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THE STUDY OF SEX DIFFERENCE IN HEPATOCARCINOGENESIS-ANALYSIS USING TGF alpha TRANSGENIC MICE-

Research Project

Project/Area Number 07670562
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionGUNMA UNIVERSITY

Principal Investigator

TAKAGI Hitoshi  GUNMA UNIVERSITY SCHOOL OF MEDICINE,THE FIRST DEPARTMENT OF INTERNAL MEDICINE,TEACHING ASSOCIATE, 医学部, 助手 (20251093)

Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1995: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsTGF alpha / hepatoma / gender / transgenic mice / androgen / LH-RH-agonist / p450
Research Abstract

We tested the mechanism of male predominant hepatocarcino-genesis using transforming growth factor alpha transgenic mice which also developed liver tumor preferentially in male. Serum level of testosteron was 1.38ng/dl in control male mice and 29.7ng/dl in transgenic mice. We observed transgenic male mice for 15 months after the treatment as follows ; sham operated (no treatment) (S), castrated (C) and castrated and 5 alpha-dihydrotestosteron complement (C+D). Serum level of testosteron was increased C-C+D-S in this order. On the other hand, body weight and liver weight were lower in (C) than in (C+D) and (S). Seven liver tumors were developed in 6 (S), 2 in (C) and 9 of 6 (C+D) transgenic mice. Two liver tumors in (C) were smaller than those in (S) and (C+D). PCNA staining showed higher labelling index in (S) and (C+D) than (C) in both liver tumors and surrounding liver tissues. Anti-androgenic effect of LH-RH agonist, leuprorelin acetate, was administered to the transgenic mice and suppressed the liver tumor formation. These results suggest the androgen has promotor like effect in hepatic tumorigenesis in TGF alpha transgenic mice and TGF alpha may enhance the androgen production. this evidence was supported by the results of the study using the cell lines (AML12) established from TGF alpha transgenic liver. AML12 produced TGF alpha in culture supernatant higher in the presense of androgen but not changed in that of estrogen. p450 2A family, which is a catabolic enzyme of the liver and highly expressed in female, was significantly expressed in MT42 male liver especially in liver tumors of transgenic mice. The result demonstrated the relationship of TGF alpha-androgen-p450 2A in liver tumor formation.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Takagi H,et al.: "Histochemical analysis of the hyperplastic stomach of TGFα transgenic mice." Dig.Dis.Sciences. 42. 91-98 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,et al.: "Hepatocellular carcinoma with pleural mefastasis complicated by hemothorax." Am J Gastroenterol. 91. 1865-1866 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ichikawa T et al.: "Effect of the EGF-receptor-inhibitor on primary caltured bepatecytes isolated from transgenic mice of transforming growth factor C" Int Hepatol Commun.3. S74- (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Matsumoto T,et al.: "Androgen supplement for costrated,TGFα transgenic male mice,restored pepatec,tumorigenesis." Int Hepatol.Commun.3. S141- (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 高木均 他: "TGFαトランスジェニックマウスの肝発癌におけるP450-2aの関与" 肝臓. 37. S173- (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,et al.: "steroid hormone-dependent overexpression of the cytochrome P450 2A in livel-tumors of TGFα transgenic male m" J Gastroenterol. in press. (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 竹内利行他: "消化管〔胃・腸〕の分子医学" 羊土社, 14 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,Fukusato T,Kawaharada U,Merlino G and Tsutsumi Y.: "Hist o chemical analysis of the hyperplastic stomach of TGFalpha transgenic mice." Dig Dis Sciences. 42. 91-98 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,Shimoda R,Uehara M,Takayama H,Yamada T,Ojima T,Abe T,Suka K,Nagamine T,Mori M and Barber A.: "Hepatocellular carcinoma with pleural metastasis complicated by hemothorax." Am J Gastroenterol. 91. 1865-1866 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,Aida K,Sohara N,Merlino G,Mori M,Negishi M.: "Steroid hormone-dependent overexpression of the cytochrome p450 2A in liver tumors of TGFalpha transgenic male mice." J Gastroenterology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,Takayama H,Shimoda R,Nagamine R.: "TGFalpha transgenic mice and hepatocarcinogenesis. (in Japanese)" Frontiers in Gastroenterology. 1. 69-78 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,Takayama H,Saitoh S,Matsumoto T,Tamura D,Shimoda R,Nagamine R,Mori M.: "TGFalpha and liver regeneration. (in Japanese)" Surgery. 59. 9-13 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ichikawa T,Takagi H,Mori M.: "Liver regeneration and EGF,TGFalpha. (in Japanese)" Molecular Medicine. (in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ichikawa T,Takehara K,Takagi H,Arai H,Shimoda R,Matsumoto T,Saito S,Yuasa T,Arai T,Nagamine T,Yamada S,Mori M.: "Effect of the EGF-receptor-inhibit or on primary cultured hepatocytes isolated from transgenic mice of transforming growth factor alpha." Int Hepatol Commun. 3 : suppl. s74 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Matsumoto T,Saitoh S,Moriguchi M,Shimoda R,Takehara K,Nagamine T,Mori M,Takagi H.: "Androgen supplement for castrated TGFalpha transgenic male mice restored hepatic tumorigenesis." Int Hepatol Commun. 3 : suppl. s141 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takagi H,Matsumoto T,Saitoh S,Sohara N,Shimoda R,Takehara K,Nagamine R,Mori M.: "Contribution of p450-2a in hepatocarcinogenesis of TGFalpha transgenic mice. (in Japanese)" Acta Hepatol Japon. 37 : suppl. 173 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takeuchi T,Hayashi N,Takagi H.: Gastroenterology and transgenic mice. Molecular Medicine of Gastroenterology (Stomach and Intestine). Sugano K ed.Yodosha Tokyo, 132-145 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Matsumoto T,Takagi H,et al: "Androgen supplement for castrated TGFα transgenic malenice restored Hapatic tumorigenesis." Int Hepatol Communic. 3. S141- (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Takagi H,et al: "Histochemical analysis of hyper plastic stomoch of TGFα Transgenic mice." Digestive Diseases and Sciences. 42. 91-98 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] 高木均 他: "TGFαと肝再生" 外科. 59. 9-13 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Takagi H,et al.: "Hepotocellular carcinoma with plearol metastosis camplicated by hemotherax." Am J Gastroenterol.91. 1865-1866 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 高木均 他: "TGFαトランスジェニックマウスと肝腫瘍の発生機序" Frentiers in Gastroenterology. 1. 69-78 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 市川武、高木均、森昌朋: "肝再生とEGF,TGFα" Molecular Medicine. (in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] 市川 武: "TGFα発現トランスジェニックマウスの初代培養肝細胞に対する3EGFレセプター阻害薬の影響" 肝臓. 36 supplement. 201- (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 松本達彦: "TGFαtransgenic miceにおける男性ホルモンの肝腫瘍発生におよぼす影響" 肝臓. 36 supplement. 334- (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 高木 均: "TGFα発現トランスジェニックマウスと肝腫瘍の発生機序" Gostroenterology Froutier. 1 (発表予定). (1996)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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