title: A possible involvement of p62/sequestosome-1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis.
abstract: OBJECTIVE
  Given autophagy is involved in the pathogenesis in primary biliary cirrhosis (PBC), we examined an involvement of p62 sequestosome-1 (p62), a specific cargo for autophagy, in the process of autophagy and cellular senescence in PBC.
  
  
  METHODS
  We examined immunohistochemically the expression of p62 in livers taken from patients with PBC (n = 46) and control livers (n = 78) and its colocalization with microtubule-associated proteins-light chain 3β (LC3), lysosome-associated membrane protein-1 (LAMP-1) and senescent markers (p16(INK) (4a) and p21(WAF) (1/Cip1) ). We examined the expression of p62 and LC3 in cultured biliary epithelial cells (BECs) treated with various stress. The effect of p62 knockdown with siRNA on stress-induced autophagy and cellular senescence was also assessed.
  
  
  RESULTS
  The expression of p62 was specifically seen in cytoplasmic aggregates in BECs in the inflamed and damaged small bile ducts (SBDs) in PBC, when compared with non-inflamed ones in PBC and in control livers (P < 0.01). The co-expression of p62 with LC3, LAMP-1 and senescent markers was seen in the inflamed SBDs in PBC, but the intracytoplasmic localization was different. The expression of p62 and LC3 was significantly upregulated in BECs treated with various stress (P < 0.01) and pretreatment with bafilomycin A1 enhanced the accumulation of p62-positive aggregates in BECs with serum deprivation. The knockdown of p62 decreased stress-induced autophagy and cellular senescence.
  
  
  CONCLUSIONS
  The aggregation of p62 is specifically increased in the damage bile ducts in PBC and may reflect dysfunctional autophagy, followed by cellular senescence in the pathogenesis of bile duct lesions in PBC.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Sasaki
authors.forename: Masami
authors.initials: M
authors.lastname: Miyakoshi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008105:Liver Cirrhosis, Biliary / Q000503:physiopathology*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C493956:CDKN1A protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C477012:MAP1LC3A protein, human; C099718:SQSTM1 protein, human