ALTERED EXPRESSION OF THE MITOTIC CHECKPOINT GENES BUB1, BUBR1, BUB3, MAD1, MAD2 AND AURKA IN CELL LINES OF CENTRAL NERVOUS SYST

BM01

BORGES, KS (ksborges@usp.br) (1,4), CORTEZ, MAAF (1,4), CASTRO-GAMERO, AM (1,4), OLIVEIRA, FM (3), VALERA, ET (2,4), SCIDELI, CA (2,4), TONE, LG (1,2,4).

Most solid malignant neoplasm show chromosomal aberrations and aneuploidy. The spindle checkpoint is the primary mechanism to ensure that two daughter cells get the same amount of DNA, and its dysfunction has been suggested to contribute to aneuploidy and carcinogenesis. Several proteins, including Mad1, Mad2, Bub1, BubR1 and Bub3, which are specifically recruited to unbound kinetochores upon checkpoint activation, are required for the spindle checkpoint. Significantly, spindle checkpoint defects are frequently observed in human cancer including breast, colon, lung, ovarian, and hepatocellular carcinomas. AURKA plays a critical role in centrosome maturation and bipolar spindle assembly, and its overexpression has been shown to induce centrosome amplification and aneuploidy in human cell lines. In this study, we investigated the expression of the genes BUB1, BUBR1, BUB3, MAD1, mad2 and AURKA in seven cell lines of CNST in relation to the not-neoplasic tissue (white brain substance) by real time-polymerase chain reaction (RQ-PCR). We used the cell lines of the pylocitic astrocytoma (R286), anaplastic astrocytoma (UW467), pediatric glioblastoma (SF188), adult glioblastoma (U343), medulloblastoma (UW3), oligodendoglioma (R280) and ependymoma (R253). The expression of the genes BUB1, BUBR1 and AURK was significantly higher in relation to the not-neoplastic tissue in all the cell lines. On the other hand, all the cell lines showed underexpression of the genes MAD1, mad2 and BUB3. Similar results were observed in others works studying cell lines with chromosomal instability. Our findings suggest that a defective mitotic checkpoint characterized by reduced expression of MAD1, mad2 and BUB3 contribute to chromosomal instability in CNST. High levels of the particular transcripts of the AURKA, BUB1 and BUBR1 could represent a cellular compensation for defects in molecular components of the mitotic spindle damage checkpoint. These results suggest that these genes may play a relevant role in CNST, and may represent putative therapeutics targets for CNST. The white substance of the brain does not is the normal counterparty of all tumors of this study, so these findings should be validated with functional tests and with studies in primary tissue samples from CNST patients.