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Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?

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Abstract

Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal–maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.

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Abbreviations

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

APC:

Antigen-presenting cells

ARE:

AU-rich elements

β2-m:

β2-microglobulin

BCC:

Basal cell carcinoma

BM:

Bone marrow

cHL:

Classical Hodgkin lymphoma

CLL:

Chronic lymphatic leukemia

CREB:

Cyclin AMP-response element binding protein

COBRA:

Combined bisulfite restriction analysis

CTL:

Cyotoxic T lymphocytes

DAC:

5-Aza-2-deoxycytidine

DC:

Dendritic cells

DLBL:

Diffuse large B cell lymphoma

EBV:

Epstein Barr virus

FAB:

French, American, British

GM-CSF:

Granulocyte-macrophage colony stimulating factor

GVHD:

Graft versus host disease

HDAC:

Histone deacetylase

HIF:

Hypoxia inducible factor

HPV:

Human papilloma virus

HRE:

Hypoxia response element

HRS:

Hodgkin Reed Sternberg

IFN:

Interferon

IHC:

Immunohistochemistry

LCR:

Locus control region

LIF:

Leukemia-inhibitory factor

MDSC:

Myeloid-derived suppressor cells

MHC:

Major histocompatibility complex

miRNA:

MicroRNA

MM:

Multiple myeloma

MMP:

Matrix metalloproteinase

NF-κB:

Nuclear factor-κB

NHL:

Non-Hodgkin lymphoma

NK:

Natural killer

RCC:

Renal cell carcinoma

RREB1:

Ras-responsive element binding protein

SCC:

Squamous cell carcinoma

SIL:

Squamous intraepithelial lesions

sHLA-G:

Soluble HLA-G

SNP:

Single nucleotide polymorphism

TGF-β:

Transforming growth factor

TIL:

Tumor-infiltrating lymphocytes

Treg:

Regulatory T cell

UTR:

Untranslated region

References

  1. Carosella ED, Favier B, Rouas-Freiss N, Moreau P, Lemaoult J (2008) Beyond the increasing complexity of the immunomodulatory HLA-G molecule. Blood 111:4862–4870

    CAS  PubMed  Google Scholar 

  2. Park GM, Lee S, Park B, Kim E, Shin J, Cho K, Ahn K (2004) Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochem Biophys Res Commun 313:606–611

    CAS  PubMed  Google Scholar 

  3. Fons P et al (2006) Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells. Blood 108:2608–2615

    CAS  PubMed  Google Scholar 

  4. Gao GF et al (2000) Classical and nonclassical class I major histocompatibility complex molecules exhibit subtle conformational differences that affect binding to CD8alphaalpha. J Biol Chem 275:15232–15238

    CAS  PubMed  Google Scholar 

  5. Lopez-Botet M, Navarro F, Llano M (1999) How do NK cells sense the expression of HLA-G class Ib molecules? Semin Cancer Biol 9:19–26

    CAS  PubMed  Google Scholar 

  6. Yan WH, Fan LA (2005) Residues Met76 and Gln79 in HLA-G alpha1 domain involve in KIR2DL4 recognition. Cell Res 15:176–182

    CAS  PubMed  Google Scholar 

  7. Pangault C, Le Friec G, Caulet-Maugendre S, Lena H, Amiot L, Guilloux V, Onno M, Fauchet R (2002) Lung macrophages and dendritic cells express HLA-G molecules in pulmonary diseases. Hum Immunol 63:83–90

    CAS  PubMed  Google Scholar 

  8. Urosevic M, Willers J, Mueller B, Kempf W, Burg G, Dummer R (2002) 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 99:609–617

    CAS  PubMed  Google Scholar 

  9. Wagner SN, Rebmann V, Willers CP, Grosse-Wilde H, Goos M (2000) Expression analysis of classic and non-classic HLA molecules before interferon alfa-2b treatment of melanoma. Lancet 356:220–221

    CAS  PubMed  Google Scholar 

  10. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED (2004) HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci USA 101:7064–7069

    CAS  PubMed  Google Scholar 

  11. Amiot L, Onno M, Drenou B, Monvoisin C, Fauchet R (1998) HLA-G class I gene expression in normal and malignant hematopoietic cells. Hum Immunol 59:524–528

    CAS  PubMed  Google Scholar 

  12. Polakova K, Krcova M, Kuba D, Russ G (2003) Analysis of HLA-G expression in malignant hematopoietic cells from leukemia patients. Leuk Res 27:643–648

    CAS  PubMed  Google Scholar 

  13. Yan WH, Lin A, Chen BG, Luo WD, Dai MZ, Chen XJ, Xu HH, Li BL (2008) Unfavourable clinical implications for HLA-G expression in acute myeloid leukaemia. J Cell Mol Med 12:889–898

    PubMed  Google Scholar 

  14. Gros F, Sebti Y, de Guibert S, Branger B, Bernard M, Fauchet R, Amiot L (2006) Soluble HLA-G molecules increase during acute leukemia, especially in subtypes affecting monocytic and lymphoid lineages. Neoplasia 8:223–230

    CAS  PubMed  Google Scholar 

  15. Urosevic M, Kamarashev J, Burg G, Dummer R (2004) Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2. Blood 103:1796–1798

    CAS  PubMed  Google Scholar 

  16. Nuckel H, Rebmann V, Durig J, Duhrsen U, Grosse-Wilde H (2005) HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia. Blood 105:1694–1698

    PubMed  Google Scholar 

  17. Rebmann V, Nuckel H, Duhrsen U, Grosse-Wilde H (2007) HLA-G in B-chronic lymphocytic leukaemia: clinical relevance and functional implications. Semin Cancer Biol 17:430–435

    CAS  PubMed  Google Scholar 

  18. Giannopoulos K, Dmoszynska A, Bojarska-Junak A, Schmitt M, Rolinski J (2008) Expression of HLA-G in patients with B-cell chronic lymphocytic leukemia (B-CLL). Folia Histochem Cytobiol 46:457–460

    CAS  PubMed  Google Scholar 

  19. Sebti Y et al (2003) Soluble HLA-G molecules are increased in lymphoproliferative disorders. Hum Immunol 64:1093–1101

    CAS  PubMed  Google Scholar 

  20. Sebti Y, Le Maux A, Gros F, De Guibert S, Pangault C, Rouas-Freiss N, Bernard M, Amiot L (2007) Expression of functional soluble human leucocyte antigen-G molecules in lymphoproliferative disorders. Br J Haematol 138:202–212

    CAS  PubMed  Google Scholar 

  21. Diepstra A, Poppema S, Boot M, Visser L, Nolte IM, Niens M, Te Meerman GJ, van den Berg A (2008) HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin’s lymphoma. Tissue Antigens 71:219–226

    CAS  PubMed  Google Scholar 

  22. Amiot L et al (2003) HLA-G and lymphoproliferative disorders. Semin Cancer Biol 13:379–385

    CAS  PubMed  Google Scholar 

  23. Leleu X et al (2005) Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance. Clin Cancer Res 11:7297–7303

    CAS  PubMed  Google Scholar 

  24. Le Maux A et al (2008) Soluble human leucocyte antigen-G molecules in peripheral blood haematopoietic stem cell transplantation: a specific role to prevent acute graft-versus-host disease and a link with regulatory T cells. Clin Exp Immunol 152:50–56

    CAS  PubMed  Google Scholar 

  25. Rouas-Freiss N, Moreau P, Ferrone S, Carosella ED (2005) HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism? Cancer Res 65:10139–10144

    CAS  PubMed  Google Scholar 

  26. Wiendl H et al (2002) A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 168:4772–4780

    CAS  PubMed  Google Scholar 

  27. LeMaoult J, Caumartin J, Carosella ED (2007) Exchanges of membrane patches (trogocytosis) split theoretical and actual functions of immune cells. Hum Immunol 68:240–243

    CAS  PubMed  Google Scholar 

  28. Paul P et al (1999) Heterogeneity of HLA-G gene transcription and protein expression in malignant melanoma biopsies. Cancer Res 59:1954–1960

    CAS  PubMed  Google Scholar 

  29. Ibrahim EC et al (2004) 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 108:243–250

    CAS  PubMed  Google Scholar 

  30. Lefebvre S, Antoine M, Uzan S, McMaster M, Dausset J, Carosella ED, Paul P (2002) 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 196:266–274

    CAS  PubMed  Google Scholar 

  31. Davidson B, Elstrand MB, McMaster MT, Berner A, Kurman RJ, Risberg B, Trope CG, Shih Ie M (2005) HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma. Gynecol Oncol 96:42–47

    CAS  PubMed  Google Scholar 

  32. Singer G et al (2003) HLA-G is a potential tumor marker in malignant ascites. Clin Cancer Res 9:4460–4464

    CAS  PubMed  Google Scholar 

  33. Menier C, Prevot S, Carosella ED, Rouas-Freiss N (2009) Human leukocyte antigen-G is expressed in advanced-stage ovarian carcinoma of high-grade histology. Hum Immunol 70:1006–1009

    CAS  PubMed  Google Scholar 

  34. Langat DK, Sue Platt J, Tawfik O, Fazleabas AT, Hunt JS (2006) Differential expression of human leukocyte antigen-G (HLA-G) messenger RNAs and proteins in normal human prostate and prostatic adenocarcinoma. J Reprod Immunol 71:75–86

    CAS  PubMed  Google Scholar 

  35. Ongaro A et al (2010) Human leukocyte antigen-G molecules are constitutively expressed by synovial fibroblasts and upmodulated in osteoarthritis. Hum Immunol 71:342–350

    CAS  PubMed  Google Scholar 

  36. Paul P et al (1998) HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci USA 95:4510–4515

    CAS  PubMed  Google Scholar 

  37. Frumento G et al (2000) Melanomas and melanoma cell lines do not express HLA-G, and the expression cannot be induced by gammaIFN treatment. Tissue Antigens 56:30–37

    CAS  PubMed  Google Scholar 

  38. Mizuno S, Emi N, Kasai M, Ishitani A, Saito H (2000) Aberrant expression of HLA-G antigen in interferon gamma-stimulated acute myelogenous leukaemia. Br J Haematol 111:280–282

    CAS  PubMed  Google Scholar 

  39. Paul P et al (2000) HLA-G, -E, -F preworkshop: tools and protocols for analysis of non-classical class I genes transcription and protein expression. Hum Immunol 61:1177–1195

    CAS  PubMed  Google Scholar 

  40. Menier C et al (2003) Characterization of monoclonal antibodies recognizing HLA-G or HLA-E: new tools to analyze the expression of nonclassical HLA class I molecules. Hum Immunol 64:315–326

    CAS  PubMed  Google Scholar 

  41. Pangault C et al (1999) HLA-G protein expression is not induced during malignant transformation. Tissue Antigens 53:335–346

    CAS  PubMed  Google Scholar 

  42. Rouas-Freiss N, Bruel S, Menier C, Marcou C, Moreau P, Carosella ED (2005) Switch of HLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis. Int J Cancer 117:114–122

    CAS  PubMed  Google Scholar 

  43. Malmberg KJ et al (2002) IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. J Clin Invest 110:1515–1523

    CAS  PubMed  Google Scholar 

  44. Bukur J et al (2003) Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma. Cancer Res 63:4107–4111

    CAS  PubMed  Google Scholar 

  45. Urosevic M, Dummer R (2008) Human leukocyte antigen-G and cancer immunoediting. Cancer Res 68:627–630

    CAS  PubMed  Google Scholar 

  46. Erikci AA, Karagoz B, Ozyurt M, Ozturk A, Kilic S, Bilgi O (2009) HLA-G expression in B chronic lymphocytic leukemia: a new prognostic marker? Hematology 14:101–105

    CAS  PubMed  Google Scholar 

  47. Chen XY, Yan WH, Lin A, Xu HH, Zhang JG, Wang XX (2008) The 14 bp deletion polymorphisms in HLA-G gene play an important role in the expression of soluble HLA-G in plasma. Tissue Antigens 72:335–341

    CAS  PubMed  Google Scholar 

  48. Urosevic M, Dummer R (2003) HLA-G in skin cancer: a wolf in sheep’s clothing? Hum Immunol 64:1073–1080

    CAS  PubMed  Google Scholar 

  49. Ye SR, Yang H, Li K, Dong DD, Lin XM, Yie SM (2007) Human leukocyte antigen G expression: as a significant prognostic indicator for patients with colorectal cancer. Mod Pathol 20:375–383

    CAS  PubMed  Google Scholar 

  50. El-Chennawi FA et al (2005) Expression of HLA-G in cancer bladder. Egypt J Immunol 12:57–64

    PubMed  Google Scholar 

  51. Lin A et al (2009) Clinical relevance and functional implications for human leukocyte antigen-G expression in non-small-cell lung cancer. J Cell Mol Med (Epub ahead of print)

  52. Yie SM, Yang H, Ye SR, Li K, Dong DD, Lin XM (2007) Expression of human leukocyte antigen G (HLA-G) correlates with poor prognosis in gastric carcinoma. Ann Surg Oncol 14:2721–2729

    PubMed  Google Scholar 

  53. Yie SM, Yang H, Ye SR, Li K, Dong DD, Lin XM (2007) Expression of HLA-G is associated with prognosis in esophageal squamous cell carcinoma. Am J Clin Pathol 128:1002–1009

    PubMed  Google Scholar 

  54. Jung YW, Kim YT, Kim SW, Kim S, Kim JH, Cho NH, Kim JW (2009) Correlation of human leukocyte antigen-G (HLA-G) expression and disease progression in epithelial ovarian cancer. Reprod Sci 16:1103–1111

    CAS  PubMed  Google Scholar 

  55. Dunker K, Schlaf G, Bukur J, Altermann WW, Handke D, Seliger B (2008) Expression and regulation of non-classical HLA-G in renal cell carcinoma. Tissue Antigens 72:137–148

    CAS  PubMed  Google Scholar 

  56. Rouas-Freiss N, Goncalves RM, Menier C, Dausset J, Carosella ED (1997) Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci USA 94:11520–11525

    CAS  PubMed  Google Scholar 

  57. Rouas-Freiss N, Marchal RE, Kirszenbaum M, Dausset J, Carosella ED (1997) 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 94:5249–5254

    CAS  PubMed  Google Scholar 

  58. Riteau B, Menier C, Khalil-Daher I, Sedlik C, Dausset J, Rouas-Freiss N, Carosella ED (1999) HLA-G inhibits the allogeneic proliferative response. J Reprod Immunol 43:203–211

    CAS  PubMed  Google Scholar 

  59. Bainbridge DR, Ellis SA, Sargent IL (2000) HLA-G suppresses proliferation of CD4(+) T-lymphocytes. J Reprod Immunol 48:17–26

    CAS  PubMed  Google Scholar 

  60. Fournel S, Aguerre-Girr M, Huc X, Lenfant F, Alam A, Toubert A, Bensussan A, Le Bouteiller P (2000) Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J Immunol 164:6100–6104

    CAS  PubMed  Google Scholar 

  61. Ristich V, Liang S, Zhang W, Wu J, Horuzsko A (2005) Tolerization of dendritic cells by HLA-G. Eur J Immunol 35:1133–1142

    CAS  PubMed  Google Scholar 

  62. Gros F, Cabillic F, Toutirais O, Maux AL, Sebti Y, Amiot L (2008) Soluble HLA-G molecules impair natural killer/dendritic cell crosstalk via inhibition of dendritic cells. Eur J Immunol 38:742–749

    CAS  PubMed  Google Scholar 

  63. Adrian Cabestre F et al (1999) HLA-G expression in human melanoma cells: protection from NK cytolysis. J Reprod Immunol 43:183–193

    CAS  PubMed  Google Scholar 

  64. Seliger B, Schlaf G (2007) Structure, expression and function of HLA-G in renal cell carcinoma. Semin Cancer Biol 17:444–450

    CAS  PubMed  Google Scholar 

  65. Maki G, Hayes GM, Naji A, Tyler T, Carosella ED, Rouas-Freiss N, Gregory SA (2008) NK resistance of tumor cells from multiple myeloma and chronic lymphocytic leukemia patients: implication of HLA-G. Leukemia 22:998–1006

    CAS  PubMed  Google Scholar 

  66. Lesport E, Baudhuin J, LeMaoult J, Sousa S, Doliger C, Carosella ED, Favier B (2009) Human melanoma cell secreting human leukocyte antigen-G5 inhibit natural killer cell cytotoxicity by impairing lytic granules polarization toward target cell. Hum Immunol 70:1000–1005

    CAS  PubMed  Google Scholar 

  67. Smith M, Bittner JGt, White S, Smith D, Horuzsko A (2008) HLA-G-treated tolerogenic dendritic cells induce tolerogenic potential by increasing expression of B7–1 (CD80) molecules. Transplant Proc 40:603–1598

    Google Scholar 

  68. Caumartin J, Favier B, Daouya M, Guillard C, Moreau P, Carosella ED, LeMaoult J (2007) Trogocytosis-based generation of suppressive NK cells. EMBO J 26:1423–1433

    CAS  PubMed  Google Scholar 

  69. LeMaoult J, Caumartin J, Daouya M, Favier B, Le Rond S, Gonzalez A, Carosella ED (2007) Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells. Blood 109:2040–2048

    CAS  PubMed  Google Scholar 

  70. Moreau P, Mouillot G, Rousseau P, Marcou C, Dausset J, Carosella ED (2003) HLA-G gene repression is reversed by demethylation. Proc Natl Acad Sci USA 100:1191–1196

    CAS  PubMed  Google Scholar 

  71. Zidi I, Guillard C, Marcou C, Krawice-Radanne I, Sangrouber D, Rouas-Freiss N, Carosella ED, Moreau P (2006) Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-kappaB inducers. Cell Mol Life Sci 63:2669–2681

    CAS  PubMed  Google Scholar 

  72. Shiroishi M et al (2006) Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Proc Natl Acad Sci USA 103:16412–16417

    CAS  PubMed  Google Scholar 

  73. Chang CC, Murphy SP, Ferrone S (2003) Differential in vivo and in vitro HLA-G expression in melanoma cells: potential mechanisms. Hum Immunol 64:1057–1063

    CAS  PubMed  Google Scholar 

  74. Menier C, Riteau B, Dausset J, Carosella ED, Rouas-Freiss N (2000) HLA-G truncated isoforms can substitute for HLA-G1 in fetal survival. Hum Immunol 61:1118–1125

    CAS  PubMed  Google Scholar 

  75. Morales PJ, Pace JL, Platt JS, Langat DK, Hunt JS (2007) Synthesis of beta(2)-microglobulin-free, disulphide-linked HLA-G5 homodimers in human placental villous cytotrophoblast cells. Immunology 122:179–188

    CAS  PubMed  Google Scholar 

  76. Atkins D, Ferrone S, Schmahl GE, Storkel S, Seliger B (2004) Down-regulation of HLA class I antigen processing molecules: an immune escape mechanism of renal cell carcinoma? J Urol 171:885–889

    CAS  PubMed  Google Scholar 

  77. Seliger B, Cabrera T, Garrido F, Ferrone S (2002) HLA class I antigen abnormalities and immune escape by malignant cells. Semin Cancer Biol 12:3–13

    CAS  PubMed  Google Scholar 

  78. Boyson JE et al (2002) Disulfide bond-mediated dimerization of HLA-G on the cell surface. Proc Natl Acad Sci USA 99:16180–16185

    CAS  PubMed  Google Scholar 

  79. Gonen-Gross T et al (2003) Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J Immunol 171:1343–1351

    CAS  PubMed  Google Scholar 

  80. Shiroishi M et al (2006) Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. J Biol Chem 281:10439–10447

    CAS  PubMed  Google Scholar 

  81. Apps R, Gardner L, Sharkey AM, Holmes N, Moffett A (2007) A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1. Eur J Immunol 37:1924–1937

    CAS  PubMed  Google Scholar 

  82. Cai MY et al (2009) Human leukocyte antigen-G protein expression is an unfavorable prognostic predictor of hepatocellular carcinoma following curative resection. Clin Cancer Res 15:4686–4693

    CAS  PubMed  Google Scholar 

  83. Sayed D, Badr G, Maximous D, Mikhail NN, Abu-Tarboush F, Alhazza IM (2010) HLA-G and its relation to proliferation index in detection and monitoring breast cancer patients. Tissue Antigens 75:40–47

    CAS  PubMed  Google Scholar 

  84. Schutt P et al (2010) Prognostic relevance of soluble human leukocyte antigen-G and total human leukocyte antigen class I molecules in lung cancer patients. Hum Immunol 71:489–495

    CAS  PubMed  Google Scholar 

  85. Zhu CB, Wang CX, Zhang X, Zhang J, Li W (2010) Serum sHLA-G levels: a useful indicator in distinguishing colorectal cancer from benign colorectal diseases. Int J Cancer (Epub ahead of print)

  86. Diaz-Lagares A, Alegre E, LeMaoult J, Carosella ED, Gonzalez A (2009) Nitric oxide produces HLA-G nitration and induces metalloprotease-dependent shedding creating a tolerogenic milieu. Immunology 126:436–445

    CAS  PubMed  Google Scholar 

  87. Onno M et al (2000) Modulation of HLA-G antigens expression in myelomonocytic cells. Hum Immunol 61:1086–1094

    CAS  PubMed  Google Scholar 

  88. Amiot L, Onno M, Drenou B, le Marchand B, Lamy T, Semana G, Fauchet R (1996) Distribution of HLA-G alternative mRNAs including soluble forms in normal lymphocytes and in lymphoid cell-derived leukemia. Eur J Immunogenet 23:311–320

    CAS  PubMed  Google Scholar 

  89. Rousseau P, Masternak K, Krawczyk M, Reith W, Dausset J, Carosella ED, Moreau P (2004) In vivo, RFX5 binds differently to the human leucocyte antigen-E, -F, and -G gene promoters and participates in HLA class I protein expression in a cell type-dependent manner. Immunology 111:53–65

    CAS  PubMed  Google Scholar 

  90. Solier C, Mallet V, Lenfant F, Bertrand A, Huchenq A, Le Bouteiller P (2001) HLA-G unique promoter region: functional implications. Immunogenetics 53:617–625

    CAS  PubMed  Google Scholar 

  91. Flajollet S, Poras I, Carosella ED, Moreau P (2009) RREB-1 is a transcriptional repressor of HLA-G. J Immunol 183:6948–6959

    CAS  PubMed  Google Scholar 

  92. Gobin SJ, Biesta P, de Steenwinkel JE, Datema G, van den Elsen PJ (2002) HLA-G transactivation by cAMP-response element-binding protein (CREB). An alternative transactivation pathway to the conserved major histocompatibility complex (MHC) class I regulatory routes. J Biol Chem 277:39525–39531

    CAS  PubMed  Google Scholar 

  93. He X et al (2010) HLA-G expression in human breast cancer: implications for diagnosis and prognosis, and effect on allocytotoxic lymphocyte response after hormone treatment in vitro. Ann Surg Oncol 17:1459–1469

    PubMed  Google Scholar 

  94. Ibrahim EC, Morange M, Dausset J, Carosella ED, Paul P (2000) Heat shock and arsenite induce expression of the nonclassical class I histocompatibility HLA-G gene in tumor cell lines. Cell Stress Chaperones 5:207–218

    CAS  PubMed  Google Scholar 

  95. Lefebvre S et al (2001) A specific interferon (IFN)-stimulated response element of the distal HLA-G promoter binds IFN-regulatory factor 1 and mediates enhancement of this nonclassical class I gene by IFN-beta. J Biol Chem 276:6133–6139

    CAS  PubMed  Google Scholar 

  96. Moreau P, Paul P, Gourand L, Prost S, Dausset J, Carosella E, Kirszenbaum M (1997) HLA-G gene transcriptional regulation in trophoblasts and blood cells: differential binding of nuclear factors to a regulatory element located 1.1 kb from exon 1. Hum Immunol 52:41–46

    CAS  PubMed  Google Scholar 

  97. Yie SM, Xiao R, Librach CL (2006) Progesterone regulates HLA-G gene expression through a novel progesterone response element. Hum Reprod 21:2538–2544

    CAS  PubMed  Google Scholar 

  98. Moreau P, Flajollet S, Carosella ED (2009) Non-classical transcriptional regulation of HLA-G: an update. J Cell Mol Med 13:2973–2989

    PubMed  Google Scholar 

  99. Bamberger AM, Jenatschke S, Schulte HM, Loning T, Bamberger MC (2000) Leukemia inhibitory factor (LIF) stimulates the human HLA-G promoter in JEG3 choriocarcinoma cells. J Clin Endocrinol Metab 85:3932–3936

    CAS  PubMed  Google Scholar 

  100. Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, Carosella ED, Paul P (1999) IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes. Int Immunol 11:803–811

    CAS  PubMed  Google Scholar 

  101. Urosevic M, Dummer R (2003) HLA-G and IL-10 expression in human cancer–different stories with the same message. Semin Cancer Biol 13:337–342

    CAS  PubMed  Google Scholar 

  102. Ugurel S, Rebmann V, Ferrone S, Tilgen W, Grosse-Wilde H, Reinhold U (2001) Soluble human leukocyte antigen–G serum level is elevated in melanoma patients and is further increased by interferon-alpha immunotherapy. Cancer 92:369–376

    CAS  PubMed  Google Scholar 

  103. Riteau B, Faure F, Menier C, Viel S, Carosella ED, Amigorena S, Rouas-Freiss N (2003) Exosomes bearing HLA-G are released by melanoma cells. Hum Immunol 64:1064–1072

    CAS  PubMed  Google Scholar 

  104. Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443

    CAS  PubMed  Google Scholar 

  105. Mouillot G, Marcou C, Zidi I, Guillard C, Sangrouber D, Carosella ED, Moreau P (2007) Hypoxia modulates HLA-G gene expression in tumor cells. Hum Immunol 68:277–285

    CAS  PubMed  Google Scholar 

  106. Mouillot G, Marcou C, Rousseau P, Rouas-Freiss N, Carosella ED, Moreau P (2005) HLA-G gene activation in tumor cells involves cis-acting epigenetic changes. Int J Cancer 113:928–936

    CAS  PubMed  Google Scholar 

  107. Menendez L, Walker LD, Matyunina LV, Totten KA, Benigno BB, McDonald JF (2008) Epigenetic changes within the promoter region of the HLA-G gene in ovarian tumors. Mol Cancer 7:43

    PubMed  Google Scholar 

  108. Polakova K, Bandzuchova E, Sabty FA, Mistrik M, Demitrovicova L, Russ G (2009) Activation of HLA-G expression by 5-aza-2-deoxycytidine in malignant hematopoetic cells isolated from leukemia patients. Neoplasma 56:514–520

    CAS  PubMed  Google Scholar 

  109. Yan WH, Lin AF, Chang CC, Ferrone S (2005) Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2′-deoxycytidine. Cell Res 15:523–531

    PubMed  Google Scholar 

  110. Holling TM, Bergevoet MW, Wierda RJ, van Eggermond MC, van den Elsen PJ (2009) Genetic and epigenetic control of the major histocompatibility complex class Ib gene HLA-G in trophoblast cell lines. Ann NY Acad Sci 1173:538–544

    CAS  PubMed  Google Scholar 

  111. Castelli EC et al (2009) In silico analysis of microRNAS targeting the HLA-G 3′ untranslated region alleles and haplotypes. Hum Immunol 70:1020–1025

    CAS  PubMed  Google Scholar 

  112. Larsen MH, Hylenius S, Andersen AM, Hviid TV (2010) The 3′-untranslated region of the HLA-G gene in relation to pre-eclampsia: revisited. Tissue Antigens 75:253–261

    CAS  PubMed  Google Scholar 

  113. Hviid TV, Rizzo R, Christiansen OB, Melchiorri L, Lindhard A, Baricordi OR (2004) HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms. Immunogenetics 56:135–141

    CAS  PubMed  Google Scholar 

  114. Iversen AC et al (2008) The HLA-G 14 bp gene polymorphism and decidual HLA-G 14 bp gene expression in pre-eclamptic and normal pregnancies. J Reprod Immunol 78:158–165

    CAS  PubMed  Google Scholar 

  115. Hviid TV, Hylenius S, Rorbye C, Nielsen LG (2003) HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels. Immunogenetics 55:63–79

    CAS  PubMed  Google Scholar 

  116. Rousseau P, Le Discorde M, Mouillot G, Marcou C, Carosella ED, Moreau P (2003) The 14 bp deletion-insertion polymorphism in the 3′ UT region of the HLA-G gene influences HLA-G mRNA stability. Hum Immunol 64:1005–1010

    CAS  PubMed  Google Scholar 

  117. Tan Z et al (2007) Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet 81:829–834

    CAS  PubMed  Google Scholar 

  118. Simoes RT et al (2009) HLA-G polymorphisms in women with squamous intraepithelial lesions harboring human papillomavirus. Mod Pathol 22:1075–1082

    CAS  PubMed  Google Scholar 

  119. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    CAS  PubMed  Google Scholar 

  120. Veit TD, Chies JA (2009) Tolerance versus immune response––microRNAs as important elements in the regulation of the HLA-G gene expression. Transpl Immunol 20:229–231

    CAS  PubMed  Google Scholar 

  121. Ischiropoulos H (2003) Biological selectivity and functional aspects of protein tyrosine nitration. Biochem Biophys Res Commun 305:776–783

    CAS  PubMed  Google Scholar 

  122. Seliger B, Abken H, Ferrone S (2003) HLA-G and MIC expression in tumors and their role in anti-tumor immunity. Trends Immunol 24:82–87

    CAS  PubMed  Google Scholar 

  123. Rebmann V, Wagner S, Grosse-Wilde H (2007) HLA-G expression in malignant melanoma. Semin Cancer Biol 17:422–429

    CAS  PubMed  Google Scholar 

  124. Aractingi S, Kanitakis J, Euvrard S, Le Danff C, Carosella ED (2003) Selective expression of HLA-G in malignant and premalignant skin specimens in kidney transplant recipients. Int J Cancer 106:232–235

    CAS  PubMed  Google Scholar 

  125. Ibrahim EC, Allory Y, Commo F, Gattegno B, Callard P, Paul P (2003) Altered pattern of major histocompatibility complex expression in renal carcinoma: tumor-specific expression of the nonclassical human leukocyte antigen-G molecule is restricted to clear cell carcinoma while up-regulation of other major histocompatibility complex antigens is primarily distributed in all subtypes of renal carcinoma. Am J Pathol 162:501–508

    CAS  PubMed  Google Scholar 

  126. Ibrahim EC, Guerra N, Lacombe MJ, Angevin E, Chouaib S, Carosella ED, Caignard A, Paul P (2001) Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma. Cancer Res 61:6838–6845

    CAS  PubMed  Google Scholar 

  127. Ishigami S et al (2006) HLA-G expression in gastric cancer. Anticancer Res 26:2467–2472

    CAS  PubMed  Google Scholar 

  128. Fukushima Y et al (1998) Increased expression of human histocompatibility leukocyte antigen-G in colorectal cancer cells. Int J Mol Med 2:349–351

    CAS  PubMed  Google Scholar 

  129. Kleinberg L et al (2006) Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma. Virchows Arch 449:31–39

    CAS  PubMed  Google Scholar 

  130. Barrier BF, Kendall BS, Sharpe-Timms KL, Kost ER (2006) Characterization of human leukocyte antigen-G (HLA-G) expression in endometrial adenocarcinoma. Gynecol Oncol 103:25–30

    CAS  PubMed  Google Scholar 

  131. Menier C, Riteau B, Carosella ED, Rouas-Freiss N (2002) MICA triggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal. Int J Cancer 100:63–70

    Google Scholar 

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Authors and Affiliations

  1. UPRES EA 4427 SeRAIC, University of Rennes 1, 2 av Prof Léon Bernard, 35043, RENNES Cedex, France

    Laurence Amiot

  2. CHU Pontchaillou, 2 rue Henri le Guilloux, 35043, RENNES Cedex, France

    Laurence Amiot

  3. Departments of Immunology, Surgery and Pathology, School of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, 5117 Centre Avenue Suite 2.26d, Pittsburgh, PA, 15213, USA

    Soldano Ferrone

  4. Institute for Transfusion Medicine, University Hospital Essen, 45147, Essen, Germany

    Hans Grosse-Wilde & Barbara Seliger

  5. Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 2, 06112, Halle (Saale), Germany

    Barbara Seliger

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  1. Laurence Amiot
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  2. Soldano Ferrone
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  3. Hans Grosse-Wilde
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  4. Barbara Seliger
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Correspondence to Barbara Seliger.

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Amiot, L., Ferrone, S., Grosse-Wilde, H. et al. Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?. Cell. Mol. Life Sci. 68, 417–431 (2011). https://doi.org/10.1007/s00018-010-0583-4

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  • DOI: https://doi.org/10.1007/s00018-010-0583-4

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