TY - JOUR
T1 - MicroRNA 335 is required for differentiation of malignant glioma cells induced by activation of cAMP/protein kinase A pathway
AU - Shu, Minfeng
AU - Zhou, Yuehan
AU - Zhu, Wenbo
AU - Zhang, Haipeng
AU - Wu, Sihan
AU - Chen, Jingkao
AU - Yan, Guangmei
PY - 2012/3
Y1 - 2012/3
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84863179521&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863179521&partnerID=8YFLogxK
U2 - 10.1124/mol.111.076166
DO - 10.1124/mol.111.076166
M3 - Article
C2 - 22172575
AN - SCOPUS:84863179521
SN - 0026-895X
VL - 81
SP - 292
EP - 298
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 3
ER -