title: A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations.
abstract: 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.
authors: Department of Gastroenterology and Hepatology, Graduate School of MedicineKyoto University, Kyoto, Japan.
authors: Soo Ki
authors: SK
authors: Kim
authors: Akihiro
authors: A
authors: Nasu
authors: Junji
authors: J
authors: Komori
authors: Takahiro
authors: T
authors: Shimizu
authors: Yuko
authors: Y
authors: Matsumoto
authors: Yasuko
authors: Y
authors: Minaki
authors: Kenji
authors: K
authors: Kohno
authors: Kazuharu
authors: K
authors: Shimizu
authors: Shinji
authors: S
authors: Uemoto
authors: Tsutomu
authors: T
authors: Chiba
authors: Hiroyuki
authors: H
authors: Marusawa
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D003564:Cytidine Deaminase / Q000235:genetics / Q000502:physiology*; D004167:Diphtheria Toxin / Q000494:pharmacology; D008099:Liver / Q000166:cytology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D013234:Stem Cells / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004167:Diphtheria Toxin; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: activation-induced cytidine deaminase (AID); hepatic progenitor cells; liver cancer; liver carcinogenesis; mutation