Upregulation of miR-23a-27a-24-2 cluster induces caspase-dependent and -independent apoptosis in human embryonic kidney cells.
Upregulation of miR-23a-27a-24-2 cluster induces caspase-dependent and -independent apoptosis in human embryonic kidney cells.
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miR-23a-27a-24-2簇的上调诱导人类胚胎肾细胞中的caspase依赖性和非依赖性凋亡。
DOI：
10.1371/journal.pone.0005848
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发表时间：
2009-06-09
期刊：
影响因子：
3.7
通讯作者：
Saini N
中科院分区：
文献类型：
--
作者：
Chhabra R;Adlakha YK;Hariharan M;Scaria V;Saini N
mirna已成为基因表达调控的重要参与者，其失调是多种疾病，特别是癌症的共同特征。目前，许多工作都集中在miRNA表达模式的研究以及miRNA靶点的验证上。在这里，我们发现HEK293T细胞中miR-23a ~ 27a ~ 24-2簇的过表达通过caspase依赖性和caspase非依赖性途径诱导凋亡，这一点通过膜联蛋白测定、caspase激活、线粒体细胞色素c和AIF（凋亡诱导因子）的释放得到证实。此外，过表达的簇调节了包括FADD （Fas相关蛋白与死亡结构域）在内的一些参与细胞凋亡的基因的表达。生物信息学上，FADD被预测为hsa-miR-27a的靶标，有趣的是，在HEK293T细胞中，FADD蛋白被发现上调，与hsa-miR-27a的极低表达一致。这种影响是直接的，因为hsa-miR-27a负调控FADD 3'UTR报告基因的表达。此外，我们还发现miR-23a ~ 27a ~ 24-2的过表达使HEK293T细胞对TNF-α细胞毒性敏感。综上所述，我们的研究表明，通过过表达miR-23a ~ 27a ~ 24-2簇，增强TNF-α诱导HEK293T细胞凋亡，为开发新的癌症治疗方法提供了新的见解。
miRNAs have emerged as important players in the regulation of gene expression and their deregulation is a common feature in a variety of diseases, especially cancer. Currently, many efforts are focused on studying miRNA expression patterns, as well as miRNA target validation. Here, we show that the over expression of miR-23a∼27a∼24-2 cluster in HEK293T cells induces apoptosis by caspase-dependent as well as caspase-independent pathway as proved by the annexin assay, caspase activation, release of cytochrome-c and AIF (apoptosis inducing factor) from mitochondria. Furthermore, the over expressed cluster modulates the expression of a number of genes involved in apoptosis including FADD (Fas Associated protein with Death Domain). Bioinformatically, FADD is predicted to be the target of hsa-miR-27a and interestingly, FADD protein was found to be up regulated consistent with very less expression of hsa-miR-27a in HEK293T cells. This effect was direct, as hsa-miR-27a negatively regulated the expression of FADD 3′UTR based reporter construct. Moreover, we also showed that over expression of miR-23a∼27a∼24-2 sensitized HEK293T cells to TNF-α cytotoxicity. Taken together, our study demonstrates that enhanced TNF-α induced apoptosis in HEK293T cells by over expression of miR-23a∼27a∼24-2 cluster provides new insights in the development of novel therapeutics for cancer.
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