Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Promoter -202 A/C Polymorphism of Insulin-like Growth Factor Binding Protein-3 Gene and Non-small Cell Lung Cancer Risk

인슐린양 성장 인자 결합 단백-3 유전자 -202 좌위의 다형성에 따른 비소세포폐암의 위험도

  • Moon, Jin Wook (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Chang, Yoon Soo (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Han, Chang Hoon (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kang, Shin Myung (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Park, Moo Suk (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Byun, Min Kwang (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Chung, Wou Young (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Park, Jae Jun (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Yoo, Kyeong Nam (Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Shin, Ju Hye (Cancer Metastasis Research Center, Yonsei University College of Medicine) ;
  • Kim, Young Sam (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Chang, Joon (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Sung Kyu (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Hee Jung (Department of Laboratory Medicine, Yonsei University College of Medicine) ;
  • Kim, Se Kyu (Department of Internal Medicine, Yonsei University College of Medicine)
  • 문진욱 (연세대학교 의과대학 내과학교실) ;
  • 장윤수 (연세대학교 의과대학 내과학교실) ;
  • 한창훈 (연세대학교 의과대학 내과학교실) ;
  • 강신명 (연세대학교 의과대학 내과학교실) ;
  • 박무석 (연세대학교 의과대학 내과학교실) ;
  • 변민광 (연세대학교 의과대학 내과학교실) ;
  • 정우영 (연세대학교 의과대학 내과학교실) ;
  • 박재준 (연세대학교 의과대학 내과학교실) ;
  • 유경남 (연세대학교 의과대학 BK21 의과학 사업단) ;
  • 신주혜 (연세대학교 의과대학 암전이 연구센터) ;
  • 김영삼 (연세대학교 의과대학 내과학교실) ;
  • 장준 (연세대학교 의과대학 내과학교실) ;
  • 김성규 (연세대학교 의과대학 내과학교실) ;
  • 김희정 (연세대학교 의과대학 병리학교실) ;
  • 김세규 (연세대학교 의과대학 내과학교실)
  • Received : 2005.01.05
  • Accepted : 2005.03.15
  • Published : 2005.04.30
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Abstract

Background : IGFBP-3 inhibits the mitogenic and anti-apoptotic activity of IGF by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from its degradation. More than half of the interindividual variations in IGFBP-3 levels are known to be genetically determined by the polymorphism at -202 locus of IGFBP-3 gene. Method : We attempted to ascertain whether A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC), using PCR-restriction fragment length polymorphism (RFLP). Our study included 104 NSCLC patients and 104 age-, gender-, and smoking status-matched control subjects. Result : In the 104 NSCLC subjects, the genotypic frequencies at the -202 site were as follows: AA = 67 (64.4%), AC = 35 (33.7%), and CC = 2 (1.9%). We did detect significant differences in the genotypic distribution between the NSCLC and the control subjects (p<0.05), and the NSCLC risk correlated significantly with AA genotype at the -202 locus (AA>AC>CC). Using CC genotype as a reference, the odds ratio (OR) for the subjects with AC genotype was 2.60 (95% CI: 0.89 - 8.60), and the OR associated with AA genotype was 5.89 (95% CI: 1.92 - 21.16). Conclusion : These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC, and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.

인슐린양 성장 인자 결합 단백-3(Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3))는 혈액 내에서 IGF와 결합하여 복합체 혹은 저장소로 작용함으로써, IGF가 수용체에 결합하는 것을 방해하여 IGF의 항세포사멸(antiapoptosis) 및 세포분열 촉진의 기능을 억제한다. 하지만, 특정 상황에서는 도리어 IGFBP-3가 IGF의 파괴를 억제하여 IGF에 의한 암세포의 분화 및 성장을 촉진할 수도 있다는 것이 알려져 있다. 대부분의 환자에서 혈액내 IGFBP-3 수치는 IGFBP-3 유전자의 -202 좌위(locus)의 다형성(polymorphism)에 의해 크게 영향을 받는다. 따라서, 저자 등은 제한 효소(restriction enzyme)를 이용하여 비소세포폐암 환자의 IGFBP-3 유전자 -202 좌위의 다형성을 분석함으로써, 이 좌위의 다형성이 비소세포폐암의 위험도와 연관되어 있는지 조사하였다. 본 연구는 104명의 비소세포폐암 환자군과, 연령, 성별, 흡연력이 비슷한 104명의 대조군을 비교 분석하였다. 대조군에서 -202 좌위 유전자 다형성의 빈도는 AA형 48명 (46.2%), AC형 45명 (43.3%), CC형 11명 (10.5%)이었고, 비소세포폐암 환자군에서 -202 좌위 유전자 다형성의 빈도는 AA형 67명(64.4%), AC형 35명 (33.7%), CC형 2명 (1.9%)이었다. -202 좌위의 유전자 다형성에 있어서 대조군과 비소세포폐암 환자군 사이에 유의한 빈도 차이가 있었으며 (p < 0.05, Pearson's ${\chi}^2-test$), 비소세포폐암의 위험도는 -202 좌위의 AA형에서 가장 높고 CC형에서 가장 낮았다. CC형을 기준으로 하면 AC형의 비교 위험도는 2.60 (95% 신뢰구간: 0.89 - 8.60)이었으며 AA형의 비교 위험도는 5.89 (95% 신뢰구간: 1.92 - 21.16)이었다. 본 연구 결과는, IGFBP-3 유전자의 -202 좌위(locus)의 다형성(polymorphism)이 비소세포폐암의 위험인자 중의 하나일 가능성을 제시하며, 따라서 비소세포폐암에 대한 항암치료 개발에 있어서 새로운 표적이 될 가능성을 시사한다.

Keywords

References

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