Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal

Abstract

MicroRNAs (miR) show characteristic expression signatures in various cancers and can profoundly affect cancer cell behavior. We carried out miR expression profiling of human glioblastoma specimens versus adjacent brain devoid of tumor. This revealed several significant alterations, including a pronounced reduction of miR-128 in tumor samples. miR-128 expression significantly reduced glioma cell proliferation in vitro and glioma xenograft growth in vivo. miR-128 caused a striking decrease in expression of the Bmi-1 oncogene, by direct regulation of the Bmi-1 mRNA 3 ¶-untranslated region, through a single miR-128 binding site. In a panel of patient glioblastoma specimens, Bmi-1 expression was significantly up-regulated and miR-128 was down-regulated compared with normal brain. Bmi-1 functions in epigenetic silencing of certain genes through epigenetic chromatin modification. We found that miR-128 expression caused a decrease in histone methylation (H3K27me 3 ) and Akt phosphorylation, and up-regulation of p21 CIP1 levels, consistent with Bmi-1 down-regulation. Bmi-1 has also been shown to promote stem cell self-renewal; therefore, we investigated the effects of miR-128 overexpression in human glioma neurosphere cultures, possessing features of glioma ''stem-like'' cells. This showed that miR-128 specifically blocked glioma self-renewal consistent with Bmi-1 downregulation. This is the first example of specific regulation by a miR of a neural stem cell self-renewal factor, implicating miRs that may normally regulate brain development as important biological and therapeutic targets against the ''stem cell-like'' characteristics of glioma. [Cancer Res 2008;68(22):9125-30]

MiR-135a functions as a selective killer of malignant glioma

“…Strong evidences support that miR-128 act as a tumorigenetic marker of glioma. This miRNA inhibits proliferation and self-renewal of glioma by targeting transcription factor E2F3a and oncogene Bmi1 (Godlewski et al, 2008;Zhang et al, 2009). In this study, we confirmed that miR-135a is a glia-enriched miRNA, suggesting its key role in functional maintenance of CNS.…”

“…One miR-NA is capable of targeting a number of genes to regulate biological processes globally. 128 and 137, and so on, have been documented as tumor suppressors capable of inhibiting cell proliferation of glioma by targeting different oncogenes (Godlewski et al, 2008;Silber et al, 2008;Zhang et al, 2009).…”

MicroRNAs and glioblastoma; the stem cell connection

“…[5][6][7] Distinct patterns of microRNA expression have been observed in many cancers including glioblastomas, and the functional significance of some of these microRNAs alterations is beginning to emerge. [8][9][10][11] These data indicate that microRNAs play roles in multiple hallmark biological characteristics of glioblastoma, including cell proliferation, invasion, angiogenesis, and also in glioma stem-like cell behavior, which will be the main focus of this article.…”

The Roles of MicroRNAs in the Cancer Invasion-Metastasis Cascade

“…Beside its roles in cell proliferation and migration as discussed above [86,87], miR-128 can specifically block the self-renewal of glioma by targeting the Bmi-1 oncogene [113]. miR-125b and miR-326 are able to inhibit proliferation and to enhance differentiation of medulloblastoma cells through repressing Smoothened (Smo), an activator of the Hedgehog pathway [114].…”