Cytoglobin suppresses oxidative damage and compensatory proliferation via inhibiting AKT/ERK1/2/CyclinD1 axis in hepatocellular carcinoma

The chronic liver injury caused by diverse etiologies provokes abnormal compensatory proliferation and contributes to hepatocarcinogenesis. Oxidative stress (OS) is an independent etiology which induces cell injury and triggers oncogenes activation and tumor suppressor genes dysfunction. Cytoglobin (CYGB) is a member of the human hexacoordinate hemoglobin (HHB) family and functions as a dynamic antioxidant enzyme. We previously reported that CYGB decreases the intracellular ROS/RNS level and inhibits HCC proliferation and stemness under normal oxidative level. In this study, we observed that CYGB is decreased in HCC tissues, particularly in tumors with p53 mutations. Its deficiency is associated with advanced stage, elevated Ki-67 proliferation index, and predicts a worse prognosis in HCC patients. Ectopic CYGB expression attenuates malondialdehyde (MDA) level and AST/ALT release, as well reduces apoptosis and subG1 percentage and simultaneously induces G1 arrest in pre-H₂O₂-treated HCC cells. In addition, CYGB expression inhibits HCC proliferation and inactivates AKT and ERK kinases, the regulative effect can be interfered by necrostatin-1 and Z-VAD-FMK. Furthermore, U0126, the MEK1/2 inhibitor, can block the regulation of CYGB upon AKT/ERK/CyclinD1 axis, as well interfere with CYGB-induced proliferative inhibition in pre-H₂O₂ treated HCC cells, whether necrostatin-1 and Z-VAD-FMK presence or not. In conclusion, CYGB controls oxidative damage-associated molecule patterns and functions as a tumor suppressor, its restoration may provide a therapeutic target against HCC with aberrant OS response.