A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations.
A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations.
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源自肝祖细胞并积累遗传改变的肝癌模型。
DOI：
10.1002/ijc.28445
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发表时间：
2014
影响因子：
6.4
通讯作者：
Hiroyuki Marusawa.
中科院分区：
文献类型：
--
作者：
Soo Ki Kim;Akihiro Nasu;Junji Komori;Takahiro Shimizu;Yuko Matsumoto;Yasuko Minaki;Kenji Kohno;Kazuharu Shimizu;Shinji Uemoto;Tsutomu Chiba;Hiroyuki Marusawa.
活化诱导的胞苷脱氨酶（AID）通过其致突变活性促进炎症相关的致癌作用。在我们的研究中，通过利用AID诱导遗传畸变的能力，我们调查了肝癌是否起源于积累逐步遗传改变的肝干/祖细胞。为此，将从AID转基因（Tg）小鼠的胎肝中富集的肝祖细胞移植到受体“毒素受体介导的条件性细胞敲除”（TRECK）小鼠中，该小鼠在白喉毒素治疗条件下具有增强的肝再生活性。使用全外显子组测序来确定肿瘤发生期间移植祖细胞中累积的遗传改变的景观。在接受来自AID Tg小鼠的富集肝祖细胞的11只受体TRECK小鼠中有7只（63.6%）发生了肝肿瘤，而在接受野生型小鼠肝祖细胞的TRECK小鼠中未观察到肿瘤发生。组织学检查显示肿瘤具有肝细胞癌的特征和部分胆管细胞癌的特征，并表达AID转基因。全外显子组测序显示，几十个基因获得单核苷酸变异的肿瘤组织来源于移植的肝祖细胞的艾滋病转基因小鼠。微阵列分析显示，大多数突变（>80%）存在于肝系细胞中活跃转录的基因中。这些发现提供了证据，表明胎儿肝祖细胞中遗传改变的积累进展为肝癌，并且诱变的选择取决于肝谱系细胞中的活性转录。
Activation‐induced cytidine deaminase (AID) contributes to inflammation‐associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient “toxin‐receptor mediated conditional cell knockout” (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild‐type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver‐lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver‐lineage cells.