Accumulation of genetic alterations in hepatic progenitor cells in mice lead to the development of liver cancers.. Mus musculus

Aberrant expression of nucleotide editing enzyme, activation-induced cytidine deaminase (AID) contributes to hepatocarcinogenesis via the accumulation of genetic alterations. In this study, we took advantage of the ability of AID to induce stepwise genetic alterations in various target genes and asked whether accumulation of genetic alterations in hepatic progenitor cells results in the development of liver cancers. For this purpose, we enriched the hepatic progenitor cells from the fetal liver derived from AID transgenic mice followed by the transplantation to recipient mice. Notably, multiple liver cancers developed in 60% of the recipient mice in 90 weeks, while no tumors were detected in the recipient mouse receiving the hepatic progenitor cells of WT mouse transplanted. The whole exome sequencing on the tumor cells using exon-capture technology in combination with ultra-deep sequencing revealed that a number of tumor related genes acquired somatic mutations during the process of malignant transformation of the progenitor cells. These findings suggested that liver cancers would originate from the hepatic stem/progenitor cells that acquire genetic alterations.