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Glial fibrillary acidic protein (GFAP) is a well\u2010known specific astrocyte biomarker and acts as a tumor suppressor gene (TSG) in glioma pathogenesis. Previously we reported that a traditional biotoxin cholera toxin could induce malignant glioma cell differentiation characterized by morphologic changes and dramatic GFAP expression. However, the molecular mechanisms underlying GFAP induction are still largely unknown. Here we demonstrate that an oncogenic pathway interleukin\u20106\/janus kinase\u20102\/signal transducer and activator of transcription 3 (IL\u20106\/JAK2\/STAT3) cascade mediates the cholera toxin\u2010induced GFAP expression. Cholera toxin dramatically stimulated GFAP expression at the transcriptional level in C6 glioma cells. Meanwhile, phosphorylation of STAT3 and JAK2 was highly induced in a time\u2010dependent manner after cholera toxin incubation, whereas no changes of STAT3 and JAK2 were observed. Furthermore, the IL\u20106 gene was quickly induced by cholera toxin and subsequent IL\u20106 protein secretion was stimulated. Importantly, exogenous recombinant rat IL\u20106 can also induce phosphorylation of STAT3 concomitant with GFAP expression while JAK2 specific inhibitor AG490 could effectively block both cholera toxin\u2010 and IL\u20106\u2010induced GFAP expression. Given that the methylation of the STAT3 binding element can suppress GFAP expression, we detected the methylation status of the critical recognition sequence of STAT3 in the promoter of GFAP gene (\u22121518\u00a0\u223c\u00a0\u22121510) and found that it was unmethylated in C6 glioma cells. In addition, neither DNA methyltransferase1 (DNMT1) inhibitor 5\u2010Aza\u20102\u2032\u2010deoxycytidine (5\u2010AZa\u2010CdR) nor silencing DNMT1 can stimulate GFAP expression, indicating that the loss of GFAP expression in C6 cells is not caused by its promoter hypermethylation. Taken together, our findings suggest that activation of a pro\u2010survival IL\u20106\/JAK2\/STAT3 cascade contributes to cholera toxin\u2010induced GFAP expression, which implies that a survival\u2010promoting signal may also play a differentiation\u2010supporting role in malignant gliomas.<\/jats:p>","DOI":"10.1016\/j.molonc.2011.03.003","type":"journal-article","created":{"date-parts":[[2011,3,24]],"date-time":"2011-03-24T12:48:05Z","timestamp":1300970885000},"page":"265-272","source":"Crossref","is-referenced-by-count":28,"title":["Activation of a pro\u2010survival pathway IL\u20106\/JAK2\/STAT3 contributes to glial fibrillary acidic protein induction during the cholera toxin\u2010induced differentiation of C6 malignant glioma 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