MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 09/2011; 31(17):3584-92. DOI: 10.1128/MCB.05821-11
Source: PubMed


Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation
(EGFRvIII), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression
analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation
of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf−/− Pten−/− EgfrvIII murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic
xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays
a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem
cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown
of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate
that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing
Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may
lead to new strategies for treating brain tumors.

Download full-text


Available from: Chun-Li Zhang
  • Source
    • "Quantitative real-time PCR (qRT-PCR) with iTaq Universal SYBR Green Supermix (Bio-Rad) was performed to profile the expression level of arbitrarily selected miRNAs in three libraries, as previously described [26]. Briefly, 1 µg of total RNA was reverse transcribed by using NCode VILO miRNA cDNA Synthesis Kit (Invitrogen). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently, YY super-male yellow catfish had been created by hormonal-induced sex reversal and sex-linked markers, which provides a promising research model for fish sex differentiation and gonad development, especially for testis development. MicroRNAs (miRNAs) have been revealed to play crucial roles in the gene regulation and gonad development in vertebrates. In this study, three small RNA libraries constructed from gonad tissues of XX female, XY male and YY super-male yellow catfish were sequenced. The sequencing data generated a total of 384 conserved miRNAs and 113 potential novel miRNAs, among which 23, 30 and 14 miRNAs were specifically detected in XX ovary, XY testis, and YY testis, respectively. We observed relative lower expression of several miR-200 family members, including miR-141 and miR-429 in YY testis compared with XY testis. Histological analysis indicated a higher degree of testis maturity in YY super-males compared with XY males, as shown by larger spermatogenic cyst, more spermatids and fewer spermatocytes in the spermatogenic cyst. Moreover, five miR-200 family members were significantly up-regulated in testis when treated by 17α-ethinylestradiol (EE2), high dose of which will impair testis development and cell proliferation. The down-regulation of miR-141 and 429 coincides with the progression of testis development in both yellow catfish and human. At last, the expression pattern of nine arbitrarily selected miRNAs detected by quantitative RT-PCR was consistent with the Solexa sequencing results. Our study provides a comprehensive miRNA transcriptome analysis for gonad of yellow catfish with different sex genotypes, and identifies a number of sex-biased miRNAs, some of that are potentially involved in testis development and spermatogenesis.
    Full-text · Article · Sep 2014 · PLoS ONE
  • Source
    • "We first investigated the contribution of miR-146a to cell growth and apoptosis in HCC cells and also compared the effect of miR-146a mimic to the siRNA specially targeting EGFR mRNA, since EGFR was documented as a target of miR-146a in various cancers [41, 47–50]. In the current study, the EGFR protein was downregulated in HCC HepG2 cells after transfection of miR-146a mimic, which implies that EGFR is a target of miR-146a in HCC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.
    Full-text · Article · May 2014 · BioMed Research International
  • Source
    • "For example, Rogler et al. [31] found that through down-regulating the target gene Smads (including Smad3, 4 and 5), which are the key genes in transforming growth factor-beta signalling of miR-23b cluster miRNAs (including miR-23b, miR-27b, miR-24-1, miR-10a, miR-26a, and miR-30a), miR-23b miRNAs can be promoted in growth and consequently repress bile duct gene expression in fetal hepatocytes. Jie et al.[32] pointed out that miR-146a expression induced by epidermal growth factor receptor (EGFR) signalling can repress human gliomagenesis by down-regulating its target gene, NOTCH1. Recent research [33] shows that miR-128 can play a similar role by targeting oncogenic receptor tyrosine kinases signalling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein-protein interaction (PPI) is one of the most important functional components of a living cell. Recently, researchers have been interested in investigating the correlation between PPI and microRNA, which has been found to be a regulator at the post-transcriptional level. Studies on miRNA-regulated PPI networks will not only facilitate an understanding of the fine tuning role that miRNAs play in PPI networks, but will also provide potential candidates for tumor diagnosis. This review describes basic studies on the miRNA-regulated PPI network in the way of bioinformatics which includes constructing a miRNA-target protein network, describing the features of miRNA-regulated PPI networks and overviewing previous findings based on analysing miRNA-regulated PPI network features.
    Full-text · Article · Feb 2014 · BMC Systems Biology
Show more