| Co-Investigator(Kenkyū-buntansha) |
NAITO Katsusuke Yamaguchi University, Faculty of Medicine, Professor, 医学部, 教授 (60115251)
SASAKI Kohsuke Yamaguchi University, Faculty of Medicine, Professor, 医学部, 教授 (80116722)
OKUDA Masaru Yamaguchi University, Veterinary, Associate Professor, 医学部, 助教授 (10325243)
吉弘 悟 山口大学, 医学部附属病院, 講師 (40284260)
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| Budget Amount *help |
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2003: ¥8,400,000 (Direct Cost: ¥8,400,000)
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| Research Abstract |
Clinical investigations :
Totally, 100 cases of clinical bladder cancer were studied on the relationship among centrosome amplification (CA), chromosome 20q13 gain, Aurora-A overexpression, chromosomal instability (CIN), aberrant expression of p53 protein, microsatellite instability (MSI), Polo-like kinase, a cell cycle-related kinase protein, (PLK-1), and patient prognosis. MSI was found only in 9 cases (9%) who showed good prognosis without CA, 20q13 gain, tumor progression. The frequency of MSI in bladder cancer was much lower than that of colo-rectal cancer reported. In contrast, CA was detected in 49 cases (49%) who showed poor prognosis with CA, 20q13 gain, Aurora-A overexpression, aberrant expression of p53 protein, and tumor progression. Overexpression of PLK-1 was significant correlation with CA, and found more in cases with higher grade, multiple tumor number, positive urine cytology. Based on these results, two hypotheses were postulated, #1 bladder cancer was biologically classified into two categories by genomic instability, i.e. CIN with poor prognosis, and MSI with good prognosis in terms of tumor progression, #2 overexpression of PLK-1 was involved in the mechanism of occurrence of CA, thereby induce the tumor progression.
Basic investigations :
In order to clarify the mechanism of the occurrence of CA and to seek the relevant gene (s) for CA, high-throughput gene expression profile was carried out by microarray technique on several mouse embryonic cell lines, biologically possessing p53 knockout and CA in character. As a result, down-regulation of BubR1, a pivotal kinase protein concerning mitotic checkpoint, was linked to the occurrence of CA, while CA was eliminated by BubR1 tranfection. From these results, it was suggested that CA may arise from the cooperation between functional loss of p53, leading to the loss of post-mitotic checkpoint at G1 phase, and down-regulation of BnbR1 expression, leading to the escape from mitotic checkpoint at M phase.
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