Article

Human Glioma Growth Is Controlled by MicroRNA-10b

Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cancer Research (Impact Factor: 9.28). 04/2011; 71(10):3563-72. DOI: 10.1158/0008-5472.CAN-10-3568
Source: PubMed

ABSTRACT MicroRNA (miRNA) expression profiling studies revealed a number of miRNAs dysregulated in the malignant brain tumor glioblastoma. Molecular functions of these miRNAs in gliomagenesis are mainly unknown. We show that inhibition of miR-10b, a miRNA not expressed in human brain and strongly upregulated in both low-grade and high-grade gliomas, reduces glioma cell growth by cell-cycle arrest and apoptosis. These cellular responses are mediated by augmented expression of the direct targets of miR-10b, including BCL2L11/Bim, TFAP2C/AP-2γ, CDKN1A/p21, and CDKN2A/p16, which normally protect cells from uncontrolled growth. Analysis of The Cancer Genome Atlas expression data set reveals a strong positive correlation between numerous genes sustaining cellular growth and miR-10b levels in human glioblastomas, while proapoptotic genes anticorrelate with the expression of miR-10b. Furthermore, survival of glioblastoma patients expressing high levels of miR-10 family members is significantly reduced in comparison to patients with low miR-10 levels, indicating that miR-10 may contribute to glioma growth in vivo. Finally, inhibition of miR-10b in a mouse model of human glioma results in significant reduction of tumor growth. Altogether, our experiments validate an important role of miR-10b in gliomagenesis, reveal a novel mechanism of miR-10b-mediated regulation, and suggest the possibility of its future use as a therapeutic target in gliomas.

Download full-text

Full-text

Available from: Santosh Kesari, Sep 03, 2015
1 Follower
 · 
216 Views
 · 
76 Downloads
  • Source
    • "It has been reported that miR-15b, miR-23b, miR-137, miR-152 and miR-195 were downregulated and function as tumor suppressors in gliomas [8] [9] [10] [11]. On the contrary, miR-10b, miR-21 and miR-221/222 were reported overexpression in gliomas, which has been suggested to promote the malignant progression of gliomas, and function as oncogenes [12] [13] [14]. In this study, we first detected the expression level of miR-383 in glioma tissues, and found that miR-383 was significantly downregulated in glioma tissues than normal brain tissues. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, microRNAs (miRNAs) have been proved to be closely related to the tumorigenesis and progression. An increasing number of researches have shown that microRNAs function as oncogenes or tumor suppressor genes in human malignant tumors. This study aims to explore the effects of microRNA-383 (miR-383) on malignant biological function of human gliomas. We detected the expression of miR-383 in glioma tissues and normal brain tissues by quantitative real-time PCR. Anchorage-independent growth assays, and flow cytometry were used to evaluate the functions of miR-383 that involves in cell growth and cell cycle. Western blotting assay was used to examine protein expression levels of Cyclin D1 (CCND1), a cell cycle-associated oncogene which has a predicted binding site of miR-383 within its 3'-untranslated region (3'-UTR), and luciferase activity assay was used to evaluate the 3'-UTR activity of CCND1. In this study, we found that miR-383 expression level was lower in gliomas than normal brain tissues. Overexpression of miR-383 in U251 and U87 cells showed a significant inhibitory effect on cell growth, which accompanied with cell cycle G0/G1 arrest as well as downregulation of CCND1 expression. Moreover, CCND1 was verified to be one of the direct targets of miR-383. In summary, this study suggested that miR-383 plays the role of tumor suppressor by targeting CCND1 in glioma cells, and may be useful for developing a new therapeutic strategy for gliomas. Copyright © 2014 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 10/2014; 453(4):833-838. DOI:10.1016/j.bbrc.2014.10.047 · 2.28 Impact Factor
  • Source
    • "The recent literature abounds in examples of the key role played by miRNAs in determining cell fate. Their fundamental importance is particularly well defined with regard to cancer emergence , progression, and response to therapy (Gabriely et al., 2011; Hurst et al., 2009; Iorio and Croce, 2012; Ma et al., 2007; Nicoloso et al., 2009). Consequently, miRNAs represent promising candidates as targets of therapeutic intervention, highlighting the importance of developing miRNA detection methods for preclinical/clinical applications. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We describe a technology for the profiling of miRNA expression in intact cells. The technology is based on sensor oligonucleotides that are cleavable, completely complementary to a target miRNA, and dual-labeled with a fluorescent dye and a quencher. Upon entering the cell, the sensor oligonucleotide binds its specific miRNA target through complementary base-pairing. This triggers assembly of the endogenous RNA Induced Silencing Complex (RISC) around the miRNA-sensor duplex and cleavage of the sensor oligonucleotide, resulting in separation between the dye and quencher, and a fluorescence turn-on. In the presented feasibility studies, we focus on a specific miRNA (miR-10b) implicated in breast cancer metastasis. Using a human breast adenocarcinoma cell line, we illustrate the application of this technology for miRNA detection with nanomolar sensitivity in both a cell-free system and intact cells.
    Chemistry & biology 01/2014; 21(2). DOI:10.1016/j.chembiol.2013.12.007 · 6.59 Impact Factor
  • Source
    • "The total amount of cellular miRNAs that was detected in our preparations was markedly low, and only very few showed considerable enrichment in the SIV-sample. The most prominent candidate, hsa-miRNA-10b, has been described to promote metastasis formation [50] and glioma growth [51], but has not been reported in the context of retroviral biology. Using the miRanda prediction tool [52], we found two putative binding sites for miR-10b on the SIV genome, but only when using relatively weak filtering options. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence indicates that regulatory small non-coding RNAs are not only components of eukaryotic cells and vesicles, but also reside within a number of different viruses including retroviral particles. Using ultra-deep sequencing we have comprehensively analyzed the content of simian immunodeficiency virions (SIV), which were compared to mock-control preparations. Our analysis revealed that more than 428,000 sequence reads matched the SIV mac239 genome sequence. Among these we could identify 12 virus-derived small RNAs (vsRNAs) that were highly abundant. Beside known retrovirus-enriched small RNAs, like 7SL-RNA, tRNA(Lys3) and tRNA(Lys) isoacceptors, we also identified defined fragments derived from small ILF3/NF90-associated RNA snaR-A14, that were enriched more than 50 fold in SIV. We also found evidence that small nucleolar RNAs U2 and U12 were underrepresented in the SIV preparation, indicating that the relative number or the content of co-isolated exosomes was changed upon infection. Our comprehensive atlas of SIV-incorporated small RNAs provides a refined picture of the composition of retrovirions, which gives novel insights into viral packaging.
    PLoS ONE 09/2013; 8(9):e75063. DOI:10.1371/journal.pone.0075063 · 3.23 Impact Factor
Show more