PT  - JOURNAL ARTICLE
AU  - Shu, Minfeng
AU  - Zhou, Yuehan
AU  - Zhu, Wenbo
AU  - Zhang, Haipeng
AU  - Wu, Sihan
AU  - Chen, Jingkao
AU  - Yan, Guangmei
TI  - MicroRNA 335 Is Required for Differentiation of Malignant Glioma Cells Induced by Activation of cAMP/Protein Kinase A Pathway
AID  - 10.1124/mol.111.076166
DP  - 2012 Mar 01
TA  - Molecular Pharmacology
PG  - 292--298
VI  - 81
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/81/3/292.short
4100  - http://molpharm.aspetjournals.org/content/81/3/292.full
SO  - Mol Pharmacol2012 Mar 01; 81
AB  - 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.