Reproductive and Developmental Biology

  • 제31권3호
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  • Pages.145-152
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  • 2007
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  • 1738-2432(pISSN)
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  • 2288-0151(eISSN)
한국동물번식학회 (The Korean Society of Animal Reproduction)
권호 표지

형질 전환 기법을 이용한 인체 간암의 마우스 모델 제작 및 특성 규명

Production and Characterization of a Transgenic Mouse Model of Human Liver Cancer

  • 이종숙 (중국길림성 연변대학 농학원) ;
  • 이정웅 (한국생명공학연구원 유전체의학연구센터) ;
  • 현병화 (한국생명공학연구원 질환모델연구센터) ;
  • 이철호 (한국생명공학연구원 질환모델연구센터) ;
  • 정규식 (한국생명공학연구원 질환모델연구센터) ;
  • 방남수 (중국길림성 연변대학 농학원) ;
  • 염영일 (한국생명공학연구원 유전체의학연구센터)
  • Li, Zhong-Shu (Department of Animal Science, College of Agriculture, Yanbian University) ;
  • Lee, Jung-Woong (Medical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology(KRIBB)) ;
  • Hyun, Byung-Hwa (Disease Model Research Center, Korea Research Institute of Bioscience & Biotechnology(KRIBB)) ;
  • Lee, Chul-Ho (Disease Model Research Center, Korea Research Institute of Bioscience & Biotechnology(KRIBB)) ;
  • Jeong, Kyu-Shick (Disease Model Research Center, Korea Research Institute of Bioscience & Biotechnology(KRIBB)) ;
  • Fang, Nan-Zhu (Department of Animal Science, College of Agriculture, Yanbian University) ;
  • Yeom, Young-Il (Medical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology(KRIBB))
  • 발행 : 2007.09.30
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⟨ 이전 논문 다음 논문 ⟩

초록

본 연구에서는 SV40 Tag을 마우스 albumin 유전자의 promoter/enhancer 조절 하에 발현하도록 설계된 재조합 유전자를 마우스 1세포기 수정란에 미세 주입하여 형질 전환마우스를 제작하고 이들의 인체 간암 모델로써의 적합성을 조사하였다. 형질 전환이 확인된 총 11개체의 founder 생쥐들 중 4개체가 간암을 일으켰고, 두 개체는 신장암을, 한 개체는 피부 및 뇌에서 종양을 각각 일으켰다. 이들로부터 외래 유전자를 계대 유전하는 3가계를 얻었다(#1-2, #1-6, #1-11). 이들 가계의 자소들에서 8주령(#1-2, #1-6)혹은 10주령(#1-11)시부터 간암이 반복적으로 발생되었으며, #1-11 founder개체에서 폐로 암세포가 전이된 것 외에는 다른 조직에서의 형태학적 변이가 발견되지 않았다. 간암 발생은 조직학적 변화에 따라 3단계로 나눌 수 있었다. 즉, 출생에서 3주령까지는 간세포의 과량증식을 보이나 세포핵의 이상은 관찰되지 않았으며, 4주령부터 7주령(#1-2, #1-6) 혹은 9주령(#1-11)까지는 diffuse liver cell dysplasia를 나타내지만 tumor nodule은 발견되지 않았고, 그 이후에는 liver dysplasia를 배경으로 간암이 발생하였다. 본 연구에서 작출한 간암 모델 마우스는 인체 간암과 일부 유사한 소견을 보였는바 인체 간암 기전 연구를 위한 유용한 동물 모델로 이용할 수 있을 것으로 생각된다.

Transgenic mice were generated by microinjecting a plasmid DNA containing the SV40 (simian virus 40) large T antigen (Tag) gene fused with mouse albumin promoter/enhancer sequences into fertilized one-cell mouse embryos. Among eleven founder transgenic animals, four developed hepatocellular carcinoma, two showed kidney cancer and one developed skin and brain tumors. Three stable transgenic lines, #1-2, #1-6 and #1-11 were established. Members of the lines #1-6 and #1-11 reproducibly developed liver tumors by 8 to 10 weeks of age but did not exhibit any phenotypic changes in other tissues. Histological changes loading to liver tumor formation occurred with predictable kinetics and could be classified into three distinct stages; (a) newborn to 3 weeks of age, characterized by hyperplastic hepatocytes with reduced amounts of cytoplasm without any nuclear alterations, (b) between 4 to 8 weeks of age, characterized by diffuse liver cell dysplasia without observable tumor nodules, and (c) 9 weeks of age and thereafter, characterized by hepatocellular carcinomas in the background of extensive liver dysplasia. Metastasis to the lung from a liver carcinoma was observed in #1-11 founder animal. This transgenic mouse system displays similarities with human liver cancers in a number of aspects and provides a useful model for the study of molecular events involved in hepatocarcinogenesis.

키워드

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