Comparative subcellular localization of NRF2 and KEAP1 during the hepatocellular carcinoma development in vivo

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1869; no. 5; p. 119222
• Main Authors: Guerrero-Escalera, Dafne, Alarcón-Sánchez, Brisa Rodope, Arellanes-Robledo, Jaime, Cruz-Rangel, Armando, del Pozo-Yauner, Luis, Chagoya de Sánchez, Victoria, Resendis-Antonio, Osbaldo, Villa-Treviño, Saul, Torres-Mena, Julia Esperanza, Pérez-Carreón, Julio Isael
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2022
• Subjects: Actin cytoskeleton; Actin Cytoskeleton - metabolism; Animals; Antioxidant response; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - veterinary; Cell Nucleus - metabolism; Cyclooxygenase 1 - genetics; Cyclooxygenase 1 - metabolism; Diethylnitrosamine - toxicity; Disease Progression; Inter-nodular heterogeneity; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; Liver Neoplasms - chemically induced; Liver Neoplasms - pathology; Liver Neoplasms - veterinary; Membrane Proteins - genetics; Membrane Proteins - metabolism; Neoplastic nodules; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NRF2 activation; Proto-Oncogene Proteins c-maf - genetics; Proto-Oncogene Proteins c-maf - metabolism; Rats; Rats, Inbred F344; Antioxidant response; Actin cytoskeleton; Neoplastic nodules; Inter-nodular heterogeneity; NRF2 activation
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2022.119222

The activation of Nuclear Factor, Erythroid 2 Like 2 – Kelch Like ECH Associated Protein 1 (NRF2-KEAP1) signaling pathway plays a critical dual role by either protecting or promoting the carcinogenesis process. However, its activation or nuclear translocation during hepatocellular carcinoma (HCC) progression has not been addressed yet. This study characterizes the subcellular localization of both NRF2 and KEAP1 during diethylnitrosamine-induced hepatocarcinogenesis in the rat. NRF2-KEAP1 pathway was continuously activated along with the increased expression of its target genes, namely Nqo1, Hmox1, Gclc, and Ptgr1. Similarly, the nuclear translocation of NRF2, MAF, and KEAP1 increased in HCC cells from weeks 12 to 22 during HCC progression. Likewise, colocalization of NRF2 with KEAP1 was higher in the cell nuclei of HCC neoplastic nodules than in surrounding cells. Moreover, immunofluorescence analyses revealed that the interaction of KEAP1 with filamentous Actin was disrupted in HCC cells. This disruption may be contributing to the release and nuclear translocation of NRF2 since the cortical actin cytoskeleton serves as anchoring of KEAP1. In conclusion, this evidence indicates that NRF2 is progressively activated and promotes the progression of experimental HCC. •Expression of KEAP1 and NRF2-targeted genes increases in multinodular HCC in vivo.•Differential localization of NRF2, PTGR1 and NQO1 denoted an inter-nodular heterogeneity.•NRF2 and KEAP1 nuclear translocation increases in liver during HCC progression.•Co-localization of KEAP1 with filamentous actin is disturbed in HCC cells.•Nuclear localization of NRF2 is higher than KEAP1 in HCC cells