Obstetrics & gynecology science

Korean Society of Obstetrics and Gynecology (대한산부인과학회)
권호 표지

Correlation of HLA-G Gene Expression with Various Prognostic Factors in the Tissue of Ovarian Carcinoma

난소암 조직에서 HLA-G유전자 발현과 예후 인자와의 상관성

Hong, Won-Ki;Kim, Young-Tae;Yoon, Bo-Sung;Kim, Sang-Wun;Kim, Sung-Hoon;Kim, Jae-Hoon;Kim, Jae-Wook;Park, Yong-Won
홍원기;김영태;윤보성;김상운;김성훈;김재훈;김재욱;박용원

  • Published : 20051200
⟨ Previous Next ⟩

Abstract

Objective: The objective of this study was to investigate the relationship between the expression of mRNA and protein of HLA-G and other clinicopathologic prognostic factors of ovarian cancer. Methods: 43 patients diagnosed with ovarian cancer from 1997 to 2005 and 5 patients with normal ovarian tissue (controls) were enrolled in this prospective study. The patient group all went through baseline studies with staging laparotomy and adjuvant chemotherapy. Quantitative real-time RT PCR and Western blot analysis were used in detecting the expression of mRNA and protein of HLA-G. Results: The mRNA expression of HLA-G ($2^{-\Delta\Delta{Ct}}$ value) in cancer group were 1.21 (0-9), and 0.01 (0-0.02) in control group, which was statistically significant (P=0.005). The expressed protein levels did not show any difference between the cancer and control groups. There also was a significant relationship between the serum CA 125 at the time of diagnosis and the HLA-G protein levels (P=0.02). But the relationship between other clinicopathologic prognostic factors and the HLA-G protein levels were not statistically significant. Conclusion: Our results showed that HLA-G mRNA expression level was much higher in ovarian cancer patient group than in those of control group. Therefore HLA-G maybe play an important role in carcinogenesis of ovarian cancer. Although the protein level of HLA-G had low significance with other prognostic factors, serum CA 125 showed a statistically significant relation with protein levels of HLA-G. Further studies based on the correlation between HLA-G and survival rate are needed to support HLA-G as a prognostic factor of ovarian cancer.

목적: 본 연구의 목적은 악성 난소암에서 quantitative real-time RT PCR과 Western blot analysis를 이용하여 HLA-G의 mRNA 와 단백질의 발현 정도를 측정한 후, 이의 발현 정도에 따라 HLA-G의 발현의 의미와 난소암의 다른 예후 인자들과의 상관 관계를 조사하는 것이다. 연구 방법: 1997년부터 2005년 현재까지 난소암으로 진단받은 환자 중 43명의 난소 조직을 실험 군으로, 정상 난소 조직 5예를 대조 군으로 하여 전향적인 연구를 시행하였다. 악성 난소암 환자는 기초 검사를 시행한 후 병기 결정을 위한 개복술을 시행하였으며 수술 후 보조 항암화학요법을 시행하였다. Quantitative real time RT PCR과 Western blot analysis 를 이용하여 HLA-G의 mRNA와 단백질의 발현을 측정하였다. 결과: 난소암 조직에서의 HLA-G의 mRNA 발현의 $2^{-\Delta\Delta{Ct}}$의 median값은 1.21 (0-9)였고, 대조 군 난소 조직에서의 median 값은 0.01 (0-0.02)로 나타나 난소암 조직과 대조 군 난소 조직 사이에 HLA-G의 mRNA 발현 차이는 통계적으로 유의하 였다 (P=0.005). Western blot analysis에 의해 난소암 조직과 대조 군 난소 조직에서의 단백질 발현은 거의 차이를 보이지 않았으며, 통계적 유의성이 없었다. 난소암에서의 HLA-G의 mRNA 발현 및 단백질 발현과 임상 병리학적 예후 인자와의 비교에 있어서, 진단 당시의 혈청 내 CA 125 수치와 HLA-G 단백질 발현과의 사이에서 통계적으로 유의한 상관성을 보였으며 (P=0.02), 다른 임상 병리학적 예후 인자들과는 통계적으로 유의한 상관 관계를 보이지 않았다. 결론: HLA-G가 정상 대조 군 난소에 비해 난소암에서 높게 발현되므로 난소암의 암 발생기전 (carcinogenesis)에 있어서 HLA-G가 중요한 역할을 하고 있다고 판단된다. HLA-G의 단백질 발현은 다른 예후 인자들과는 통계적으로 유의한 상관 관계를 보이지 않았으나, 예후 인자 중 하나인 혈청 내 CA 125 수치와 유의한 상관관계를 나타내었다. HLA-G가 예후 예측인자로 사용되기 위해서는 향후 생존율과 연관된 연구가 추가로 뒷받침되어야 할 것으로 사료된다.

Keywords

References

  1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M, Cancer statistics, 2001. CA Cancer J Clin 2001; 51: 15-36 https://doi.org/10.3322/canjclin.51.1.15
  2. 보건복지부. 한국중앙암등록 사업 연례보고서. 서울, 2003
  3. Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol 2000; 19: 3-10 https://doi.org/10.1002/1098-2388(200007/08)19:1<3::AID-SSU2>3.0.CO;2-S
  4. 이종승, 김영태, 김재욱, 박기현, 김성훈. 난소 종양 환자에서 유세포 분석을 통한 DNA 정량검사의 예후적 의의. 대한산부회지 2004; 47: 1100-6
  5. 조남훈, 김영태, 김성훈, 노종환, 김재욱. 상피성 난소암에서 핵 DNA 정량검사와 Cycline A의 예후적 의의. 대한산부회지 2004; 47: 1309-16
  6. Baker W. Molecular biology and genetics of epithelial ovarian cancer in update on epithelial ovarian cancer. Obstet Gynecol Clin North Am 1994; 21: 25-40
  7. Seliger B, Cabrera T, Garrido F, Ferrone S. HLA class I antigen abnormalities and immune escape by malignant cells. Semin Cancer Biol 2002; 12: 3-13 https://doi.org/10.1006/scbi.2001.0404
  8. Carosella ED, Paul P, Moreau P, Rouas-Freiss N. HLA-G and -E: fundamental and physiopathological aspects. Immunol Today 2000; 21: 532-4 https://doi.org/10.1016/S0167-5699(00)01707-2
  9. Paul P, Rouas-Freiss N, Khalil-Daher I, Moreau P, Riteau B, Le Gal FA, et al. HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci USA 1998; 95: 4510-5 https://doi.org/10.1073/pnas.95.8.4510
  10. Rouas-Freiss N, Marchal RE, Kirszenbaum M, Dausset J, Carosella ED. The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors? Proc Natl Acad Sci USA 1997; 94: 5249-54 https://doi.org/10.1073/pnas.94.10.5249
  11. Rebmann V, Busemann A, Lindemann M, Grosse-Wilde H. Detection of HLA-G5 secreting cells. Semin Cancer Biol 2003; 13: 371-7 https://doi.org/10.1016/S1044-579X(03)00028-2
  12. Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O'Callaghan CA, et al. Human myrlomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol 1998; 160: 3096-100
  13. Allan DS, Colonna M, Lanier LL, Churakova TD, Abrams JS, Ellis SA, et al. Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. J Exp Med 1999; 189: 1149-56 https://doi.org/10.1084/jem.189.7.1149
  14. Ibrahim el C, Aractingi S, Allory Y, Borrini F, Dupuy A, Duvillard P, et al. Analysis of HLA antigen expression in benign and malignant melanocytic lesions reveals that upregulation of HLA-G expression correlates with malignant transformation, high inflammatory infiltration and HLA-A1 genotype. Int J Cancer 2004; 108: 243-50 https://doi.org/10.1002/ijc.11456
  15. Malmberg KJ, Levitsky V, Norell H, de Matos CT, Carlsten M, Schedvins K, et al. IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. J Clin Invest 2002; 110: 1515-23
  16. Singer G, Rebmann V, Chen YC, Liu HT, Ali SZ, Reinsberg J, et al. HLA-G is a potential tumor marker in malignant ascites. Clin Cancer Res 2003; 9: 4460-4
  17. Serov F, Scully RE, Solbin LE. Histologic typing of ovarian tumors. In: International Classification of Tumors. Geneva: World Health Organization, 1973
  18. Windbichler G, Hausmaninger H, Stummvoll W, Graf AH, Kainz C, Lahodny J, et al. $\gamma$-interferon reduces expression of the protooncogene c-erb-2 in human ovarian carcinoma cells. Cancer Res 1990; 50: 7037-41
  19. Berek JS, Welander C, Schink JC, Grossberg H, Montz FJ, Zigelboim J. A phase I-II trial of intraperitoneal cisplatin and $\alpha$-interferon in patients with persistent epithelial ovarian cancer. Gynecol Oncol 1991; 75: 10-4 https://doi.org/10.1006/gyno.1999.5532
  20. Paul P, Rouas-Freiss N, Khalil-Daher I, Moreau P, Riteau B, Le Gal FA, et al. HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci USA 1998; 95: 4510-5 https://doi.org/10.1073/pnas.95.8.4510
  21. Ibrahim EC, Guerra N, Lacombe MJ, Angevin E, Chouaib S, Carosella ED, et al. Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma. Cancer Res 2001; 61: 6838-45
  22. Pazmany L, Mandelboim O, Gomez VM, Daniel MD, Todd CB, Hugh TR, et al. Human leucocyte antigen-G and its recognition by natural killer cells. J Reprod Immuno 1999; 43: 127-37 https://doi.org/10.1016/S0165-0378(99)00028-5
  23. Urosevic M, Kurrer MO, Kamarashev J, Mueller B, Weder W, Burg G, et al. Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production. Am J Pathol 2001; 159: 817-24 https://doi.org/10.1016/S0002-9440(10)61756-7
  24. Urosevic M, Willers J, Mueller B, Kempf W, Burg G, Dummer R. HLA-G protein up-regulation in primary cutaneous lymphomas is associated with interleukin-10 in large cell T-cell lymphomas and indolent B-cell lymphomas. Blood 2002; 99: 609-17 https://doi.org/10.1182/blood.V99.2.609
  25. Davidson B, Elstrand MB, McMaster MT, Berner A, Kurman RJ, Risberg B, et al. HLA-G expression in effusion is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma. Gynecol Oncol 2005; 96: 42-7 https://doi.org/10.1016/j.ygyno.2004.09.049
  26. Omura GA, Brady MF, Homesley HD, Yordan E, Major FJ, Buchsbaum HJ, et al. Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 1991; 9: 138-50
  27. Baak JP, Chan KK, Stolk JG, Kenemans P. Prognostic factors in borderline and invasive ovarian tumors of the common epithelial type. Pathol Res Pract 1987; 182: 755-74 https://doi.org/10.1016/S0344-0338(87)80040-7