Bmi1 is required for hepatic progenitor cell expansion and liver tumor development.
Bmi1 is required for hepatic progenitor cell expansion and liver tumor development.
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Bmi1 是肝祖细胞扩增和肝肿瘤发展所必需的
DOI：
10.1371/journal.pone.0046472
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Fan L;Xu C;Wang C;Tao J;Ho C;Jiang L;Gui B;Huang S;Evert M;Calvisi DF;Chen X
Bmi1 是一种多梳组转录抑制因子，它与调节多种干细胞或祖细胞的自我更新和增殖有关。此外，Bmi1 已被证明在多种肿瘤类型中发挥癌基因的作用。在本研究中，我们利用 Bmi1 敲除小鼠研究了 Bmi1 在调节肝卵圆细胞（成人肝脏中双能祖细胞的主要类型）中的功能意义，以及 Bmi1 在肝癌发生过程中的作用。我们发现 Bmi1 的缺失显着限制了化学诱导的小鼠肝脏卵圆细胞的扩张。 Bmi1缺陷小鼠中同时删除Ink4a/Arf完全挽救了卵圆细胞扩张表型。此外，Bmi1 的消除可延迟 AKT 和 Ras 共表达诱导的肝癌发生。这种抗肿瘤作用伴随着肝肿瘤样本中肝卵圆细胞标志物表达的丧失。总之，我们的数据表明，Bmi1 是通过解除小鼠 Ink4a/Arf 基因座的调节来实现肝卵圆细胞扩张所必需的。我们的研究还首次提供了证据表明 Bmi1 表达是肝癌体内发展所必需的，因此代表了人类肝癌创新治疗的一个有希望的靶点。
Bmi1 is a polycomb group transcriptional repressor and it has been implicated in regulating self-renewal and proliferation of many types of stem or progenitor cells. In addition, Bmi1 has been shown to function as an oncogene in multiple tumor types. In this study, we investigated the functional significance of Bmi1 in regulating hepatic oval cells, the major type of bipotential progenitor cells in adult liver, as well as the role of Bmi1 during hepatocarcinogenesis using Bmi1 knockout mice. We found that loss of Bmi1 significantly restricted chemically induced oval cell expansion in the mouse liver. Concomitant deletion of Ink4a/Arf in Bmi1 deficient mice completely rescued the oval cell expansion phenotype. Furthermore, ablation of Bmi1 delayed hepatocarcinogenesis induced by AKT and Ras co-expression. This antineoplastic effect was accompanied by the loss of hepatic oval cell marker expression in the liver tumor samples. In summary, our data demonstrated that Bmi1 is required for hepatic oval cell expansion via deregulating the Ink4a/Arf locus in mice. Our study also provides the evidence, for the first time, that Bmi1 expression is required for liver cancer development in vivo, thus representing a promising target for innovative treatments against human liver cancer.
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影响因子：
13.5
作者：
Dorrell, Craig;Erker, Laura;Lanxon-Cookson, Kelsea M.;Abraham, Stephanie L.;Victoroff, Tristan;Ro, Simon;Canaday, Pamela S.;Streeter, Philip R.;Grompe, Markus
通讯作者：
Grompe, Markus
影响因子：
3.7
作者：
Becker M;Korn C;Sienerth AR;Voswinckel R;Luetkenhaus K;Ceteci F;Rapp UR
通讯作者：
Rapp UR
影响因子：
11.2
作者：
Chiba, Tetsuhiro;Miyagi, Satoru;Iwama, Atsushi
通讯作者：
Iwama, Atsushi
影响因子：
4.7
作者：
EVARTS, RP;NAGY, P;THORGEIRSSON, SS
通讯作者：
THORGEIRSSON, SS
影响因子：
10.5
作者：
Lessard, J;Schumacher, A;Sauvageau, G
通讯作者：
Sauvageau, G