Upregulation of miR-23a∼27a∼24-2 Cluster Induces Caspase-Dependent and -Independent Apoptosis in Human Embryonic Kidney Cells

Abstract

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.

TGF-β-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7

“…Upon the inhibition of miR-27a using miR-27a inhibitors, we found significant increases in the levels of p38, MAP2K4, MAP2K7 and TAB3 (Figure 4b). Consistent with the results from another report, 23 miR-27a also reduced the expression of FADD. Furthermore, miR27a significantly reduced the transcriptional levels of the target molecules p38, MAP2K7, TAB3 and FADD but not TAB2 (Figure 4c).…”

Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis

“…Studies have illustrated that the mir-23aw27aw24-2 cluster functions as a growth-promoting and antiapoptotic factor targeting the Smad pathway in hepatocellular carcinoma cells (Huang et al 2008). However, a recent study demonstrated that the mir-23aw27aw24-2 cluster could induce caspase-dependent and -independent apoptosis in human embryonic kidney cells (Chhabra et al 2009). The pro-apoptotic and antiapoptotic nature of the mir-23aw27aw24-2 cluster suggests that this cluster may play different roles under different physiological and pathological conditions.…”

“…The effects of miR-23a on XIAP and caspase-3 expression in human granulosa cells Recent studies have shown that mir-23a can induce caspase-dependent and -independent apoptosis in human embryonic kidney cells, both of which occur via the mitochondrial membrane disruption pathway (Chhabra et al 2009). The KEGG pathway analysis demonstrated that mir-23a may regulate the antiapoptotic function of XIAP (Fig.…”

miR-484 regulates mitochondrial network through targeting Fis1

“…For example, miR-122 modulates cyclin G1 silencing and increases sensitivity of cells to undergoing apoptosis 32 . The miR-23a-27a-24-2 cluster induces caspase-dependent and -independent apoptosis 33 . Histone deacetylases are related to cell survival and their expression can be repressed by miR-449a 34 .…”