论文部分内容阅读
Background: Tumorigenesis is caused by an uncontrolled cell cycle and the altered expression of many genes.Hedgehog pathway leads to activation of Gli, glioma-associated oncogene transcription factors, which transcriptionally regulate target genes.Regulated Hedgehog signaling activity is critical during embryogenesis while aberrantly activated Hedgehog signaling is evident in a variety of human cancers.However, it remains unclear how Hedgehog pathway is involved in the pathogenesis of human glioma.To explore the involvement of aberrant Hedgehog pathway in the pathogenesis of human glioma, we investigated the expression and activation of Hedgehog pathway in human glioma and examined the effect of Gli inhibition.Results:To evaluate the gene expression of Hedgehog pathway, we performed immunohistochemistry and real-time PCR using human glioma cell lines and human glioma biopsy specimens.To evaluate the effect of Gli inhibition, we did cell viability, colony formation, cell cycle in vitro and xenograft model in vivo.Both immunohistochemistry and real-time PCR revealed over-expression of Gli and target genes of transcription factor Gli in human glioma biopsy specimens.These findings showed that Hedgehog pathway is activated in human glioma.Inhibition of Gli by GANT61, a specific inhibitor of Gli1 and Gli2, slowed the growth of glioma cells in vitro and in vivo.Cell cycle analysis revealed that GANT61 promoted cell cycle arrest.GANT61 reduced the expression of accelerators of the cell cycle including cyclin E2.In addition,CDK2 and CDK6 were down-regulated by GANT61 treatment.CDKN1A (p21) and p27 were up-regulated by GANT61 treatment.Suppression of both Gli1 and Gli2 by shRNA mimicked the changes in cell viability, cell cycle and gene expression observed in GANT61-treated human glioma cell lines.Conclusions: Our results suggest that inactivation of Gli may be a useful approach to the treatment of glioma.