Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

Abstract

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 2/2 Deltalike protein (Dlk) 1 hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf 2/2 Dlk 1 cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk 1 cells. Although Ink4a/Arf 2/2 Dlk 1 cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf 2/2 Dlk 1 cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five downregulated 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 1 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.

BMI1 as a novel target for drug discovery in cancer

“…Ample evidence exists linking BMI1 expression levels to selfrenewal and maintenance of both normal and cancer stem cells [Bruggeman et al, 2007a;Chiba et al, 2010;Yu et al, 2011]. The study of BMI1 knockout mice revealed that BMI1 is indispensable for the self-renewal of normal hematopoietic stem cells (HSC) [Park et al, 2003] More recently, the Schuringa laboratory demonstrated that BMI1 expression is required for maintenance and self-renewal of not only normal but also leukemic stem and progenitor cells .…”

“…The study of BMI1 knockout mice revealed that BMI1 is indispensable for the self-renewal of normal hematopoietic stem cells (HSC) [Park et al, 2003] More recently, the Schuringa laboratory demonstrated that BMI1 expression is required for maintenance and self-renewal of not only normal but also leukemic stem and progenitor cells . In an assessment of acute myeloid leukemia stem cell (LSC) populations, van Gosilga et al [2007] showed that CD34 [Chiba et al, 2010;Yu et al, 2011]. For instance, Chiba et al [2010] demonstrated the polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma, while Abdouh et al [2009] showed BMI1 protein is involved in GBM tumor growth and is required to sustain cancer initiating stem cell renewal.…”

Epigenetic Mechanisms in Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Potential New Link Between Stem Cells, Virology and Cancer

“…It is essential for self-renewal of both hematopoietic stem cells as well as neural stem cells through Ink4a/Arf locus (Bruggeman et al, 2005;Oguro et al, 2006). Similarly, BMI1 enhances selfrenewal of hepatic stem cells through repression of Ink4a/Arf locus (Chiba et al, 2010). We have previously shown that CDKN2A is preferentially methylated in HCV caused HCC (Feng et al, 2010) and HCV infection directly down regulates CDKN2A.…”

BMI-1, a promising therapeutic target for human cancer

“…Chiba et al have indicated that repression of Ink4a/Arf is crucial in the oncogenic transformation of hepatic stem cells (75). A number of studies have also demonstrated that BMI-1 is able to promote stem cell self-renewal mainly by interfering with two signaling pathways, p16…”