Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
Mol Cancer. 2010 Sep 2;9:229. doi: 10.1186/1476-4598-9-229.
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. However the underlying mechanism involved in cell survival modulation of miR-221/222 remains elusive.
Here 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.
To 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.
miR-221 和 miR-222（miR-221/222）在包括神经胶质瘤在内的多种人类恶性肿瘤中经常上调。最近的研究表明，miR-221/222 通过靶向 p27 和 p57 来调节细胞生长和细胞周期进程。然而，miR-221/222 调节细胞存活的潜在机制仍不清楚。
在这里，我们表明 miR-221/222 通过靶向人神经胶质瘤细胞中的促凋亡基因 PUMA 抑制细胞凋亡。miR-22/22 的强制表达诱导细胞存活，而 miR-221/222 的敲低则使细胞凋亡。此外，miR-221/222 通过靶向 PUMA-3'UTR 降低 PUMA 蛋白水平。没有 3'UTR 的 PUMA cDNA 的引入消除了 miR-221/222 诱导的细胞存活。值得注意的是，miR-221/222 的敲低诱导 PUMA 表达和细胞凋亡，并显著减少异种移植模型中的肿瘤生长。最后，在神经胶质瘤组织中，PUMA 和 miR-221/222 的表达呈负相关。
据我们所知，这些数据首次表明 miR-221/222 通过靶向神经胶质瘤中的 PUMA 直接调节细胞凋亡，并且 miR-221/222 可能是神经胶质瘤干预的潜在治疗靶点。
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