2001 Fiscal Year Final Research Report Summary
Investigation of Apoptosis-inducing/-inhibiting Oncogenes in Neuroblastoma and Its Relationship to the Patients Prognosis
| Project/Area Number |
10671675
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatric surgery
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| Research Institution | St. Marianna University School of Medicine |
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Principal Investigator |
NAKADA Koonosuke St. Marianna University, Pediatric Surgery, Professor, 医学部, 教授 (70081734)
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| Co-Investigator(Kenkyū-buntansha) |
WAKISAKA Munechika St. Marianna University, Pediatric Surgery, Assistant Professor, 医学部, 講師 (30267596)
KOIZUMI Hirotaka St. Marianna University, Pathology, Assistant Professor, 医学部, 講師 (10215155)
TAKAKUWA Toshifumi St. Marianna University, Pathology, Associate Professor, 医学部, 助教授 (90121201)
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| Project Period (FY) |
1998 – 2001
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| Keywords | neuroblastoma / apoptosis / Fas / caspase 3 / caspase 9 |
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| Research Abstract |
We investigated first the mechanisms of apoptosis in neuroblastoma (NB)s by examining the expression profiles of Fas, Fas ligand and caspase 3 in 42 primary tumors. Immunohistochemically, no or weak Fas expression was detected in most NBs (86 %), whereas high levels of expression of Fas ligand and procaspase 3 were noted in more than 70 % of the tissues, respectively. Western blot analysis of 10 NBs confirmed the lack of Fas expression and strong FasL expression in all samples and fluent pro-caspase 3 expression in 5 tumors. Immunostaining for p17 subunit of caspase 3 heterodimer showed that active caspase 3 was mainly localized in apoptosic tumor cells.
Second, we investigated the expression of caspase-9, caspase-3, and XIAP in 20 NB specimens to understand how Fas-independent apoptosis occurs in the tumors. Western blotting of caspase-9 showed ubiquitous expression of pro-form protein and active forms (Lp37/p35) in 9 tumors (45 %). Pro-caspase-3 was detected in all tissues and active forms (p24/p17) in 13 tumors (65 %). Moreover, seven of the p24/p17-positive tumors (54 %) co-expressed p37/p35, suggesting that caspase-3 was activated by caspase-9 in these tumors. Whereas all NBs expressed XIAP, its amount was reduced in 9 tumors of which 6 contained p37/p35. This implied that the expression level of XIAP in the tumors with active caspase-9 might be suppressed so that they could undergo apoptosis efficiently.
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[Publications] Kaneko M, Tsuchida Y, Uchino J, Takeda T, Iwafuchi M, Ohnuma N, Mugishima H, Yokoyama J, Mshihira H, Nakada K, et al: "Treatment results of advanced neuroblastoma with the first Japanese study group protocol"J Pediatr Hematology/Oncology. 21. 190-197 (1999)
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[Publications] Ohnuma N, Kaneko M, Yamamoto K, Etoh T, Mugishima H, Ohhira M, Yokoyama J, Bessho F, Honna T, Yoshizawa J, Nakada K, et al.: "Long-term survivors of advanced neuroblastoma with MYCN amplification : A report of 19 patients surviving disease-free for more than 66 months"J clinical Oncology. 17. 3216-3227 (1999)
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