Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and -independent manners in mice.
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.


CONCLUSIONS
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.
Chiba
Tetsuhiro
T
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Seki
Atsuyoshi
A
Aoki
Ryutaro
R
Ichikawa
Hitoshi
H
Negishi
Masamitsu
M
Miyagi
Satoru
S
Oguro
Hideyuki
H
Saraya
Atsunori
A
Kamiya
Akihide
A
Nakauchi
Hiromitsu
H
Yokosuka
Osamu
O
Iwama
Atsushi
A
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D024002:HMGB Proteins / Q000378:metabolism; D008099:Liver / Q000196:embryology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D023421:Models, Animal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D055760:SOXF Transcription Factors / Q000378:metabolism
C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D024002:HMGB Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; D063150:Polycomb Repressive Complex 1