title: Accumulation of phosphorylated p62 is associated with NF-E2-related factor 2 activation in hepatocellular carcinoma.
abstract: BACKGROUND
  Frequent alterations are observed in glucose metabolism in hepatocellular carcinoma (HCC). Activation of various enzymes, including ones involved in the pentose phosphate pathway, by NF-E2-related factor 2 (NRF2), controls redox homeostasis in HCC. However, the mechanisms mediating NRF2 activation remain unclear. Here, we aimed to investigate the correlation between NRF2, Kelch-like ECH-associated protein 1 (KEAP1) syntheses and p62 phosphorylation in HCC.
  
  
  METHODS
  Biospecimens were collected from 30 patients with HCC. Protein samples were prepared through subcellular localization. Protein synthesis and phosphorylation were measured by sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting. Statistical correlations among immunoblotting data and clinical features were analyzed using SPSS.
  
  
  RESULTS
  Compared to non-tumor counterpart, phosphorylated p62 was accumulated in HCC (12/30; 40% of patients). Nuclear localization of NRF2 was frequently augmented in HCC (19/30; 63.3%). Statistically, p62 phosphorylation was associated with augmented activation of NRF2 (P = 0.001). Accumulation of p62 per se was moderately associated with NRF2 activation (P = 0.132). Loss of KEAP1 protein, on the other hand, poorly correlated with NRF2 activation (P = 1.000).
  
  
  CONCLUSIONS
  In Japanese HCC, NRF2 activation is associated with phosphorylation of p62, but not with KEAP1 status.
authors.affiliation: Second Department of Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Center for Research Support, Dokkyo Medical University, Tochigi, Mibu, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Second Department of Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hachiya
authors.affiliation: Second Department of Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.
authors.forename: Norisuke
authors.initials: N
authors.lastname: Shibuya
authors.affiliation: Second Department of Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Second Department of Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kubota
mesh_terms: D001343:Autophagy; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001707:Biopsy, Needle; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D006801:Humans; D007150:Immunohistochemistry; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D012042:Registries; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D014408:Biomarkers, Tumor; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C118585:P62 protein, human; D016601:RNA-Binding Proteins
keywords: Hepatocellular carcinoma; NF-E2-related factor 2; Pentose phosphate pathway; Selective autophagy; p62