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タイトル: A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations.
著者: Kim, Soo Ki
Nasu, Akihiro
Komori, Junji
Shimizu, Takahiro  KAKEN_id  orcid https://orcid.org/0000-0001-8392-2526 (unconfirmed)
Matsumoto, Yuko
Minaki, Yasuko
Kohno, Kenji
Shimizu, Kazuharu
Uemoto, Shinji  KAKEN_id
Chiba, Tsutomu
Marusawa, Hiroyuki  KAKEN_id
著者名の別形: 金, 秀基
丸澤, 宏之
キーワード: liver cancer
hepatic progenitor cells
activation-induced cytidine deaminase (AID)
mutation
liver carcinogenesis
発行日: 16-Sep-2013
出版者: wiley
誌名: International journal of cancer
巻: 134
号: 5
開始ページ: 1067
終了ページ: 1076
抄録: 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.
著作権等: This is the peer reviewed version of the following article: Kim, S. K., Nasu, A., Komori, J., Shimizu, T., Matsumoto, Y., Minaki, Y., Kohno, K., Shimizu, K., Uemoto, S., Chiba, T. and Marusawa, H. (2014), A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations. Int. J. Cancer, 134: 1067–1076, which has been published in final form at http://dx.doi.org/10.1002/ijc.28445
This is not the published version. Please cite only the published version.
この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
URI: http://hdl.handle.net/2433/197134
DOI(出版社版): 10.1002/ijc.28445
PubMed ID: 23959426
出現コレクション:学術雑誌掲載論文等

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