Cell-Cycle Genes Inhibition Effects in Glioblastoma

Author(s)

Andressa Gois Morales

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2012-07-17

Examining board members

Luiz Gonzaga Tone; Carlos Gilberto Carlotti Junior; Suely Kazue Nagahashi Marie; Catarina Satie Takahashi; Elvis Terci Valera

• Advisor: Luiz Gonzaga Tone; Maria Sol Brassesco Annichini

Abstract

Astrocytic tumors are originated from astrocitytes and classified according to the World Health Organization into pilocytic astrocytoma (grade I), subependymal giant cell astrocytoma (grade I), pleomorphic xanthoastrocytoma (grade II), diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III) and Glioblastoma (GBM) (grade IV). Glioblastoma is the most common brain tumor in adults with a very poor prognosis and a median survival of 14 months. Because their role in cell cycle control, several authors have previously ponited the BUB gene family as new therapeutic target candidates. These genes participate in the mitotic checkpoint by preventing the premature separation of sister chromatids. The aims of this study were to study the expression of BUB1, BUB3 e BUBR1 in samples of patients with low-grade gliomas (I and II) and glioblastoma, evaluate any association of gene expression with patient survival and analyze BUB1 e BUBR1 inhibition (by iRNA) effects, on SF188, a pediatric cell line. BUB1 and BUBR1 were found hyperexpressed in glioblastoma samples and in low-grade gliomas when compared with white matter samples (p<0.05). The analysis of the expression of these genes in glioblastoma samples compared with grade I and II samples showed a hyperexpression of BUB1 and BUBR1, while BUB3 was hipoexpressed in glioblastoma (p<0.05). In the survival analysis, the hipoexpression of BUB1 and BUBR1 genes were related with a better survival when all patients were considered. The BUB1 and BUBR1 inhibition resulted in decreased proliferation and colony formation, along with increased apoptosis when combined with temozolomide. Experiments with the inhibition of genes also were performed in association with irradiation. This combination demonstrated decreased proliferation and colony formation. Our results suggest that BUB1 and BUBR1 might be interesting targets for future treatment of glioblastoma, nonetheless further studies are necessary to confirm this potencial. (AU)

• FAPESP's process: 09/09305-3 - CELL-CYCLE GENES INHIBITION EFFECTS IN GLIOBLASTOMA
• Grantee: Andressa Gois Morales
• Support Opportunities: Scholarships in Brazil - Doctorate