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.


Available from: Santosh Kesari, Mar 30, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence has proved that potassium channels (K+ channels) are involved in regulating cell proliferation, cell cycle progression and apoptosis of tumor cells. However, the precise cellular mechanisms are still unknown. In the present study, we investigated the effect and mechanisms of quinidine, a commonly used voltage‑gated K+ channel blocker, on cell proliferation and apoptosis of human glioma U87‑MG cells. We found that quinidine significantly inhibited the proliferation of U87‑MG cells and induced apoptosis in a dose‑dependent manner. The results of caspase colorimetric assay showed that the mitochondrial pathway was the main mode involved in the quinidine‑induced apoptotic process. Furthermore, the concentration range of quinidine, which inhibited voltage‑gated K+ channel currents in electrophysiological assay, was consistent with that of quinidine inhibiting cell proliferation and inducing cell apoptosis. In U87‑MG cells treated with quinidine (100 µmol/l), 11 of 2,042 human microRNAs (miRNAs) were upregulated and 16 were downregulated as detected with the miRNA array analysis. The upregulation of miR‑149‑3p and downregulation of miR‑424‑5p by quinidine treatment were further verified by using quantitative real‑time PCR. In addition, using miRNA target prediction program, putative target genes related to cell prolif-eration and apoptosis for two differentially expressed miRNAs were predicted. Taken together, these data suggested that the anti‑proliferative and pro‑apoptosis effect of voltage‑gated K+ channel blocker quinidine in human glioma cells was mediated at least partly through regulating expression of miRNAs, and provided further support for the mechanisms of voltage‑gated K+ channels in mediating cell proliferation and apoptosis.
    International Journal of Oncology 11/2014; 46(2). DOI:10.3892/ijo.2014.2777 · 2.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite considerable progress being made in understanding pancreatic cancer (PC) pathogenesis, it still remains the 10th most often diagnosed malignancy in the world and 4th leading cause of cancer related deaths in the United States with a five year survival rate of only 6%. The aggressive nature, lack of early diagnostic and prognostic markers, late clinical presentation, and limited efficacy of existing treatment regimens make PC a lethal cancer with high mortality and poor prognosis. Therefore, novel reliable biomarkers and molecular targets are urgently needed to combat this deadly disease. MicroRNAs (miRNAs) are short (19–24 nucleotides) non-coding RNA molecules implicated in the regulation of gene expression at post-transcriptional level and play significant roles in various physiological and pathological conditions. Aberrant expression of miRNAs has been reported in several cancers including PC and is implicated in PC pathogenesis and progression, suggesting their utility in diagnosis, prognosis and therapy. In this review, we summarize the role of several miRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (p53, p16, SMAD4, etc.) involved in PC development, their prospective roles as diagnostic and prognostic markers and as a therapeutic targets.
    Advanced Drug Delivery Reviews 10/2014; DOI:10.1016/j.addr.2014.10.020 · 12.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ezrin is overexpressed in a variety of neoplastic cells and involved in the later stages of tumor progression and metastasis. Ezrin expression can be regulated at both the transcriptional and post-transcriptional levels. We used a combination of bioinformatics and experimental techniques to demonstrate that the miR-204 is a direct negative regulator of ezrin. Overexpression of miR-204 mimics decreased the activity of a luciferase reporter containing the ezrin 3' UTR and led to repression of ezrin protein. In contrast, ectopic expression of miR-204 inhibitor elevated ezrin expression. We also show that miR-204 is down-regulated in a panel of glioma tissues and in high invasive glioma cell lines we examined. Moreover, miR-204 mimics significantly reduced glioma cell migration and invasion, while miR-204 inhibitor generated the opposite results. Finally, overexpression of miR-204 and knockdown of ezrin reduced glioma cell invasion, and these effects could be rescued by re-expression of ezrin. These findings reveal that miR-204 could be partly due to its inhibitory effects on glioma cell migration and invasion through regulating ezrin expression.
    Molecular and Cellular Biochemistry 07/2014; 396(1-2). DOI:10.1007/s11010-014-2148-6 · 2.39 Impact Factor