Análise do perfil do número de cópias e transcriptoma de pacientes com gliomas e em linhagens de glioblastomas tratadas com pisosterol

Abstract

Central Nervous System Tumors (CNS) account for approximately 2% of all cancers. Although the incidence of CNS tumors is small, compared to other neoplasms, these tumors are among the most serious human malignancies because they affect the organ responsible for the coordination and integration of all organic activities. Gliomas represent approximately 80% of all intracranial tumors, typically affecting adults, with a high incidence between 40 and 65 years of age. Although numerous anti-glioma drugs have already been developed, they induce adverse reactions and their therapeutic effects are not satisfactory. The objective of this study was to evaluate and compare the profile of Copy Number Variation (CNV) and gene expression of patients diagnosed with gliomas and in glioblastomas cell lines (U87-MG, U343, AHOL1 and 1321N1) treated with pisoterol. For rhe experiments done with the cell lines treated with pisoterol, we demonstrated that they were highly sensitive to pisoterol treatment. This drug reduced the number of live cells in a dose-dependent manner. In addition, we demonstrated that after 48h of exposure to pisoterol, all cell lines were blocked in G2/M. Finally, we demonstrate that the pisosterol can modulate the expression of several genes of ATM/ATR pathway, promoting apoptosis. We demonstrated on genomic scale that all the cell lines had more genes that were significantly down-regulated than up-regulated after the treatment with pisosterol. For the experiments done with the gliomas biopsies, we demonstrated that only 11 genes (TNFRSF1A, SNAPC2, CASP8, IRAK3, GPX3, FZD9, TFAP2C, CDH1, RPRM, POU4F3 and MGMT) exhibited changes in the pattern of methylation in all grades analyzed. In addition, the methylation pattern of these 11 genes had correlations with some clinicopathological characteristics, such as age, sex and histological grade. And finally, we made a molecular characterization describing the CNVs of the gliomas originating from Belém-PA.