2006 Fiscal Year Final Research Report Summary
Molecular targeted therapy by inducing cancer cell senesence
| Project/Area Number |
14104014
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | KYUSHU UNIVERCITY |
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Principal Investigator |
WAKE Norio Kyushu University, Faculty of Medicine, Professor, 医学研究院, 教授 (50158606)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Hiroaki Kyushu University, Hospital, Assistant Professor, 病院・講師 (70260700)
KATO Kiyoko Kyushu University, Medical Institute of Bioregulation, Assistant Professor, 生体防御医学研究所, 講師 (10253527)
SONODA Kenzo Kyushu University, Hospital, Research Associate, 病院・助手 (30294929)
UEOKA Yosuke Kyushu University, Hospital, Research Associate, 病院・助手 (50372743)
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| Project Period (FY) |
2002 – 2006
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| Keywords | Molecular targeted Therapy / Cancer / senescence / Erα / MDM2 / p53 / p21 / HDAC inhibitor |
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| Research Abstract |
A. We have cloned the NECCl gene from human chromosome 4 as a senescence inducing gene in choriocaracinoma cells. We investigated the placental anatomy of NECCl KO (-/-) mouse embryos. In the KO placeuta hypertrophy of giant cell layer and suppression of spongio-trophoblast layer formation were noticeable, respectively. NECCl expression was transiently detected in 8.5-11.5 dpc wild type mouse placenta. NECCl was involved in the negative regulation of differentiation from trophoblast stem cell to giant cell.
B. We have cloned the EGLNl gene that has the potential to induce endometrial cancer cell senescence from lg42 region. EGLNl was a member of prolyl hydroxylase family and regulated HIF1 α protein degradation. Inhibition of HIFl α-mediated signaling by FIH or HIFlsiRNA also induced the cancer cell senescence. Overexpression of EGLNl in endometrial cancer cells was able to induce cell senescence through upregulation of p21 CDK ihibitor.
C. We found the ER α activation by the oncogenic K-Ras mutant. Expression of PR or dominant-negative ER mutant elicited the cancer cell senescence. ER α inactivation resulted in the downregulation of MDM2 followed by p53 activation and subsequent p21 upregulation. We have demonstrated the efficacy of new therapies targetted i)functional inactivation of ER α and ii)suppression of MDM2 protein expression, respectively.
D. We have demonstrated the anti-tumor activity of Sodium Butyrate and Valproic acid that are HDAC inhibitors. Both agents were able to induce cancer cell senescence through p21 upregulation. This effect was independent of p53. Now we are planning the clinical research by using Valproic acid.
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Research Products
(8 results)
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[Journal Article] Adenovirus-Mediated Calponin h1 Gene Therapy Directed Against Peritoneal Dissemination of Ovarian Cancer : Bifunctional Therapeutic Effects on Peritoneal Cell Layerand Cancer Cells2006
Author(s)
Ogura T, Kobayashi H, Ueoka Y, Okugawa K, Kato K, Hirakawa T, Hashimoto S, Taniguchi S, Hashimoto S, Wake N, Nakano H
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Journal Title
Clin Cancer Res 12(17)
Pages: 5216-5223
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Adenovirus-Mediated Calponin h1 Gene Therapy Directed Against Peritoneal Dissemination of Ovarian Cancer : Bifunctional Therapeutic Effects on Peritoneal Cell Layer and Cancer Cells2006
Author(s)
Ogura T, Kobayashi H, Ueoka Y, Okugawa K, Kato K, Hirakawa T, Hashimoto S, Taniguchi S, Hashimoto S, Wake N, Nakano H
-
Journal Title
Clin Cancer Res 12(17)
Pages: 5216-5223
Description
「研究成果報告書概要(欧文)」より
