Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis
Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis
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DOI：
10.2353/ajpath.2006.051237
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发表时间：
2006-09-01
影响因子：
6
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
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作者：
Sasaki, Motoko;Ikeda, Hiroko;Nakanuma, Yasuni
受损小胆管中表达p16（INK4a）和p21（WAF1/Cip）的胆道上皮细胞的细胞衰老可能是原发性胆汁性肝硬化中胆管进行性损失的关键。我们研究了抑制p16（INK4a）表达的多梳群基因bmi1在胆道细胞衰老的发病机制中的作用。采用免疫组织化学方法检测Bmi1在原发性胆汁性肝硬化患者（18例）、其他病变患者（19例）和正常肝脏（16例）肝脏中的表达。我们研究了氧化应激和靶向bmi1的短干扰RNA （siRNA）对培养小鼠胆道上皮细胞衰老的影响。Bmi1在对照肝脏的胆道上皮细胞核中广泛表达。相比之下，43%的原发性胆汁性肝硬化1/2期患者受损小胆管中bmi1表达显著降低，与p16（INK4a）表达升高相一致。在培养的胆道上皮细胞中，H2O2氧化应激显著降低bmi1的表达，随后升高P16（INK4a）的表达。敲低bmi1诱导p16（INK4a）表达增加，细胞增殖减少，细胞衰老增加。综上所述，氧化应激导致的bmi1表达降低可能参与了原发性胆汁性肝硬化中胆道上皮细胞衰老的发病机制。
Cellular senescence of biliary epithelial cells with p16(INK4a) and p21(WAF1/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 p16(INK4a) 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 p16(INK4a) expression. in cultured billiary epithelial cells, oxidative stress by H2O2 treatment significantly decreased bmi1 expression, followed by increased P16(INK4a) expression. A knockdown of bmi1 induced increased p16(INK4a) 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.