MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma

Abstract

BackgroundMiR-221 and miR-222 (miR-221/222) are frequently up-regulated in various types of human malignancy including glioblastoma. Recent studies have reported that miR-221/222 regulate cell growth and cell cycle progression by targeting p27 and p57. However the underlying mechanism involved in cell survival modulation of miR-221/222 remains elusive.ResultsHere we showed that miR-221/222 inhibited cell apoptosis by targeting pro-apoptotic gene PUMA in human glioma cells. Enforced expression of miR-22/222 induced cell survival whereas knockdown of miR-221/222 rendered cells to apoptosis. Further, miR-221/222 reduced PUMA protein levels by targeting PUMA-3'UTR. Introducing PUMA cDNA without 3'UTR abrogated miR-221/222-induced cell survival. Notably, knockdown of miR-221/222 induces PUMA expression and cell apoptosis and considerably decreases tumor growth in xenograft model. Finally, there was an inverse relationship between PUMA and miR-221/222 expression in glioma tissues.ConclusionTo our knowledge, these data indicate for the first time that miR-221/222 directly regulate apoptosis by targeting PUMA in glioblastoma and that miR-221/222 could be potential therapeutic targets for glioblastoma intervention.

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…70,71 As for the pro-survival BCL-2 family members, BCL-2 and MCL-1 appear to be the prominent targets of miRNA-mediated regulation. Both are targeted by miR-29 and miR-153, [72][73][74] and BCL-2 expression is also regulated by miR-15, miR-16, 75 miR-195 76 and the p53-inducible miR-34.…”

Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

“…Soy isoflavones appear to be safe and effective in pre-clinical studies but clinical trials supporting their efficacy are still required (Virk-Baker et al, 2010). Shi et al, 2010;Ren et al, 2010;Conti et al, 2009;Chen et al, 2008;Papagiannakopoulos et al, 2008;Gabriely et al, 2008;corsten et al, 2007;Chan et al, 2005 miR-34a Oncogenes Wang et al, 2011;Zhang CZ et al, 2010;Lorimer, 2009;Conti et al, 2009;Lukiw et al, 2009;Gillies & Lorimer, 2007 (Lino & Merlo, 2009;Patel et al, 2009;Redzic, 2011). Moreover, the capillary endothelium on the brain side is completely surrounded or wrapped by astroglial end feet (Patel et al, 2009;Redzic, 2011).…”

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

“…Thus, forced expression of miR‐221/222 and the subsequent downregulation of PUMA, promotes cell survival. Therefore, the knockdown of miR‐221/222 is able to induce cell death and decrease tumor growth 48, 49. miR‐221/222 can also target the cell growth‐suppressive CDK inhibitors P27 and P57 50 and thus are tightly linked to cell cycle checkpoints for initiation of S phase.…”