Loss of Brain-enriched miR-124 MicroRNA Enhances Stem-like Traits and Invasiveness of Glioma Cells

Brain Tumour Centre and Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2012; 287(13):9962-71. DOI: 10.1074/jbc.M111.332627
Source: PubMed


miR-124 is a brain-enriched microRNA that plays a crucial role in neural development and has been shown to be down-regulated in glioma and medulloblastoma, suggesting its possible involvement in brain tumor progression. Here, we show that miR-124 is down-regulated in a panel of different grades of glioma tissues and in all of the human glioma cell lines we examined. By integrated bioinformatics analysis and experimental confirmation, we identified SNAI2, which is often up-regulated in glioma, as a direct functional target of miR-124. Because SNAI2 has been shown to regulate stem cell functions, we examined the roles of miR-124 and SNAI2 in glioma cell stem-like traits. The results showed that overexpression of miR-124 and knockdown of SNAI2 reduced neurosphere formation, CD133(+) cell subpopulation, and stem cell marker (BMI1, Nanog, and Nestin) expression, and these effects could be rescued by re-expression of SNAI2. Furthermore, enhanced miR-124 expression significantly inhibited glioma cell invasion in vitro. Finally, stable overexpression of miR-124 and knockdown of SNAI2 inhibited the tumorigenicity and invasion of glioma cells in vivo. These findings reveal, for the first time, that the tumor suppressor activity of miR-124 could be partly due to its inhibitory effects on glioma stem-like traits and invasiveness through SNAI2.

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    • "miR-124 is a miRNA enriched in the brain and plays a crucial role in gastrulation and neural development [23], [24]. In addition, the expression of miR-124 was suppressed in several types of cancer, including medulloblastoma, glioma, oral squamous cell carcinomas and hepatocellular carcinoma [25]–[27]. Interestingly, its expression was down-regulated in breast cancer specimens and cell lines, and enforced expression of miR-124 showed a reduction in cell motility and invasion in human breast cancer cells [28]. Over expression of miR-124 was linked to the suppression of inhibitory member of apoptosis-stimulating protein of p53 (iASPP), which subsequently led to an increased expression of NF-κB (p65) [29], [30]. "
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    • "Overexpression of miR-124 has consistently been found to inhibit the CD133+ cell subpopulation of the neurosphere and to downregulate stem cell markers, such as BMI1, Nanog, and Nestin. These effects could be rescued by re-expression of SNAI2, another direct target of miR-124 (Xia et al., 2012). "
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    • "A glioma study indicated that miR-124 is downregulated in both glioma tissues and cell lines. Through an integrated bioinformatics analysis and experimental confirmation, Xia et al34 identified SNAI2 as a potential direct target of miR-124, thereby restricting stem-like properties. In a study of pancreatic cancer, Wang et al35 reported that miR-124 is silenced by hypermethylation in tumor tissues and that miR-124 inhibits cell proliferation, invasion, and metastasis by targeting Rac 1 and inactivating the MKK4-JNK-c-Jun pathway. "
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