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MECHANISMS OF CLONAL DELETION OF HEPATOCELLULAR CARCINOMA BY ACYCLICRETINOID

Research Project

Project/Area Number 10557055
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Gastroenterology
Research InstitutionGIFU UNIVERSITY

Principal Investigator

MORIWAKI Hisataka  GIFU UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (50174470)

Co-Investigator(Kenkyū-buntansha) OKUNO Masataka  GIFU UNIVERSITY,SCHOOL OF MEDICINE, 医学部・附属病院, 講師 (10204140)
OMORI Masahide  TOKAI WOMEN'S COLLAGE, FACULTY OF HUMANITIES, PROFESSOR, バイオサイエンスセンター, 教授 (30278212)
SHIDOJI Yoshihiro  SIEBOLD UNIVERSITY, CELLULAR BIOCHEMISTRY SECTION, PROFESSOR, 看護栄養学部, 教授 (00111518)
SHIRATORI Yoshimune  GIFU UNIVERSITY, SCHOOL OF MEDICINE, 医学部, 助手 (20313877)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1998: ¥3,000,000 (Direct Cost: ¥3,000,000)
KeywordsCANCER CHEMOPREVENTION / HEPATOCELLULAR CARCINOMA / RETINOID / RETINOID X RECEPTOR / DIFFERENTIATION INDUCTION / APOPTOSIS / CASPASE / レチノイドX受容体 / 遺伝子変異
Research Abstract

Retinoid inhibit the tumor promotion phase of mutistep carcinogenesis. We have conducted investigations of chemoprevention of hepatocellular carcinoma by retionoids and confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis (New Engl J Med, 1996). Moreover, we reveled significant difference in the survival rate between the retinoid and the placebo groups with a median follow-up of 62 months (P=0.04). Among selected patients variables at the time of randomization, proportional hazards analysis revealed that the administration of acyclic retinoid was the only independent factor that significantly improved survival of the patients. The estimated relative risk of death was 0.3 (95 percent confidence interval, 0.1 to 0.8) in the acyclic retinoid group as compared with the placebo group (New Engl J Med, 340 : 1046-1047 ; 1999).
Acyclic retinoid prevents hepatocarcinogenesis by eradicating premalignant and latent malignant clones of transformed cells from the liver. We demonstrate the mechanism of this clonal deletion at the cellular level. Production of albumin was recovered while that of AFP-L3 was reduced after exposure of the cells to acyclic retinoid for 2 days. In parallel, both TERT mRNA expression and telomerase activity were down-regulated. The cells subsequently died due to apoptosis. Serial increases in mitochondrial membrane permeability and caspase-9 and -3 activities induced apoptosis. Acyclic retinoid first induces differentiation and reduces telomerase activity. Subsequent late apoptosis completes the clonal deletion of the cells.
We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (55 results)

All Other

All Publications (55 results)

  • [Publications] Muto Y, et al.: "Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma."Digestion. 59. 89-91 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okuno M, et al.: "Suppressive effect of low amounts of safflower and perilla oils on diethylnitrosamine-induced hepatocarcinogenesis in male F344 rats."Nutr Cancer. 30. 186-193 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okuno M, et al.: "Protease inhibitors suppress TGF-β generation by hepatic stellate cells."J Hepatol. 29. 1031-1032 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kajiwara K, et al.: "Oral supplementation with branched-chain amino acids improves the survival rate of rats with carbon tetrachloride-induced liver cirrhosis."Dig Dis Sci. 43. 1572-1579 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Onogi N, et al.: "Antiproliferative effect of carotenoids on human colon cancer cells without being converted to retinoic acid."Nutr Cancer. 32. 20-24 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwai H, et al.: "Removal of endotoxin and cytokines in patients with acute hepatic failure by plasma exchange."Crit Care Med. 26. 873-876 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kato M, et al.: "Preferential use of branched-chain amino acids as an energy substrate in patients with liver cirrhosis."Int Med. 37. 429-434 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Muto Y, et al.: "Prevention of second primary tumors by an acyclic retinoid in patients with bepatocellular carcinoma."N Engl J Med. 340. 1046-1047 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okuno M, et al.: "Increased 9, 13-di-cis-retinoic acid in rat hepatic fibrosis : Implication for a potential link between retinoid loss and TGF-β Mediated fibrogenesis In vivo."J Hepatology. 30. 1073-1080 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsushita T, et al.: "IL-12 Indudes specific cytotoxicity against regenerating hepatocytes in vivo."Int Immunol. 11. 657-665 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kimura K, et al.: "Immunopathogenesis of hepatic fibrosis in chronic inflammatory liver disease. Novel fibrosis model in conA induced liver injury."Int Immunol. 11. 1491-1500 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kimura K, et al.: "Elevated intracellular IFN-γ levels in circulating CD8+lymphocytes in patients with fulminant hepatitis."J Hepatol. 31. 579-583 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sano K, et al.: "Effects of cytokines on the binding of leukocytes to cultures rat hepatocytes and on the expression of ICAM-1 by hepatocytes."Dig Dis Sci. 44. 796-805 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, et al.: "Lethal hepatic apoptosis mediated by tumor necrosis factor receptor, unlike Fas-mediated apoptosis, requires hepatocyte sensitization in mice."J Hepatol. 31. 997-1005 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, et al.: "Interleukin-10 inhibits hepatic injury and tumor necrosis factor-α and interferon-γ mRNA expression induced by staphylococcal enterotoxin B or lipopolysaccharide in galactosamine-sensitized mice."J Hepatol. 31. 815-824 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Moriwaki H, et al.: "Nutritional pharmacotherapy of chronic liver disease : from support of liver failure to prevention of liver cancer."J Gastroenterol. 35. 13-17 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, et al.: "Control of cyclin-dependent kinase inhibitors, p21 and p27, and cell cycle progression in rat hepatocytes by extracellular matrix."J Hepatol. 32. 488-496 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, et al.: "High levels of serum interleukin-10 and tumor necrosis factor a are associated with fatality in fulminant hepatitis."J Infect Dis. 182. 1103-1108 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miwa Y, et al.: "Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis."Hepatology Res. 18. 184-189 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kato M, et al.: "Both insulin sensitivity and glucose sensitivity are impaired in patients with nondiabetic liver cirrfosis."Hepatology Res. 17. 93-101 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Muto Y, Moriwaki H, Shiratori Y.: "Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma."Digestion. 59. 89-91 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okuno M, Tanaka T, Komaki C, Nagase S, Shiratori Y, Muto Y, Kajiwara K, Maki T, Moriwaki H.: "Suppressive effect of low amounts of safflower and perilla oils on diethylnitrosamine-induced hepatocarcinogenesis in male F344 rats."Nutr Cancer. 30. 186-193 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okuno M, Moriwaki H, Muto Y, Kojima S.: "Protease inhibitors suppress TGF-β generation by hepatic stellate cells."J Hepatol. 29. 1031-1032 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kajiwara K, Okuno M, Kobayashi T, Honma N, Maki T, Kato M, Ohnishi H, Muto Y, Moriwaki H.: "Oral supplementation with branched-chain amino acids improves the survival rate of rats with carbon tetrachloride-induced liver cirrhosis."Dig Dis Sci. 43. 1572-1579 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Onogi N, Moriwaki H, Muto Y, Kojima S.: "Antiproliferative effect of carotenoids on human colon cancer cells without being converted to retinoic acid."Nutr Cancer. 32. 20-24 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwai H, Nagaki M, Naito T, Ishiki Y, Murakami N, Sugihara J, Muto Y, Moriwaki H.: "Removal of endotoxin and cytokines in patients with acute hepatic failure by plasma exchange."Crit Care Med. 26. 873-876 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kato M, Miwa Y, Tajika M, Hiraoka T, Muto Y, Moriwaki H.: "Preferential use of branched-chain amino acids as an energy substrate in patients with liver cirrhosis."Int Med. 37. 429-434 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Muto Y, Moriwaki H, Saito A.: "Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma."N Engl J Med. 340. 1046-1047 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okuno M, Moriwaki H, Onuki K, Masushige S, Muto Y, Scott L Friedman, Kato S, Kojima S.: "Increased 9, 13-di-cis-retinoic acid in rat hepatic fibrosis : Implication for a potential link between retinoid loss and TGF-β Mediated fibrogenesis In vivo."J Hepatology. 30. 1073-1080 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsushita T, Ando K, Kimura K, Ohnishi H, Imawari M, Muto Y, Moriwaki H.: "IL-12 Indudes specific cytotoxicity against regenerating hepatocytes in vivo."Int Immunol. 11. 657-665 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kimura K, Ando K, Ohnishi H, Ishikawa T, Kakumu S, Takemura M, Muto Y, Moriwaki H.: "Immunopathogenesis of hepatic fibrosis in chronic inflammatory liver disease. Novel fibrosis model in conA induced liver injury."Int Immunol. 11. 1491-1500 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kimura K, Ando K, Tomita E, Ohnishi H, Ishikawa T, Kakumu S,Muto Y, Moriwaki H.: "Elevated intracellular IFN-γ levels in circulating CD8+lymphocytes in patients with fulminant hepatitis."J Hepatol. 31. 579-583 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sano K, Nagaki M, Sugiyama A, Hatakeyama H, Ohnishi H, Muto Y, Moriwaki H.: "Effects of cytokines on the binding of leukocytes to cultured rat hepatocytes and on the expression of ICAM-1 by hepatocytes."Dig Dis Sci. 44. 796-805 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, Sugiyama A, Osawa Y, Naiki T, Nakashima S, Nozawa Y, Moriwaki H.: "Lethal hepatic apoptosis mediated by tumor necrosis factor receptor, unlike Fas-mediated apoptosis, requires hepatocyte sensitization in mice."J Hepatol. 31. 997-1005 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, Tanaka M, Sugiyama A, Ohnishi H, Moriwaki H.: "Interleukin-10 inhibits hepatic injury and tumor necrosis factor-α and interferon-γ mRNA expression induced by staphylococcal enterotoxin B or lipopolysaccharide in galactosamine-sensitized mice."J Hepatol. 31. 815-824 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Moriwaki H, Tajika M, Miwa Y, Kato M, Yasuda I, Shiratori Y, Okuno M, Kato T, Ohnishi H, Muto Y.: "Nutritional pharmacotherapy of chronic liver disease : from support of liver failure to prevention of liver cancer."J Gastroenterol. 35. 13-17 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, Sugiyama A, Naiki T, Ohsawa Y, Moriwaki H.: "Control of cyclin-dependent kinase inhibitors, p21 and p27, and cell cycle progression in rat hepatocytes by extracellular matrix."J Hepatol. 32. 488-496 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagaki M, Iwai H, Naiki T, Ohnishi H, Muto Y, Moriwaki H.: "High levels of serum interleukin- 10 and tumor necrosis factor a are associated with fatality in fulminant hepatitis."J Infect Dis. 182. 1103-1108 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miwa Y, Shiraki M, Kato M, Tajika M, Mohri H, Murakami H, Kato T, Ohnishi H, Morioku T, Muto Y, Moriwaki H.: "Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis."Hepatology Res. 18. 184-189 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kato M, Asano H, Miwa Y, Tajika M, Yamato M, Tomita E, Tokuyama K, Muto Y, Moriwaki H.: "Both insulin sensitivity and glucose sensitivity are impaired in patients with non-diabetic liver cirrfosis."Hepatology Res. 17. 93-101 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Moriwaki H.: "Nutritional pharmacotherapy of chronic liver disease : from support of liver failure to prevention of liver cancer."J Gastroenterol. 35. 13-17 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nagaki M.: "Control of cyclin-cependent kinase inhibitors, p21 and p27, and cell cycle progression in rat hepatocytes by extracellular matrix."J Hepatol. 32. 488-496 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nagaki M.: "High levels of serum interleukin-10 and tumor necrosis factor a are associated with fatality in fulminant hepatitis."J Infect Dis. 182. 1103-1108 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miwa Y.: "Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis."Hepatology Res. 18. 184-189 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kato M.: "Both insulin sensitivity and glucose sensitivity are impaired in patients with non-diabetic liver cirrfosis."Hepatology Res. 17. 93-101 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Moriwaki Hisataka: "Frontiers in Hepatology-Progress in Hepatocellular Carcinoma Treatment"Tokyo, Springer-Verlag. 7 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shiratori Yoshimune: "Immunoassays for PIVKA-II"Tokyo, Eisai Co., LTD. 7 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Muto Y.: "Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma"N Engl J Med. 340. 1046-1047 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Okuno M.: "Increased 9.13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo"J. Hepatol.. 30. 1073-1080 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masataka Okuno: "Liver Diseases and hepatic sinusoidal cells"Elsevier Science, Amsterdam.. 10 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hisataka Moriwaki: "Frontiers in Hepatology-Progress in Hepatocellular carcinoma Treatment-"Spinger-Verlag, Tokyo. 7 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Muto Y.: "Prevention of second primary tumors by an acyclic retinoid,polyprenoic acid,in patients with hepatocellular carcinoma." Digestion. 59. 89-91 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okuno M.: "Protease inhibitors suppress TGF-β generation by hepatic stelate cells." J.Hepatol.29. 1031-1032 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Muto Y.: "Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma" N Engl J Med. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okuno M.: "Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis : Implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo" J.Hepatology. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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