| Budget Amount *help |
¥3,830,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
Suboellularly localized (nuclear and/or cytoplasmic) survivin has various functions, and correlates with prognosis of malignant tumors. However there have been no reports about the significance of subcellularly localized survivin in high-grade astrocytomas. The aim of the our first paper was to examine the relationship between prognosis and subcellular localization of survivin in high-grade astrocytoma. Methods We immunohistochemically examined the pattern of subcellular localization of survivin expression (nuclear, cytoplasmic, or both)in 51 patients with highgrade astrocytoma (19 anaplastic astrocytomas; 32 glioblastomas). We statistically examined the relationship between survivin localization and prognosis, using multivariate analysis including other clinicopathological factors (age, sex, WHOgrade, extent of resection, MEB-1 labeling hide, and expression of p53 and epidermal growth factor receptor). Results All specimens stained positive for survivinilocalized in nucleus only (nucl
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ear-positive group), 10cases (20%); localized in cytoplasm only (cytoplasmicpositive group), 23cases (45%); simultaneous expression in nucleus and cytoplasm (nuclear-cytoplasmic group), 19cases (35%). There was no significant difference in prognosis between the nuclear-positive group and cytoplasmic-positive group (P=0.796). However, the nuclear-cytoplasmic group had significantly shorter overall survival than the nuclear-positive group and the cytoplasmic-positive group (P<0.0001). Conclusions We found that simultaneous expression of survivin in both the nucleus and cytoplasm is an important prognostic factor for high-grade astrocytoma. The present findings indicate that subcelluliar localization of survivin expression is a reliable prognostic factor for patients with this tumor.
Furthermore, survivin, a regulator of chromosome segregation, is highly expressed and known to induce radioresistance in human gliomas. In second paper, we examined the effect of survivin suppression on radiosensitivity in malignant glioma cells, while focusing on centrosome aberration and chromosome instability (CIN). We suppressed survivin by small interfering RNA transktion, and examined the radiosensitivity using a clonogenic assay and a trypan blue exclusion assay in U251MG (p53mutant) and D54MG (p53 wild type) cells. To assess the CIN status, we determined the number of centrosomes using an immunolluorescence analysis, and the centromeric copy number by fluorescence in situ hybridisation. As a result, the radiosensitisation differed regarding the p53 status as U251MG cells quickly developed extreme centrosome amplification (1/4CIN) and enhanced the radiosensitivity, while centrosome amplification and radiosensitivity increased more gradually in D54MG cells. TUNED assay showed that survivin inhibition did not lead to apoptosis after irradiation. This cell death was accompanied by an increased degree of aneuploidy, suggesting mitotic cell death. Therefore, survivin inhibition may be an attractive therapeutic target to overcome the radioresistance while, in addition, proper attention to CIN (centrosome number) is considered important for improving radiosensitivity in human glioma. Less
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