Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis.
Cellular senescence of biliary epithelial cells with p16INK4a and p21WAF1/Cip expression in damaged small bile ducts may be critical for progressive bile duct loss in primary biliary cirrhosis. We investigated the involvement of bmi1, a polycomb group gene repressing p16INK4a expression, in the pathogenesis of biliary cellular senescence. Bmi1 expression was examined immunohistochemically in livers taken from the patients with primary biliary cirrhosis (n=18) and other diseased (n=19) and normal livers (n=16). We examined the effect of oxidative stress and a short interference RNA (siRNA) targeting bmi1 on cellular senescence in cultured mouse biliary epithelial cells. Bmi1 was widely expressed in the nuclei of biliary epithelial cells in the control livers. In contrast, bmi1 expression was significantly decreased in damaged small bile ducts in 43% of livers with primary biliary cirrhosis of stage 1/2, coordinating with the increased p16INK4a expression. In cultured biliary epithelial cells, oxidative stress by H2O2 treatment significantly decreased bmi1 expression, followed by increased P16INK4a expression. A knockdown of bmi1 induced increased p16INK4a expression, decreased cell proliferation, and increased cellular senescence. In conclusion, the decreased bmi1 expression caused by oxidative stress may be involved in the pathogenesis of cellular senescence of biliary epithelial cells in primary biliary cirrhosis.
Sasaki
Motoko
M
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
Ikeda
Hiroko
H
Sato
Yasunori
Y
Nakanuma
Yasuni
Y
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D006861:Hydrogen Peroxide; D063150:Polycomb Repressive Complex 1