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Phosphodiesterase type 5 regulates glioblastoma invasiveness

Valeriana Cesarini, Dept. of Biomedicine and Prevention, University of Rome Torvergata, Rome, Italy; Maurizio Martini, Dept. of Pathology, Catholic University, Rome Italy; Roberto Pallini, Dept. of Neurosurgery, Catholic University Rome, Italy; Lucia Ricci Vitiani, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Luigi Maria Larocca, Dept. of Pathology, Catholic University, Rome, Italy; Emmanuele A. Jannini, Dept. of System Medicine, University of Rome Torvergata, Rome, Italy; Susanna Dolci Dept. of Biomedicine and Prevention, University of Rome Torvergata, Rome, Italy

Phosphodiesterase type 5 (PDE5), a cGMP-specific hydrolytic enzyme, is expressed in many tumors included Glioblastoma Multiforme(GBM). We analyzed by immunohistochemistry PDE5 expression in 80 patients affected by GBM with different grade of aggressiveness. We found that in a cohort of 65 patients, about 50% of them showed a strong PDE5 positivity within cancer cells while others cases were completely negative. By analyzing retrospective data of these patients we found that high levels of PDE5 expression in tumor cells strongly correlated with a major survival probability of patients (p=0.0028). To understand if PDE5 downregulation favours glioblastoma cells survival and/or invasiveness we silenced PDE5 in glioblastoma cell line T98G. Silenced cells did not show any modification of the proliferation rate compared to the scrambled controls, however they were strongly activated in their migration and invasion capacity. We found that in Hif1 downregulates PDE5 mRNA, protein levels and promoter activity in T98G cells increasing their invasion capacity. The transcription factor BRN2 has been shown to repress PDE5 expression and increase invasiveness in melanoma cells. We found that BRN2 represses PDE5 expression and promoter activity also in T98G cells. These results suggest that PDE5 could be a prognostic marker for GBM and that BRN2 and Hif1a can regulate invasiveness of glioblastoma through PDE5 down-regulation.

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