermethylated in the HCC patients. In vitro, RUNX3 hypermethylation was experimentally induced by H2O2. Our findings suggest that oxidative stress is a cause of RUNX3 promoter hypermethylation in HCC cells.
Highlights
Liver cancer is a leading cancer in Thailand comprising of two main forms
The β-coefficient of plasma protein carbonyl and total antioxidant capacity (TAC) controlled for age and sex were 1.64 (95%CI: 0.55 - 2.73, P=0.003) and -0.02 (95%CI:-0.02 - -0.01, P
RUNX3 hypermethylation is frequently detected in the hepatocellular carcinoma (HCC) tissues (Yang et al, 2014, Zhang et al, 2015), suggesting a vital role in the HCC genesis
Summary
Liver cancer is a leading cancer in Thailand comprising of two main forms. One is cholangiocarcinoma, and the other is hepatocellular carcinoma (HCC). Oxidative stress is considerably increased in HBV-associated HCC patients (Tsai et al, 2009, Nair et al, 2010, Zhao et al, 2011), and has been believed to play an important role in the development of viral-induced HCC (Marra et al, 2011, Higgs et al, 2014). An epigenetic hallmark that is found in all carcinomas including HCC is an alteration of DNA methylation (Herceg and Paliwal, 2011). Silencing of TSG via DNA methylation is well recognized in the carcinogenesis of HCC (Sceusi et al, 2011). Promoter hypermetnylation of RUNX3 is associated with increased risk for HCC (Yang et al, 2014, Zhang et al, 2015).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
