Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis

Abstract

Bmi1 is a polycomb group proto-oncogene that has been implicated in multiple tumor types. However, its role in hepatocellular carcinoma (HCC) development has not been well studied. In this article, we report that Bmi1 is overexpressed in human HCC samples. When Bmi1 expression is knocked down in human HCC cell lines, it significantly inhibits cell proliferation and perturbs cell cycle regulation. To investigate the role of Bmi1 in promoting liver cancer development in vivo, we stably expressed Bmi1 and/or an activated form of Ras (RasV12) in mouse liver. We found that while Bmi1 or RasV12 alone is not sufficient to promote liver cancer development, coexpression of Bmi1 and RasV12 promotes HCC formation in mice. Tumors induced by Bmi1/RasV12 resemble human HCC by deregulation of genes involved in cell proliferation, apoptosis, and angiogenesis. Intriguingly, we found no evidence that Bmi1 regulates Ink4A/Arf expression in both in vitro and in vivo systems of liver tumor development. In summary, our study shows that Bmi1 can cooperate with other oncogenic signals to promote hepatic carcinogenesis in vivo. Yet Bmi1 functions independent of Ink4A/Arf repression in liver cancer development. (Mol Cancer Res 2009;7(12):1937-45)

Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling

“…As a member of the polycomb group (PcG) family, Bmi-1 has an essential role in embryogenesis and regulation of cell cycle. Moreover, it serves as a pro-oncogene in tumorigenicity [39] and also contributes to the maintenance of the cancer stem cells [29,40].…”

“…The two tumor suppressors play important roles in regulating cell cycle arrest and carcinogenesis. P14 ARF binds and inhibits the P53 antagonist Mdm2, leading to the accumulation of P53 [29,40]. Furthermore, P16 Ink4a is frequently inactivated in tumors and activation of P16 Ink4a -Rb signaling results in senescence [41].…”

Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators

“…Primary human MDMs were transfected with 100 nM scrambled or ON-TARGETplus SMARTpool siRNA against Twist1, Twist2, c-Maf, Bmi1, ATF4, C/EBPα, Runx1, Runx2, (Dharmacon, Lafayette, CO) (4 pooled siRNAs for each gene), or with 2 μg pT3-EF1a-Bmi1 (Addgene plasmid 31783 kindly deposited by X. Chen (23)), c-Maf (GeneCopoeia, Rockville, MD) or empty vector using Amaxa nucleofector technology (Amaxa, San Diego, CA).…”

Epigenetic Modification of Histone 3 Lysine 27

“…Co-immunoprecipitation Assays-HEK293 cells were transfected with expression plasmids pCR3.1-HNF4␣ and either FLAG-MED25 or siRNA (Thermo Fisher, L-014689-01) against MED25 using Lipofectamine 2000 (Invitrogen); cells were also co-transfected with pCMVHA-EED, pCMVHAhEZH2 (26), pCMVHA-SUZ12 (27), or pT3-EF1a-BMI1 (28). Nuclear extracts were prepared as described previously (29) and immunoprecipitated with 2 g of HNF4␣ (rabbit, sc-8987, Santa Cruz Biotechnology), hemagglutinin (HA) (rat, catalog No.…”