title: Bmi1 is required for hepatic progenitor cell expansion and liver tumor development.
abstract: Bmi1 is a polycomb group transcriptional repressor and it has been implicated in regulating self-renewal and proliferation of many types of stem or progenitor cells. In addition, Bmi1 has been shown to function as an oncogene in multiple tumor types. In this study, we investigated the functional significance of Bmi1 in regulating hepatic oval cells, the major type of bipotential progenitor cells in adult liver, as well as the role of Bmi1 during hepatocarcinogenesis using Bmi1 knockout mice. We found that loss of Bmi1 significantly restricted chemically induced oval cell expansion in the mouse liver. Concomitant deletion of Ink4a/Arf in Bmi1 deficient mice completely rescued the oval cell expansion phenotype. Furthermore, ablation of Bmi1 delayed hepatocarcinogenesis induced by AKT and Ras co-expression. This antineoplastic effect was accompanied by the loss of hepatic oval cell marker expression in the liver tumor samples. In summary, our data demonstrated that Bmi1 is required for hepatic oval cell expansion via deregulating the Ink4a/Arf locus in mice. Our study also provides the evidence, for the first time, that Bmi1 expression is required for liver cancer development in vivo, thus representing a promising target for innovative treatments against human liver cancer.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Lingling
authors.initials: L
authors.lastname: Fan
authors.forename: Chuanrui
authors.initials: C
authors.lastname: Xu
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Junyan
authors.initials: J
authors.lastname: Tao
authors.forename: Coral
authors.initials: C
authors.lastname: Ho
authors.forename: Lijie
authors.initials: L
authors.lastname: Jiang
authors.forename: Bing
authors.initials: B
authors.lastname: Gui
authors.forename: Shiang
authors.initials: S
authors.lastname: Huang
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D015870:Gene Expression; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008840:Microfilament Proteins; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D018631:ras Proteins; C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; C514862:Akt1 protein, mouse; C485190:Twf1 protein, mouse