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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

MicroRNA 335 Is Required for Differentiation of Malignant Glioma Cells Induced by Activation of cAMP/Protein Kinase A Pathway

Minfeng Shu, Yuehan Zhou, Wenbo Zhu, Haipeng Zhang, Sihan Wu, Jingkao Chen and Guangmei Yan
Molecular Pharmacology March 2012, 81 (3) 292-298; DOI: https://doi.org/10.1124/mol.111.076166
Minfeng Shu
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Yuehan Zhou
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Wenbo Zhu
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Haipeng Zhang
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Sihan Wu
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Jingkao Chen
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Guangmei Yan
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Abstract

Glioma is the most common malignant cancer affecting the central nerve system, with dismal prognosis. Differentiation-inducing therapy is a novel strategy that has been preliminarily proved effective against malignant glioma. We have reported previously that activation of cAMP/protein kinase A (PKA) pathway is capable of inducing glioma cell differentiation, characterized by astrocyte-like shape and dramatic induction of astrocyte biomarker glial fibrillary acidic protein (GFAP). However, little progress has been made on molecular mechanisms related. Here we demonstrate that microRNA 335 (miR-335) is responsible for the glioma cell differentiation stimulated by activation of cAMP/PKA pathway. In the cAMP elevator cholera toxin-induced differentiation model of rat C6 glioma cells, miR-335 was significantly up-regulated, which was mimicked by other typical cAMP/PKA pathway activators (e.g., forskolin, dibutyryl-cAMP) and abolished by PKA-specific inhibitor (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i] [1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720). In an assay measuring gain and loss of miR-335 function, exogenetic miR-335 resulted in induction of GFAP, whereas miR-335 specific inhibitor antagomir-335 violently blocked cholera toxin-induced GFAP up-regulation. It is noteworthy that in human U87-MG glioma cells and human primary culture glioma cells, miR-335 also mediated cholera toxin-induced differentiation. Taken together, our findings suggest that miR-335 is potently required for differentiation of malignant glioma cells induced by cAMP/PKA pathway activation, and a single microRNA may act as an important fate determinant to control the differentiation status of malignant gliomas, which has provided a new insight into differentiation-inducing therapy against malignant gliomas.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by Key program, National Natural Science Foundation of China [Grant 30830111]; Guangzhou Program Project of Science Technology [Grant 2008Z1-E561]; National Key Projects of Science and Technology [Grants 2009ZX09102-013, 2009ZX09102-217]; and Guangdong Natural Science Foundation [Grant S2011040004371].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.076166.

  • ABBREVIATIONS:

    PKA
    protein kinase A
    GFAP
    glial fibrillary acidic protein
    miRNA
    microRNA
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    WHO
    World Health Organization
    dbcAMP
    dibutyryl cAMP
    KT5720
    (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, hexyl ester
    qRT-PCR
    quantitative real-time polymerase chain reaction
    IL
    interleukin
    JAK
    Janus tyrosine kinase
    STAT
    signal transducer and activator of transcription
    MEST
    mesoderm-specific transcript.

  • Received September 30, 2011.
  • Accepted December 15, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Rapid CommunicationAccelerated Communication

The Crucial Role of miR-335 in Glioma Cell Differentiation

Minfeng Shu, Yuehan Zhou, Wenbo Zhu, Haipeng Zhang, Sihan Wu, Jingkao Chen and Guangmei Yan
Molecular Pharmacology March 1, 2012, 81 (3) 292-298; DOI: https://doi.org/10.1124/mol.111.076166

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Rapid CommunicationAccelerated Communication

The Crucial Role of miR-335 in Glioma Cell Differentiation

Minfeng Shu, Yuehan Zhou, Wenbo Zhu, Haipeng Zhang, Sihan Wu, Jingkao Chen and Guangmei Yan
Molecular Pharmacology March 1, 2012, 81 (3) 292-298; DOI: https://doi.org/10.1124/mol.111.076166
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