Cytoglobin Deficiency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway
Cytoglobin Deficiency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway
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DOI：
10.1016/j.ajpath.2014.12.017
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发表时间：
2015-04-01
影响因子：
6
通讯作者：
Kawada, Norifumi
中科院分区：
文献类型：
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作者：
Le Thi Thanh Thuy;Matsumoto, Yoshinari;Kawada, Norifumi
本研究旨在阐明细胞珠蛋白(Cygb)在非酒精性脂肪性肝炎(NASH)肝纤维化和癌症发生中的作用。对NASH和肝细胞癌患者的Cygb表达进行了评估。在Cygb缺陷型(Cygb(-/-))或野生型(WT)小鼠中，通过给予胆碱缺乏氨基酸限定的饲料建立小鼠NASH模型，其中一些小鼠采用巨噬细胞缺失和N-乙酰半胱氨酸处理。从WT(HSCsCygb-Wild)和Cygb(-/-)(HSCsCygb-空)小鼠分离出原代培养的小鼠HSCs。结果显示，NASH和肝细胞癌患者细胞色素B的表达降低。胆碱缺乏氨基酸处理8周可引起Cygb(-/-)小鼠明显的炎症和纤维化，巨噬细胞缺失可抑制这种炎症和纤维化。令人惊讶的是，在32周时，尽管WT组小鼠没有形成肿瘤，但所有Cygb(-/-)小鼠都患上了肝癌，N-乙酰半胱氨酸治疗后情况有所改善。在Cygb(-/-)小鼠中，参与活性氧代谢的31个基因的表达发生了显著的变化。HSCsCygb-Null和Cygb siRNA转染的HSCsCygb-Wild均表现出预激活状态。我们的发现为了解肝纤维化期间在HSC中表达的Cygb在NASH的癌症发展中所起的作用提供了重要的见解。
This study was conducted to clarify the role of cytoglobin (Cygb), a globin expressed in hepatic stellate cells (HSCs), in the development of Liver fibrosis and cancer in nonalcoholic steatohepatitis (NASH). Cygb expression was assessed in patients with NASH and hepatocellular carcinoma. Mouse NASH model was generated in Cygb-deficient (Cygb(-/-)) or wild-type (WT) mice by giving a choline-deficient amino acid defined diet and, in some of them, macrophage deletion and N-acetyl cysteine treatment were used. Primary-cultured mouse HSCs isolated from WT (HSCsCygb-wild) or Cygb(-/-) (HSCsCygb-null) mice were characterized. As results, the expression of CYGB was reduced in patients with NASH and hepatocellular carcinoma. Choline-deficient amino acid treatment for 8 weeks induced prominent inflammation and fibrosis in Cygb(-/-) mice, which was inhibited by macrophage deletion. Surprisingly, at 32 weeks, despite no tumor formation in the WT mice, all Cygb(-/-) mice developed liver cancer, which was ameliorated by N-acetyl cysteine treatment. Altered expression of 31 genes involved in the metabolism of reactive oxygen species was notable in Cygb(-/-) mice. Both HSCsCygb-null and Cygb siRNA-transfected-HSCsCYgb-wild exhibited the preactivation condition. Our findings provide important insights into the role that Cygb, expressed in HSCs during liver fibrosis, plays in cancer development with NASH.