title: The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma.
abstract: Side population (SP) cell analysis and sorting have been successfully applied to hepatocellular carcinoma (HCC) cell lines to identify a minor cell population with cancer stem cell properties. However, the molecular mechanisms operating in SP cells remain unclear. The polycomb gene product BMI1 plays a central role in the self-renewal of somatic stem cells in a variety of tissues and organs and seems to be implicated in tumor development. In this study, we determined the critical role of BMI1 in the maintenance of cancer stem cells with the SP phenotype in HCC cell lines. BMI1 was preferentially expressed in SP cells in Huh7 and PLC/PRF/5 HCC cells compared with the corresponding non-SP cells. Lentiviral knockdown of BMI1 considerably decreased the number of SP cells in both Huh7 and PLC/PRF/5 cells. Long-term culture of purified SP cells resulted in a drastic reduction in the SP subpopulation upon the BMI1 knockdown, indicating that BMI1 is required for the self-renewal of SP cells in culture. More importantly, the BMI1 knockdown abolished the tumor-initiating ability of SP cells in nonobese diabetic/severe combined immunodeficiency mice. Derepression of the INK4A and ARF genes that are major targets for BMI1 was not necessarily associated with impaired self-renewal of SP cells caused by BMI1 knockdown. In conclusion, our findings define an important role for BMI1 in the maintenance of tumor-initiating SP cells in HCC. BMI1 might be a novel therapeutic target for the eradication of cancer stem cells in HCC.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Aoki
authors.forename: Atsuyoshi
authors.initials: A
authors.lastname: Seki
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yonemitsu
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.forename: Hideki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C069077:BMI1 protein, human; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1