Cancer Letters

Cancer Letters

Volume 353, Issue 1, 10 October 2014, Pages 25-31
Cancer Letters

Mini-review
The emerging role of tumor-suppressive microRNA-218 in targeting glioblastoma stemness

https://doi.org/10.1016/j.canlet.2014.07.011Get rights and content

Highlights

  • miRNAs are epigenetic regulators of glioblastoma stemness.

  • Aberrant expression of miR-218 can be observed in malignant gliomas.

  • Roles of miR-218 and its target genes in glioblastoma stemness are summarized.

  • The molecular mechanisms of miR-218 in targeting glioblastoma stemness are elucidated.

Abstract

Glioblastoma multiforme (GBM) is by far the most common and most aggressive malignant primary tumor in humans and has poor outcomes despite many advances in treatment using combinations of surgery, radiotherapy and chemotherapy. Recent studies demonstrate that GBM contains a subpopulation of cancer cells with stem cell characteristics, including self-renewal and multipotentiality, and that these cancer stem cells contribute to disease progression. MicroRNAs (miRNAs) are small non-coding regulatory RNA molecules that regulate a variety of cellular processes, including stem cell maintenance. An accumulating body of evidence shows that miR-218 may act as a tumor suppressor by inhibiting glioblastoma invasion, migration, proliferation and stemness through its different targets, indicating the great potential and relevance of miR-218 as a novel class of therapeutic target in glioblastoma.

Introduction

Glioblastoma multiforme (GBM) is the most frequently occurring primary tumor of the central nervous system [1]. The term GBM is synonymous with World Health Organization (WHO) grade IV astrocytoma, which is characterized by uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, and rampant genomic instability [2], [3]. Despite measurable advances in cancer treatment, such as surgery, radiation and chemotherapy, the median overall survival of patients with the most malignant glioblastoma is approximately 1 to 2 years [4]. One of the major causes of tumor recurrence is the infiltrative property of GBM cells, because of their highly invasive nature, it is difficult to clear glioblastoma cells with local therapeutic modalities [5].

GBM may arise from cancer stem cells that display neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies [6]. The development of stem cell-like properties is recognized in glioblastoma, and these cancer stem cells can propagate tumors in vivo [7], [8]. Exploring the molecular mechanism through which glioblastoma maintains stemness will allow the development of novel therapies that may promote the differentiation or target the stem cell-like properties of glioblastoma [9]. Recently, miR-218 was newly found to modulate the GBM stemness [10]. In this review, we focus on the novel role of miR-218 in the modulation of the stemness of glioblastoma.

Section snippets

miRNAs are novel epigenetic regulators of glioblastoma stemness

MicroRNAs (miRNA) are endogenous, small, non-coding RNAs that are 19–25 nucleotides in length and regulate gene expression by antisense complementarity to specific mRNAs. Extensive evidence indicates that miRNAs regulate a variety of cellular processes, including cell differentiation, cell proliferation, apoptosis, stress resistance, stem cell maintenance and metabolism [11], [12], [13], [14], [15]. One miRNA may have many targets, and one gene may be targeted by multiple miRNAs; thus, miRNAs

miR-218 regulates glioblastoma migration/invasion, proliferation, and apoptosis by targeting different genes

miRNAs can regulate many targets to affect a variety of cellular processes and tumor growth. miR-218 is downregulated in glioblastoma and regulates tumor growth through numerous direct gene targets in a number of different cell lines. In this section of the manuscript, we review the targets of miR-218 and their functions in glioblastoma migration/invasion, proliferation and apoptosis (Fig. 1).

miR-218 regulates glioblastoma stemness through epigenetic pathways

The overexpression of miR-218 leads to a significant decrease in the volume of glioblastoma neurospheres stably expressing miR-218 and reduces the self-renewal capacity of glioblastoma stem-like cells. The stem cell markers, such as CD133, SOX2, Nestin, and Bmi1, in glioblastoma neurospheres are reduced as a result of miR-218 overexpression [10]. These results suggest that miR-218 regulates glioblastoma stem-like cells in part by blocking Bmi1-associated pathways.

Bmi1 is a polycomb group

Slits/miR-218/Bmi1 epigenetics microcircuitry modulates glioblastoma stemness

Two genes encoding miR-218, namely miR-218–1 and miR-218–2, are located at 4p15.31 and 5q35.1 within the introns of Slit2 and Slit3, respectively [83], [94]. It has been reported that intronic miRNAs are transcribed together with their host gene mRNAs, and a significant positive correlation has been found between Slit2 and pre-miR-218–1 and between Slit3 and pre-miR-218–2 in many cancers [83], [94]. Consistent with its tumor suppressor activity, Slit2 is down-regulated in glioblastoma compared to

Conclusions and outlooks

Recent advances have demonstrated that miR-218 can work as a tumor suppressor by regulating a complex regulatory framework to coordinately downregulate many oncogenes and thereby inhibit the invasion, migration, proliferation, and self-renewal of glioblastoma cancer stem-like cells. miR-218 is downregulated in human glioblastoma, and the restoration of miR-218 expression with a miRNA mimic would inhibit glioblastoma development, particularly glioblastoma stemness. The ability of miR-218 to

Conflict of Interest

The authors declare no conflicts of interest.

Acknowledgments

This work was supported by the National Natural Science Foundation of China-China (No. 81272801), the National Key Basic Research Program of China (“973” Project) (2010CB933900), a scientific research program funded by the Shaanxi Provincial Health Department (Program Nos. 2014D21 and 2014D24), Scientific Research Program Funded by Shaanxi Provincial Education Department (Program No. 14JK1617) and the Program for Youth Science and Technology Star of Shaanxi Province (2014KJXX-76). We apologize

References (123)

  • L.A. Shuman Moss et al.

    Matrix metalloproteinases: changing roles in tumor progression and metastasis

    Am. J. Pathol.

    (2012)
  • B. Wu et al.

    Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration

    Immunity

    (2007)
  • D. Hanahan et al.

    Hallmarks of cancer: the next generation

    Cell

    (2011)
  • J. Li et al.

    Oncoprotein Bmi-1 renders apoptotic resistance to glioma cells through activation of the IKK-nuclear factor-kappaB Pathway

    Am. J. Pathol.

    (2010)
  • C.A. Fasano et al.

    ShRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development

    Cell Stem Cell

    (2007)
  • F.M. Raaphorst

    Self-renewal of hematopoietic and leukemic stem cells: a central role for the Polycomb-group gene Bmi-1

    Trends Immunol.

    (2003)
  • L. Morey et al.

    Polycomb group protein-mediated repression of transcription

    Trends Biochem. Sci.

    (2010)
  • R. Dammann et al.

    CpG island methylation and expression of tumour-associated genes in lung carcinoma

    Eur. J. Cancer

    (2005)
  • F.B. Furnari et al.

    Malignant astrocytic glioma: genetics, biology, and paths to treatment

    Genes Dev.

    (2007)
  • H. Ohgaki et al.

    Genetic pathways to glioblastoma: a population-based study

    Cancer Res.

    (2004)
  • F.G. Davis et al.

    Current epidemiological trends and surveillance issues in brain tumors

    Expert Rev. Anticancer Ther.

    (2001)
  • M. Teodorczyk et al.

    Sensing invasion: cell surface receptors driving spreading of glioblastoma

    J. Cell. Physiol.

    (2010)
  • N. Goffart et al.

    Glioblastoma-initiating cells: relationship with neural stem cells and the micro-environment

    Cancers

    (2013)
  • S. Bao et al.

    Glioma stem cells promote radioresistance by preferential activation of the DNA damage response

    Nature

    (2006)
  • J. Godlewski et al.

    MicroRNAs and glioblastoma; the stem cell connection

    Cell Death Differ.

    (2010)
  • Y. Tu et al.

    MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1

    Cancer Res.

    (2013)
  • X. Chen et al.

    Horizontal transfer of microRNAs: molecular mechanisms and clinical applications

    Protein & cell

    (2012)
  • D. Floyd et al.

    Micro-masters of glioblastoma biology and therapy: increasingly recognized roles for microRNAs

    Neuro-oncology

    (2014)
  • R. Ma et al.

    Upregulation of miR-196b confers a poor prognosis in glioblastoma patients via inducing a proliferative phenotype

    PLoS ONE

    (2012)
  • R. Ma et al.

    Circulating microRNAs in cancer: origin, function and application

    J. Exp. Clin. Cancer Res. CR

    (2012)
  • A. Esquela-Kerscher et al.

    Oncomirs – microRNAs with a role in cancer

    Nat. Rev. Cancer

    (2006)
  • H.M. Jeon et al.

    ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2

    Cancer Res.

    (2011)
  • D. Schraivogel et al.

    CAMTA1 is a novel tumour suppressor regulated by miR-9/9*in glioblastoma stem cells

    EMBO J.

    (2011)
  • H. Li et al.

    Stress response of glioblastoma cells mediated by miR-17-5p targeting PTEN and the passenger strand miR-17-3p targeting MDM2

    Oncotarget

    (2012)
  • S.H. Moon et al.

    PI3K/Akt and Stat3 signaling regulated by PTEN control of the cancer stem cell population, proliferation and senescence in a glioblastoma cell line

    Int. J. Oncol.

    (2013)
  • F. Guessous et al.

    Oncogenic effects of miR-10b in glioblastoma stem cells

    J. Neurooncol.

    (2013)
  • M. Kamal et al.

    Loss of CSMD1 expression is associated with high tumour grade and poor survival in invasive ductal breast carcinoma

    Breast Cancer Res. Treat.

    (2010)
  • G. Gabriely et al.

    MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators

    Mol. Cell. Biol.

    (2008)
  • S. Zhang et al.

    MicroRNA-21 inhibitor sensitizes human glioblastoma U251 stem cells to chemotherapeutic drug temozolomide

    J. Mol. Neurosci.: MN

    (2012)
  • Y. Li et al.

    A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells

    Brain Tumor Pathol.

    (2011)
  • Y. Li et al.

    MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes

    Cancer Res.

    (2009)
  • F. Guessous et al.

    MicroRNA-34a is tumor suppressive in brain tumors and glioma stem cells

    Cell Cycle

    (2010)
  • X. Fan et al.

    NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts

    Stem Cells

    (2010)
  • X. Fan et al.

    Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors

    Cancer Res.

    (2006)
  • J. Wang et al.

    Notch promotes radioresistance of glioma stem cells

    Stem Cells

    (2010)
  • S.M. Chen et al.

    MicroRNA-495 inhibits proliferation of glioblastoma multiforme cells by downregulating cyclin-dependent kinase 6

    World J. Surg. Oncol.

    (2013)
  • M.K. Kiessling et al.

    High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade

    Blood

    (2011)
  • Z. Kan et al.

    Diverse somatic mutation patterns and pathway alterations in human cancers

    Nature

    (2010)
  • Y. Wu et al.

    Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

    Oncogene

    (2010)
  • L. Brault et al.

    PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

    Haematologica

    (2010)
  • Cited by (48)

    • Signaling pathways governing glioma cancer stem cells behavior

      2023, Cellular Signalling
      Citation Excerpt :

      Tu et al. documented that overexpression of miR-218 reduced proliferation, migration, invasion, and stem-like qualities of glioma cells via targeting the Wnt pathway and the stem cell markers including Bmi1, CD133, Nestin, SOX2. Their results also showed that Bmi1 probably has a role in stem cell growth [220], and miR-218 by modulation of a wide range of genes can stop the self-renewal of GCSCs [221]. miR-145 has an atypically low-expression level in GCSCs.

    • miR-218 and miR-129 regulate breast cancer progression by targeting Lamins

      2018, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      In the present study, we have identified critical roles for miR-218 and miR-129 in breast cancer progression (miR-218 serves as a ‘tumor suppressor’ and miR-129 acts as an ‘oncogene (oncomir)’), suggesting that these may be novel miRNA biomarkers for breast cancer prognosis, including TNBC. Several studies have reported that miR-218 is downregulated in cancer tissues [18,19]. However, the prognostic role of miR-218 in breast cancer, particularly TNBC, is unclear.

    • Deubiquitylating enzymes as cancer stem cell therapeutics

      2018, Biochimica et Biophysica Acta - Reviews on Cancer
    • Discovery and functional characterization of novel miRNAs in the marine medaka Oryzias melastigma

      2016, Aquatic Toxicology
      Citation Excerpt :

      Concordant with previous reports, the brain is enriched with miRNA activity, and miRNAs are critical in neuronal functions (Fineberg et al., 2009; Nielsen et al., 2009). More specifically, miRNAs play roles in the proliferation and self-renewal of neuronal cells (Fineberg et al., 2009; Gao and Jin, 2014; Lulli et al., 2015). As miRNA expression patterns are highly conserved between organisms, the functional characterization of new miRNAs on brain development in fish may provide potential candidates for the treatment of different degenerative nerve diseases such as Alzheimer's disease and Parkinson’s disease in humans.

    View all citing articles on Scopus
    View full text