...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
【24h】

Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.

机译：肝脏特异性抑制素的缺失会导致小鼠自发性肝损伤，纤维化和肝细胞癌。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Prohibitin 1 (PHB1) is a highly conserved, ubiquitously expressed protein that participates in diverse processes including mitochondrial chaperone, growth and apoptosis. The role of PHB1 in vivo is unclear and whether it is a tumor suppressor is controversial. Mice lacking methionine adenosyltransferase 1A (MAT1A) have reduced PHB1 expression, impaired mitochondrial function, and spontaneously develop hepatocellular carcinoma (HCC). To see if reduced PHB1 expression contributes to the Mat1a knockout (KO) phenotype, we generated liver-specific Phb1 KO mice. Expression was determined at the messenger RNA and protein levels. PHB1 expression in cells was varied by small interfering RNA or overexpression. At 3 weeks, KO mice exhibit biochemical and histologic liver injury. Immunohistochemistry revealed apoptosis, proliferation, oxidative stress, fibrosis, bile duct epithelial metaplasia, hepatocyte dysplasia, and increased staining for stem cell and preneoplastic markers. Mitochondria are swollen and many have no discernible cristae. Differential gene expression revealed that genes associated with proliferation, malignant transformation, and liver fibrosis are highly up-regulated. From 20 weeks on, KO mice have multiple liver nodules and from 35 to 46 weeks, 38% have multifocal HCC. PHB1 protein levels were higher in normal human hepatocytes compared to human HCC cell lines Huh-7 and HepG2. Knockdown of PHB1 in murine nontransformed AML12 cells (normal mouse hepatocyte cell line) raised cyclin D1 expression, increased E2F transcription factor binding to cyclin D1 promoter, and proliferation. The opposite occurred with PHB1 overexpression. Knockdown or overexpression of PHB1 in Huh-7 cells did not affect proliferation significantly or sensitize cells to sorafenib-induced apoptosis. Conclusion: Hepatocyte-specific PHB1 deficiency results in marked liver injury, oxidative stress, and fibrosis with development of HCC by 8 months. These results support PHB1 as a tumor suppressor in hepatocytes.
机译：抑制素1（PHB1）是一种高度保守的，无处不在的表达蛋白，参与各种过程，包括线粒体伴侣，生长和凋亡。 PHB1在体内的作用尚不清楚，是否是抑癌药尚有争议。缺少蛋氨酸腺苷转移酶1A（MAT1A）的小鼠具有降低的PHB1表达，损害线粒体功能，并自发发展为肝细胞癌（HCC）。若要查看是否减少的PHB1表达有助于Mat1a基因敲除（KO）表型，我们生成了肝脏特异性Phb1 KO小鼠。在信使RNA和蛋白质水平确定表达。细胞中PHB1的表达因小干扰RNA或过表达而发生变化。在第3周，KO小鼠表现出生化和组织学肝损伤。免疫组织化学显示细胞凋亡，增殖，氧化应激，纤维化，胆管上皮化生，肝细胞异型增生，以及干细胞和肿瘤前标记物的染色增加。线粒体肿胀，许多没有明显的cr裂。差异基因表达显示与增殖，恶性转化和肝纤维化相关的基因高度上调。从20周开始，KO小鼠会出现多个肝结节，而从35周到46周，有38％的小鼠患有多灶性肝癌。与人HCC细胞系Huh-7和HepG2相比，正常人肝细胞中的PHB1蛋白水平更高。敲低小鼠未转化的AML12细胞（正常小鼠肝细胞）中的PHB1会提高细胞周期蛋白D1的表达，增加与细胞周期蛋白D1启动子结合的E2F转录因子，并使其增殖。 PHB1过表达则相反。在Huh-7细胞中PHB1的敲低或过表达不会显着影响增殖或使细胞对索拉非尼诱导的细胞凋亡敏感。结论：肝细胞特异的PHB1缺乏会导致肝损伤，氧化应激和肝癌发展8个月时的纤维化。这些结果支持PHB1作为肝细胞中的肿瘤抑制剂。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号