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.
Highlights
MiR-221 and miR-222 are frequently up-regulated in various types of human malignancy including glioblastoma
We have demonstrated that miR-221/222 are of important role in regulation of cell apoptosis by direct targeting pro-apoptotic molecule PUMA in cell culture and xenograft model
Annexin V-labeling revealed that knockdown of miR-221 and miR-222 significantly increased cell apoptosis compared to the cells treated with scramble oligonucleotide (Fig. 1C)
Summary
MiR-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. Deregulation of miRNAs has been observed in various types of human malignancy, including lymphoma, colorectal cancer, lung cancer, breast cancer, papillary thyroid carcinoma, hepatocellular carcinoma and glioblastoma [1,2,3,4,5,6,7]. We have demonstrated that miR-221/222 are of important role in regulation of cell apoptosis by direct targeting pro-apoptotic molecule PUMA in cell culture and xenograft model. MiR-221/222 directly interact with 3′UTR of PUMA to repress PUMA expression These findings indicate that PUMA is a bona fide target of miR-221/222 and these 2 miRNAs could be critical therapeutic targets for glioblastoma intervention
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