MiR-139 Inhibits Mcl-1 Expression and Potentiates TMZ-Induced Apoptosis in Glioma.
ABSTRACT AIMS: Mcl-1, an antiapoptotic member of the Bcl-2 family, is overexpressed in human glioblastoma, conferring a survival advantage to tumor cells. The mechanisms underlying its dysregulation have not been clarified. In this study, we explored the involvement of micro-RNAs that acted as endogenous sequence-specific suppressors of gene expression. METHODS AND RESULTS: Using computational and TCGA analysis, we identified miR-139 as being downregulated in glioblastoma in comparison with human brain tissue, as well as possessing a putative target site in Mcl-1 mRNA. Overexpression of miR-139 led to a clear decrease in Mcl-1 expression in gliomas. Reporter assays revealed direct post-transcriptional regulation involving miR-139 and the 3'-untranslated region of Mcl-1. Human glioma tissues with low expression of miR-139 displayed higher expression of Mcl-1 protein than those with high expression, suggesting that low miR-139 contributes to Mcl-1 overexpression. In addition, upregulation of miR-139 suppressed the proliferation and enhanced temozolomide (TMZ)-induced apoptosis. Finally, we observed that Mcl-1 knockdown resulted in similar effects compared with miR-139 transfection. CONCLUSION: Our results suggested that miR-139 negatively regulated Mcl-1 and induced apoptosis in cooperation with an anticancer drug TMZ in glioma.
SourceAvailable from: Zhaohui Huang[Show abstract] [Hide abstract]
ABSTRACT: MicroRNAs (miRNAs) that exert function by posttranscriptional suppression have recently brought insight in our understanding of the role of non-protein-coding RNAs in carcinogenesis and metastasis. In this study, we described the function and molecular mechanism of miR-139-5p in colorectal cancer (CRC) and its potential clinical application in CRC. We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues (NCTs), and decreased miR-139-5p was associated with poor prognosis. Functional analyses demonstrated that ectopic expression of miR-139-5p suppressed CRC cell migration and invasion in vitro and metastasis in vivo. Mechanistic investigations revealed that miR-139-5p suppress CRC cell invasion and metastasis by targeting AMFR and NOTCH1. Knockdown of the two genes phenocopied the inhibitory effect of miR-139-5p on CRC metastasis. Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression. Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients. Together, our data indicate that miR-139-5p is a potential tumor suppressor and prognostic factor for CRC, and targeting miR-139-5p may repress the metastasis of CRC and improve survival. Electronic supplementary material The online version of this article (doi:10.1007/s13238-014-0093-5) contains supplementary material, which is available to authorized users.Protein & Cell 08/2014; 5(11). DOI:10.1007/s13238-014-0093-5 · 2.85 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are novel and potent regulators in myogenesis. However, the molecular mechanisms that many miRNAs regulate myoblast proliferation and differentiation which are largely unknown. Here, we found that miR-139-5p increased during C2C12 myoblast proliferation, while presenting an inverse trend during C2C12 myoblast differentiation. Flow cytometry and EdU incorporation assay showed that miR-139-5p slowed down the growth of C2C12 cells. Additional study demonstrated that ectopic introduction of miR-139-5p into C2C12 cells blocked myoblast differentiation. Importantly, we demonstrated for the first time that Wnt1, which is associated with the Wnt/β-catenin signaling pathway, was a direct target of miR-139-5p. Moreover, we found that the expression level of Wnt1 was suppressed significantly (p < 0.01) by miR-139-5p, which triggered inhibition of Wnt/β-catenin signaling through upregulation of glycogen synthase kinase 3 beta (GSK-3β; p < 0.05) and downregulation of p-GSK-3β (p < 0.01), β-catenin (p < 0.05), and nuclear β-catenin (p < 0.01). Taken together, these results suggest that miR-139-5p is an important negative regulator in myogenesis through blocking the Wnt1-mediated Wnt/β-catenin signaling pathway.Biochemistry and Cell Biology 09/2014; DOI:10.1139/bcb-2014-0079 · 2.35 Impact Factor
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ABSTRACT: MicroRNAs represent an abundant class of endogenously expressed 18-25 nucleotide non-coding RNA molecules that function to silence gene expression through a process of post-transcriptional modification. They exhibit varied and widespread functions during normal development and tissue homeostasis, and accordingly their dysregulation plays major roles in many cancer types. Gliomas are cancers arising from the central nervous system. The most malignant and common glioma is glioblastoma multiforme (GBM), and even with aggressive treatment (surgical resection, chemotherapy, and radiation), average patient survival remains less than two years. In this review we will summarize the current findings regarding microRNAs in GBM and the biological and clinical implications of this data.Neurochemistry International 06/2014; DOI:10.1016/j.neuint.2014.06.002 · 2.65 Impact Factor