Annals of Surgical Oncology

, Volume 14, Issue 10, pp 2721–2729 | Cite as

Expression of Human Leukocyte Antigen G (HLA-G) Correlates with Poor Prognosis in Gastric Carcinoma

  • Shang-mian Yie
  • Hong Yang
  • Shang-rong Ye
  • Ke Li
  • Dan-dan Dong
  • Xin-mei Lin
Gastrointestinal Oncology



We had previously demonstrated that human leukocyte antigen G (HLA-G) was expressed in a majority of primary colorectal carcinomas and that the detection of HLA-G expression had a strong and independent prognostic value for that cancer. Currently, we investigate whether or not HLA-G is also expressed in patients with gastric carcinoma and whether the expression has any clinical application value.


The expression of HLA-G was investigated immunohistochemically in 160 patients with gastric carcinoma. The correlation between HLA-G status and various clinicopathological parameters was analyzed with the levels of HLA-G expression used to compare the survival length amongst patients.


HLA-G protein expression was observed in 71% (113 of 160) of the primary site of gastric carcinomas, but not in the normal stomach tissues. HLA-G expression in the tumors was significantly correlated with the tumor location, histological grade, depth of invasion, lymph nodal metastasis, clinical stages of the disease, and host immune response (P= .012, .008, .001, .038, .030, and .016, respectively). Patients with HLA-G positive tumors had a significantly shorter survival time than those patients with tumors that were HLA-G negative (P = .001). As well, in multivariate analysis, HLA-G demonstrated an independent prognostic factor (P = .0001, relative risk 9.08; 95% confidence interval, 3.44–24.0).


Overall, our results indicated that the expression of HLA-G is a characteristic feature of gastric carcinoma and that immunostaining by anti-HLA-G antibody may be a potentially useful prognostic indicator.


Human leukocyte antigen G (HLA-G) Immunohistochemistry Gastric carcinoma Prognosis 


  1. 1.
    Tanaka K, Yoshioka T, Bieberich C, et al. Role of the major histocompatibility complex class I antigens in tumor growth and metastasis. Ann Rev Immunol 1988; 6:359–80CrossRefGoogle Scholar
  2. 2.
    Ferrone S, Marincola FM. Loss of HLA class I antigens by melanoma cells: molecular mechanism, functional significance and clinical relevance. Immunol Today 1995; 16:487–94PubMedCrossRefGoogle Scholar
  3. 3.
    Garrido F, Ruiz-Cabello F, Cabrera T, et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today 1997; 18:89–95PubMedCrossRefGoogle Scholar
  4. 4.
    Hicklin DJ, Marincola FM, Ferrone S. HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 1999; 5:178–86PubMedCrossRefGoogle Scholar
  5. 5.
    Seliger B, Abken H, Ferrone S. HLA-G and MIC expression in tumors and their role in anti-tumor immunity. TRENDS in Immunol 2003; 24:82–7CrossRefGoogle Scholar
  6. 6.
    LeMaoult J, Le Discorde M, Rouas-Freiss N, et al. Biology and functions of human leukocyte antigen-G in health and sickness. Tissue Antigens 2003: 62: 273–84PubMedCrossRefGoogle Scholar
  7. 7.
    Singer G, Kurman RJ, McMaster MT, et al. HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. Am J Surg Pathol 2002; 26:914–20PubMedCrossRefGoogle Scholar
  8. 8.
    Ibrahim EC, Aractingi S, Allory Y, 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; 108:243–50CrossRefGoogle Scholar
  9. 9.
    Bukur J, Rebmann V, Grosse-Wilde H, et al. Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma. Cancer Res 2003; 63:4107–11PubMedGoogle Scholar
  10. 10.
    Urosevic M, Kurrer MO, Kamarashev J, et al. Human leukocyte antigen G up-regulation in lung cancer associates with high-grade human histology, leukocyte antigen class I loss and interleukin-10 production. Am J Pathol 2001; 159:817–24PubMedGoogle Scholar
  11. 11.
    Lefebvre S, Antoinc M, Uzan S, et al. Specific activation of the non-classical class I histocompatibility HLA-G antigen and expression of the ILT2 inhibitory receptor in human breast cancer. J Pathol 2002; 196:266–74PubMedCrossRefGoogle Scholar
  12. 12.
    Urosevic M, Willers J, Mueller B, et al. HLA-G protein up-regulation in primary cutaneous lymphomas is associated with interleukin-10 expression in large cell T-cell lymphomas and indolent B-cell lymphomas. Blood 2002; 99:609–17PubMedCrossRefGoogle Scholar
  13. 13.
    Davidson B, Elstrand MB, McMaster MT, et al. HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma. Gynecol Oncol 2005; 96:42–7PubMedCrossRefGoogle Scholar
  14. 14.
    Barrier BF, Kendall BS, Sharpe-Timms K, et al. Characterization of human leukocyte antigen-G (HLA-G) expression in endometrial adenocarcinoma. Gynecol Oncol 2006; 103:25–30PubMedCrossRefGoogle Scholar
  15. 15.
    Hansel DE, Rahmanb A, Wilentz RE, et al. HLA-G upregulation in pre-malignant and malignant lesions of the gastrointestinal tract Int J Gastrointest Cancer 2005; 35:15–24PubMedCrossRefGoogle Scholar
  16. 16.
    Fukushima Y, Oshika Y, Nakamura M, et al. Increased expression of human histocompatibility leukocyte antigen-G in colorectal cancer cells. Int J Mo Med 1998; 2:349–51Google Scholar
  17. 17.
    Ishigami S, Natsugoe S, Miyazono F, et al. HLA-G expression in gastric cancer. Anticancer Res 2006: 2467–72Google Scholar
  18. 18.
    Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol 2003; 81:199–252PubMedCrossRefGoogle Scholar
  19. 19.
    Le Discorde M, Moreau P, Sabatier P, et al. Expression of HLA-G in human cornea, an immune-privileged tissue. Hum Immunol 2003; 64:1039–44PubMedCrossRefGoogle Scholar
  20. 20.
    Ito T, Ito N, Saathoff M, et al. Immunology of the human nail apparatus: the nail matrix is a site of relative immune privilege. J Invest Dermatol 2005; 125:1139–48PubMedCrossRefGoogle Scholar
  21. 21.
    Cirulli V, Zalatan J, McMaster M, et al. The class I HLA repertoire of pancreatic islets comprises the nonclassical class Ib antigen HLA-G. Diabetes 2006; 55:1214–22PubMedCrossRefGoogle Scholar
  22. 22.
    Bainbridge DR, Ellis SA, Sargent IL. HLA-G suppresses proliferation of CD4 (+) T-lymphocytes. J Reprod Immunol 2000; 48:17–26PubMedCrossRefGoogle Scholar
  23. 23.
    Lila N, Rouas-Freiss N, Dausset J, et al. Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci USA 2001; 98:12150–5PubMedCrossRefGoogle Scholar
  24. 24.
    Le Gal FA, Riteau B, Sedlik C, et al. HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int Immunol 1999; 11:1351–6PubMedCrossRefGoogle Scholar
  25. 25.
    Riteau B, Menier C, Khalil-Daher I, et al. HLA-G1 co-expression boosts the HLA class I-mediated NK lysis inhibition. Int Immunol 2001; 13:193–201PubMedCrossRefGoogle Scholar
  26. 26.
    Rebmann V, Regel J, Stolke D, et al. Secretion of sHLA-G molecules in malignancies. Semin Cancer Biol 2003; 13:371–7PubMedCrossRefGoogle Scholar
  27. 27.
    Sebti Y, Le Friec G, Pangault C, et al. Soluble HLA-G molecules are increased in lymphoproliferative disorders. Hum Immunol 2003; 64:1093–101PubMedCrossRefGoogle Scholar
  28. 28.
    Nuckel H, Rebmann V, Durig J, et al. HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia. Blood 2005; 105:1694–8PubMedCrossRefGoogle Scholar
  29. 29.
    Ugurel S, Rebmann V, Ferrone S, et al. Soluble human leukocyte antigen-G serum level is elevated in melanoma patients and is further increased by interferon-alpha immunotherapy. Cancer 2001; 92:369–76PubMedCrossRefGoogle Scholar
  30. 30.
    Singer G, Rebmann V, Chen YC, et al. HLA-G is a potential tumor marker in malignant ascites. Clin Cancer Res 2003; 9:4460–4PubMedGoogle Scholar
  31. 31.
    Ye SR, Yang H, Li K, et al. Human leukocyte antigen G (HLA-G) expression: as a significant prognostic indicator for patients with colorectal cancer. Modern Pathol 2007; 20:375–83CrossRefGoogle Scholar
  32. 32.
    Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer 2001; 37(suppl):4–66CrossRefGoogle Scholar
  33. 33.
    Yang L, Parkin DM, Ferlay J, et al. Estimates of cancer incidence in China for 2000 and projections for 2005. Cancer Epidemiol Biomarkers Prev 2005; 14:243–50PubMedCrossRefGoogle Scholar
  34. 34.
    Fenogilo-Preiser C, Carneiro F, Correa P, et al. Gastric carcinoma. In: Hamilton S, Aaltonin L (ed.) Pathology and Genetics. Tumors of the Digestive System, vol. 1, Lyon, France: Lyon Press, 2000:37–52Google Scholar
  35. 35.
    Menier C, Saez B, Horejsi V, et al. Characterization of monoclonal antibodies recognizing HLA-G or HLA-E: new tools to analyze the expression of nonclassical HLA class I molecules. Hum Immunol 2003; 64:315–26PubMedCrossRefGoogle Scholar
  36. 36.
    Alexander J, Watanabe T, Wu TT, et al. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 2001; 158:527–35PubMedGoogle Scholar
  37. 37.
    Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide. Lyon: IARC Press, Cited April 15, 2005. Available from: URL:
  38. 38.
    Yang L. Incidence and mortality of gastric cancer in China. World J Gastroenterol 2006; 12:17–20PubMedGoogle Scholar
  39. 39.
    Crawford J. The gastrointestinal tract. In: Robbins SLCR, Kumar V, Schoen FJ (ed.) Pathologic Basis of Disease. Philadelphia: WB Saunders Co., 1994:755–83Google Scholar
  40. 40.
    Pinto-de-sousa J, David L, Seixas M, et al. Clinicopathologic profiles and prognosis of gastric carcinoma from the cardia, fundus/body and antrum. Dig Surg 2001; 18:102–10PubMedCrossRefGoogle Scholar
  41. 41.
    Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 1975–2001, with a special feature regarding survival. Cancer 2004; 101:3–27PubMedCrossRefGoogle Scholar
  42. 42.
    Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Stewart M, Hamilton SM. Gastric Adenocarcinoma: Review and Considerations for Future Directions. Ann Surg 2005; 241:27–39PubMedGoogle Scholar
  43. 43.
    Rouas-Freiss N, Philippe Moreau P, et al. HLA-G Proteins in Cancer: Do They Provide Tumor Cells with an Escape Mechanism? Cancer Res 2005; 65:10139–44PubMedCrossRefGoogle Scholar
  44. 44.
    Malmberg KJ, Levitsky V, Norell H, et al. IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism J Clin Invest 2002; 110:1515–23PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  • Shang-mian Yie
    • 1
    • 3
  • Hong Yang
    • 2
  • Shang-rong Ye
    • 1
  • Ke Li
    • 2
  • Dan-dan Dong
    • 2
  • Xin-mei Lin
    • 1
  1. 1.Chengdu Bioengineering Institute for Cancer ResearchChengduP.R. China
  2. 2.Department of PathologySichuan Provincial People’s HospitalChengduP.R. China
  3. 3.Core LaboratorySichuan Academy of Medical Sciences, Sichuan Provincial People’s HospitalChengduP.R. China

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