These authors contributed equally to this work.
Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and -independent manners in Mice†
Article first published online: 11 JUN 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Volume 52, Issue 3, pages 1111–1123, September 2010
How to Cite
Chiba, T., Seki, A., Aoki, R., Ichikawa, H., Negishi, M., Miyagi, S., Oguro, H., Saraya, A., Kamiya, A., Nakauchi, H., Yokosuka, O. and Iwama, A. (2010), Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and -independent manners in Mice. Hepatology, 52: 1111–1123. doi: 10.1002/hep.23793
Potential conflict of interest: Nothing to report.
- Issue published online: 26 AUG 2010
- Article first published online: 11 JUN 2010
- Manuscript Accepted: 31 MAY 2010
- Manuscript Received: 19 APR 2010
- Global COE program (Global Center for Education and Research in Immune System Regulation and Treatment) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and grants from the Chiba Serum Institute Memorial Fund for Health Medical Welfare, Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST), the Takeda Science Foundation, and the Uehara Memorial Foundation
We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1−/− Delta-like protein (Dlk)+ hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf−/− Dlk+ cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk+ cells. Although Ink4a/Arf−/− Dlk+ cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf−/− Dlk+ cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five down-regulated genes as candidate downstream targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk+ cells strongly suppressed colony propagation and tumor growth. Conclusion: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells. (Hepatology 2010)