Journal of Chest Surgery

The Korean Society for Thoracic and Cardiovascular Surgery (대한심장혈관흉부외과학회)
권호 표지

Activity of Matrix Metalloproteinase-2 and its Significance after Resection of Stage I Non-small Cell Lung Cancer

제1기 비소세포폐암 환자의 수술적 절제 후 Matrix Metalloprotainase-2 활성도에 따른 재발 및 예후

  • Kim Sang Hui (Cancer Research Center for Clinical Research, Samsung Biomedical Research Institue) ;
  • Hong Young-Sook (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Lee Jinseon (Cancer Research Center for Clinical Research, Samsung Biomedical Research Institue) ;
  • Son Dae-Soon (Cancer Research Center for Clinical Research, Samsung Biomedical Research Institue) ;
  • Lim Yu-Sung (Cancer Research Center for Clinical Research, Samsung Biomedical Research Institue) ;
  • Song In-Seung (Cancer Research Center for Clinical Research, Samsung Biomedical Research Institue) ;
  • Lee Hye-Sook (Cancer Research Center for Clinical Research, Samsung Biomedical Research Institue) ;
  • Kim Do Hun (Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim Jingook (Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Choi Yong Soo (Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • 김상희 (삼성생명과학연구소 임상의학연구소 암연구센터) ;
  • 홍영숙 (이화여자대학교 의과대학 생화학교실) ;
  • 이진선 (삼성생명과학연구소 임상의학연구소 암연구센터) ;
  • 손대순 (삼성생명과학연구소 임상의학연구소 암연구센터) ;
  • 임유성 (삼성생명과학연구소 임상의학연구소 암연구센터) ;
  • 송인승 (삼성생명과학연구소 임상의학연구소 암연구센터) ;
  • 이혜숙 (삼성생명과학연구소 임상의학연구소 암연구센터) ;
  • 김도훈 (성균관대학교 의과대학 삼성서울병원 흉부외과) ;
  • 김진국 (성균관대학교 의과대학 삼성서울병원 흉부외과) ;
  • 최용수 (성균관대학교 의과대학 삼성서울병원 흉부외과)
  • Published : 2005.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Matrix metalloproteinase-2 (MMP-2) is a class of proteolytic enzymes that digest collagen type IV and other components of the basement membrane. It plays a key role in the local invasion and the formation of distant metastases by various malignant tumors. The aim of this study was to evaluate the activity of MMP-2 and its significance as a prognostic marker in resected stage I non-small cell lung cancer (NSCLC). Material and Method: In this study we obtained fresh-frozen samples of tumor and non-tumor tissues from 34 patients with stage I NSCLC who underwent resection without preoperative radiotherapy or chemotherapy. After the extraction of total protein from tissue samples, MMP-2 activities were assessed by gelatin-substrate-zymography. The activities were divided into the higher or lower groups. Result: The MMP-2 activities were higher in tumor tissues than in non-tumor tissues. The MMP-2 activity of non-tumor tissues in recurrent group was higher than in non-recurrent group (p<0.01). Also the patients with higher MMP-2 activity of non-tumor tissues showed poor 5 year survival (p<0.01). Conclusion: This result indicates that the higher level of MMP-2 activity in the non-tumor tissue is associated with the recurrence and survival after the resection of stage I NSCLC. Therefore, MMP-2 activity in the non-tumor tissue could be used as a potential prognostic marker for the resected stage I-NSCLC.

기질금속단백분해효소-2 (MMP-2)는 기저막과 세포 외 기질의 분해에 작용하여 악성종양의 국소침윤 및 원격전이에 중요한 역할을 담당한다. 본 연구는 수술적인 절제를 시행 받은 제1기 비소세포폐암에서 MMP-2의 활성도를 측정하고 예후인자로서의 의미를 분석하고자 하였다. 대상 빛 방법: 수술 전 방사선 또는 항암제 요법을 시행하지 않은 병리학적 제1기 비소세포폐암 환자 34명을 대상으로 하였다. 폐엽 절제 조직에서 종양 조직과 비종양 조직의 단백질을 각각 추출하여 젤라틴-기질-단백분해효소 분석법을 시행하였다. 결과: MMP-2 활성도는 비종양 조직보다 종양 조직에서 높았다. 종양 조직, 비종양 조직 모두에서 비재발군에 비해 재발군의 MMP-2활성도가 높았으나 비종양 조직에서의 차이가 통계적 유의성이 있었다(p<0.01). 생존율 분석에서도 MMP-2 활성도가 높을 경우 불량한 생존을 보였으며 역시 비종양 조직에서 통계적인 의미가 있었다(p<0.01). 결론: 제1기 비소세포 페암 환자의 절제 폐엽 조직 중 비종양 조직에서의 MMP-2 활성도는 재발 및 생존과 연관성이 있으며 예후 인자로서의 가능성이 있다.

Keywords

References

  1. Lyons JG, Birkedal-Hansen B, Moore WG, O'Grady RL, Birkedal-Hansen H. Characteristics of a 95-kDa matrix metalloproteinase produced by mammary carcinoma cells. Biochemistry 1991;30:1449-56 https://doi.org/10.1021/bi00220a001
  2. Sreenath T, Matrisian LM, Stetler-Stevenson W, Gattoni-Celli S, Pozzatti RO. Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential. Cancer Res 1992;52:4942-7
  3. Powell WC, Knox JD, Navre M, et al. Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. Cancer Res 1993;53:417-22
  4. Polette M, Clavel C, Muller D, Abecassis J, Binninger I, Birembaut P. Detection of mRNAs encoding collagenase I and stromelysin 2 in carcinomas of the head and neck by In situ hybridization. Invasion Metastasis 1991;11:76-83
  5. Liabakk NB, Talbot I, Smith RA, Wilkinson K, Balkwill F. Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res 1996;56:190-6
  6. Shima I, Sasaguri Y, Kusukawa J, et al. Production of matrix metalloproteinase-2 and metalloproteinase-3 related to malignant behavior of esophageal carcinoma. A clinicopathologic study. Cancer 1992;70:2747-53 https://doi.org/10.1002/1097-0142(19921215)70:12<2747::AID-CNCR2820701204>3.0.CO;2-5
  7. Passlick B, Sienel W, Seen-Hibler R, et al. Overexpression of matrix metalloproteinase 2 predicts unfavorable outcome in early-stage non-small cell lung cancer. Clin Cancer Res 2000;6:3944-8
  8. Delebecq TJ, Porte H, Zerimech F, et al. Overexpression level of stromelysin 3 is related to the lymph node involvement in non-small cell lung cancer. Clin Cancer Res 2000;6:1086-92
  9. Mackay AR, Gomez DE, Cottam DW, Rees RC, Nason AM, Thorgeirsson UP. Identification of the 72-kDa (MMP-2) and 92-kDa (MMP-9) gelatinase/type IV collagenase in preparations of laminin and Matrigel. Biotechniques 1993;15: 1048-51
  10. Stetler-Stevenson WG, Liotta LA, Kleiner DE Jr. Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 1993;7:1434-41 https://doi.org/10.1096/fasebj.7.15.8262328
  11. Thomas P, Khokha R, Shepherd FA, Feld R, Tsao M. Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. J Pathol 2000;190: 150-6 https://doi.org/10.1002/(SICI)1096-9896(200002)190:2<150::AID-PATH510>3.0.CO;2-W
  12. Cox G, Jones JL, O'Byrne KJ. Matrix metalloproteinase 9 and the epidermal growth factor signal pathway in operable non-small cell lung cancer. Clin Cancer Res 2000;6:2349-55
  13. Michael M, Babic B, Khokha R, et al. Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J Clin Oncol 1999;17:1802-8 https://doi.org/10.1200/JCO.1999.17.6.1802
  14. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991;64:327-36 https://doi.org/10.1016/0092-8674(91)90642-C
  15. Tryggvason K, Hoyhtya M, Pyke C. Type IV collagenase in invasive tumors. Breast Cancer Res Treat 1993;24:209-18 https://doi.org/10.1007/BF01833261
  16. Ray JM, Stetler-Stevenson WG. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J 1994;7:2062-72
  17. Moses MA. The regulation of neovascularization by matrix metalloproteinases & their inhibitors. Stem Cells 1997;15:180 https://doi.org/10.1002/stem.150180
  18. Chamber AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997;89:1279
  19. Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem 1999;274:21491 https://doi.org/10.1074/jbc.274.31.21491
  20. Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U.S.A 1990;87:5578 https://doi.org/10.1073/pnas.87.14.5578
  21. Crawford HC, Matrisian LM. Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. Enzyme Protein 1996;49:20-37 https://doi.org/10.1159/000468614
  22. Nakagawa T, Kubota T, Kabuto M, et al. Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases- 1 by human brain tumors. J Neurosurg 1994;81: 69-77 https://doi.org/10.3171/jns.1994.81.1.0069