Advanced oxidation protein products induce S-phase arrest of hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway

Abstract

Liver regeneration has important clinical importance in the setting of partial hepatectomy (PH). Following PH, quiescent hepatocytes can reenter cell cycle to restore liver mass. Hepatocyte cell cycle progression, as the basic motivations of liver regeneration, can be disrupted by multiple pathological factors such as oxidative stress. This study aimed to evaluate the role of advanced oxidation protein products (AOPP) in S-phase arrest in hepatocytes. Serum AOPP level were measured during the perioperative period of PH in 33 patients with hepatocellular carcinoma (HCC). Normal Sprague Dawley rats, human and murine liver cell line (HL-7702 and AML-12) were challenged with AOPP prepared by incubation of rat serum albumin (RSA) with hypochlorous acid, and the effect of AOPP on hepatocytes cell cycle progression and liver regeneration was studied after PH. AOPP levels were increased following partial hepatectomy (PH) in patients with primary liver cancer. AOPP treatment impaired liver regeneration in rats following 70% partial hepatectomy. S-phase arrest was induced by AOPP administration in hepatocytes derived from the remnant liver at controlled times following partial hepatectomy in rats, and in HL-7702 and AML-12 cells. The effect of AOPP on hepatocyte S phase arrest was mainly mediated by a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) generation, downregulation of downstream β-catenin signaling and decreased cyclin-dependent kinase 2 (CDK2) expression, which inhibited S-phase progression in hepatocytes. This study provides preliminary evidence that AOPP can induce S-phase arrest in hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway. These findings suggest a novel pathogenic role of AOPP contributing to the impaired liver regeneration and may provide the basis for developing new strategies to improve liver regeneration in patients undergoing PH.

Keywords: Advanced oxidation protein products; Cyclin-dependent kinase 2; Liver regeneration; Reactive oxygen species; S-phase arrest; β-catenin.