Abstract 2681: Prediagnostic levels of urinary 8-epi-prostaglandin F2α and prostaglandin E2 metabolite, biomarkers of oxidative damage and inflammation, and risk of hepatocellular carcinoma

Abstract

Abstract Background: Chronic inflammation causes persistent liver injury and consecutive regeneration, potentially leading to fibrosis and cirrhosis, and consequently, to the development of hepatocellular carcinoma (HCC). Prostaglandin E2 (PGE2) is one of the major end-products of the cyclooxygenase-2 (COX-2) pathway, an enzyme that is an important mediator of inflammation. Oxidative stress, which results from the generation of reactive oxygen species (ROS) by environmental risk factors or cellular mitochondrial dysfunction, may be involved in the progression of chronic liver disease to the development of HCC. 8-epi-prostaglandin F2α (8-epi-PGF2α) is a product of lipid peroxidation, which has been recognized as a specific, chemically stable, quantitative marker of systemic and integrated measure of oxidative stress. Method: We evaluated the associations for urinary levels of 8-epi-PGF2α and PGE-M, a metabolite of PGE2, with HCC risk in a prospective cohort of 18,244 men in Shanghai, China. After 25 years of follow-up, 347 participants developed HCC. For each case, two control subjects were chosen and matched on age (±2 years), date of sample collection (±1 months), and neighborhood of residence. Urinary 8-epi-PGF2α and PGE-M were quantified using validated liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) assays. The logistic regression method was used to calculate the odds ratio (OR) and its 95% confidence interval (CI) associated with higher levels of both urinary 8-epi-PGF2α and PGE-M. Results: 8-epi-PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 vs 0.80 pmol/mg creatinine, P <0.001). The OR of HCC for the highest relative to the lowest quartile of 8-epi-PGF2α were 2.51 (95% CI 1.60 - 3.93, P trend < 0.001) after adjustment for age, cigarette smoking, alcohol consumption, liver cirrhosis, and hepatitis 1 B surface antigen. This association remained significant after excluding all HCC cases diagnosed within the first 10 years of follow-up. The present study did not find any significant association between urinary PEG-M and HCC risk. Discussion: 8-Isoprostanes have been found to be significantly elevated in patients with non-alcoholic steatohepatitis (NASH). Our findings support a significant role of oxidative stress in the development of HCC, especially in those without traditional risk factors. The null finding on PGE-M and HCC risk is consistent with results of epidemiological studies that did not show a statistically significant association for HCC risk with use of COX-2 inhibitors. Citation Format: Jian-Min Yuan, Menno Grouls, Steven G. Carmella, Renwei Wang, Alicia Heskin, Yang Jiang, Yuting Tan, Jennifer Adams-Haduch, Yu-Tang Gao, Stephen S. Hecht. Prediagnostic levels of urinary 8-epi-prostaglandin F2α and prostaglandin E2 metabolite, biomarkers of oxidative damage and inflammation, and risk of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2681.