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MicroRNA 335 is required for differentiation of malignant glioma cells induced by activation of cAMP/protein kinase A pathway.

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.
AuthorsMinfeng Shu, Yuehan Zhou, Wenbo Zhu, Haipeng Zhang, Sihan Wu, Jingkao Chen, Guangmei Yan
JournalMolecular pharmacology (Mol Pharmacol) Vol. 81 Issue 3 Pg. 292-8 (Mar 2012) ISSN: 1521-0111 [Electronic] United States
PMID22172575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA Primers
  • MIRN335 microRNA, human
  • MicroRNAs
  • Cholera Toxin
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
Topics
  • Animals
  • Base Sequence
  • Brain Neoplasms (pathology)
  • Cell Differentiation (physiology)
  • Cholera Toxin (pharmacology)
  • Cyclic AMP (metabolism)
  • Cyclic AMP-Dependent Protein Kinases (metabolism)
  • DNA Primers
  • Enzyme Activation
  • Gene Expression Regulation (drug effects)
  • Glioma (pathology)
  • Humans
  • MicroRNAs (genetics, physiology)
  • Rats
  • Real-Time Polymerase Chain Reaction

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