| Project/Area Number |
12670473
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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 |
Gastroenterology
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| Research Institution | GIFU UNIVERSITY |
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Principal Investigator |
SHIRATORI Yoshimune GIFU UNIVERSITY, SCHOOL OF MEDICINE, ASSISTANT, 医学部附属病院, 助手 (20313877)
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| Co-Investigator(Kenkyū-buntansha) |
SHIDOJI Yoshihiro SIEBOLD UNIVERSITY, CELLULAR BIOCHEMISTRY SECTION, PROFESSOR, 看護栄養学部, 教授 (00111518)
OKANO Yukio GIFU UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (10177066)
MORIWAKI Hisataka GIFU UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (50174470)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | RETINOID / HEPATOCELLULAR CARCINOMA / CANCER CHEMOPREVENTION / CLONAL DELETION / NUCLEAR RECEPTOR / APOPTOSIS / UBIQUITINATION / INTERFERON |
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| Research Abstract |
We have conducted investigations of chemoprevention of hepatocellular carcinoma by retlonoids and confirmed the clinical effects of acyclic retionid, a synthetic retinoid analog, on second primary hepatocarcinogenesis. We reported the difference in ubiquitination of retinoid X receptor (RXR) α in human normal liver and hepatocellular carcinoma (HCC). We revealed that switching of the ubiquitin/proteasome-dependent degradation of RXR α may be responsible for the aberrant growth of HCC and its suppression by retinoids. Interferons (IFNs)- α and - β also induce apoptosts of HCC cells and are used clinically in the prevention of HCC. Acyclic retinoid enhanced anti-tumor effects of not only IFN-β but also IFN-α, however, natural retinoic acid (all-trans and 9-cis retinoic acid) failed to exert such effect. This combination effect was likely due to enhanced apoptosis induction as characterized by DNA fragmentation and chromatin condensation. Pretreatment of the HCC cells with acyclic retinoid followed by IFN-β, but not the converse, induced such cytotoxic effect. Acyclic retinoid increased the expression of type 1 IFN receptor (IFNR) and inclusion with anti-type 1 IFNR antibody abolished the synergistic growth suppression by the combination. Moreover, the retinoid up-regulated the expression and DNA-binding activity of STAT1, an intracelluiar signal transducing molecule of IFNR. Thus, acyclic retinoid seemed to enhance the sensitivity of HCC cells to IFN-β and thereby promoted the cancer cell death. These results suggest a future clinical use of the combination of acyclic retinoid and IFN-β in the biochemoprevention of HCC. We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.
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