Bmi1is Required For Hepatic Progenitor Cell Expansion And Liver Tumor Development

Bmi1is a polycomb group transcriptional repressor and it has been implicated in regulatingself-renewal and proliferation of many types of stem or progenitor cells. In addition, Bmi1has been shown to function as an oncogene in multiple tumor types. In this study, weinvestigated the functional significance of Bmi1in regulating hepatic oval cells, the majortype of bipotential progenitor cells in adult liver, as well as the role of Bmi1duringhepatocarcinogenesis using Bmi1knockout mice. We found that loss of Bmi1significantlyrestricted chemically induced oval cell expansion, while not affecting hepatocyteproliferation, in the mouse liver. Concomitant deletion of Ink4a/Arf in Bmi1deficient micecompletely rescued the oval cell expansion pH&Enotype. FurtH&Ermore, ablation of Bmi1delayed hepatocarcinogenesis induced by AKT and Ras co-expression. This antineoplasticeffect was accompanied by the loss of hepatic oval cell marker expression in the liver tumorsamples. In summary, our data demonstrated that Bmi1is required for hepatic oval cellexpansion via deregulating the Ink4a/Arf locus in mice. Our study also provides theevidence, for the first time, that Bmi1expression is required for liver cancer developmentin vivo, thus representing a promising target for innovative treatments against human HCC.