2, 4 Of note, it has been demonstrated that Bmi1 is necessary for the maintenance of not only leukemic stem cells but also cancer stem cells in solid tumors.5, 6 Considering that high expression levels of Bmi1 are reported in a wide range of malignancies, Bmi1 could be a general regulator of cancer stem cells as in normal stem cells. Disruption of the tightly regulated self-renewal process is considered a key early event in carcinogenesis.7 Enhancement or selleck chemical reacquisition of the self-renewal capability in hematopoietic stem or progenitor cells is essential for

leukemogenesis.8 We also showed that forced expression of Bmi1 accelerated the self-renewal of hepatic stem/progenitor cells and eventually induced their transformation in an in vivo transplant model.3 However, the molecular machinery underlying the Bmi1-mediated transformation of hepatic stem/progenitor

cells remains unclear. The Ink4a/Arf locus, which encodes a cyclin-dependent kinase (CDK) inhibitor, p16Ink4a, and a tumor suppressor, p19Arf, is a pivotal target of Bmi1.9 We showed that de-repressed p16Ink4a and p19Arf expression in Bmi1-deficient mice was tightly associated with a loss of self-renewing hematopoietic stem cells (HSCs). Deletion SCH772984 concentration of both the Ink4a and Arf genes substantially restored the self-renewal capacity of Bmi1-deficient HSCs. Bmi1 thus regulates HSCs by acting as a critical failsafe against the p16Ink4a and p19Arf-dependent senescence pathway.10, 11 Deletion of Ink4a/Arf similarly rescues neural stem cell (NSC) self-renewal and frequencies in Bmi1-deficient mice, although its effect is reportedly partial.12 In the

oncogenic setting, the Ink4a–retinoblastoma protein (Rb) and Arf-p53 cellular senescence pathways trigger oncogene-induced senescence to eliminate transforming cells that potentially develop into cancer stem cells.2 Given selleck chemicals llc that enhanced expression of BMI1 and reduced expression of INK4A/ARF are frequently observed in human hepatocellular carcinoma (HCC) samples,13, 14 it would be of importance to understand the contribution of the Ink4a/Arf locus to the oncogenic functions of Bmi1 in cancer and search for as-yet-unknown target genes of Bmi1 other than Ink4a/Arf. In the present study, we prepared hepatic stem/progenitor cells from fetal livers of Bmi1-deficient and Ink4a/Arf-deficient mice and characterized their self-renewal capacity and effects of Bmi1 overexpression on them. Through these analyses, we found that the Ink4a/Arf-independent function of Bmi1 is also essential for its full oncogenic activity in hepatic stem/progenitor cells. Our microarray screening successfully identified candidate downstream targets for Bmi1 in hepatic stem/progenitor cells.