Of FACT complex and oxidative stress response: a KEAP1/NRF2-dependent novel mechanism sustaining hepatocellular carcinoma progression

摘要: Hepatocellular carcinoma (HCC) is the most common primary liver cancer that usually develops in cirrhotic patients, except for progressive non-alcoholic fatty disease (where tumour may develop also non-cirrhotic liver).1 HCC currently leading cause of mortality representing fifth and second worldwide.1 Although screening programmes can allow to identify at an earlier stage patients risks, still a minority survive 5 years from diagnosis, despite treatment. Current treatment options have limitations first-line drugs approved systemic therapy, like sorafenib lenvatinib, best offer additional 3 months survival emphasising urgent need novel molecular targets more effective therapies.1 Chronic progression towards development as well are highly affected by microenvironmental cues very complex scenario involving inter-relationships between cells (cancer cells, tumour-associated macrophages or fibroblasts stem cells) processes events inflammatory response, fibrogenic progression, autophagy, hypoxic conditions oxidative stress.2 In particular, increase intracellular levels reactive oxygen species (ROS) represents feature which counterbalanced upregulation antioxidant defenses, particularly through relevant Kelch-like ECH-associated protein 1 (KEAP1) nuclear factor erythroid 2-related 2 (NRF2) pathway.3 this pathway, KEAP1, E2-ligase normally negatively regulating NRF2 stability via ubiquitin–proteasome degradation, inactivated under stress; preserves degradation allows its translocation binding response element (ARE) sequences promoter genes, displacing BTB domain CNC homolog (BACH1, selective …