head JofIMAB
Journal of IMAB - Annual Proceeding (Scientific Papers)
Publisher: Peytchinski Publishing
ISSN: 1312-773X (Online)
Issue: 2018, vol. 24, issue3
Subject Area: Dental&Oral Medicine
DOI: 10.5272/jimab.2018243.2133
Published online: 31 August 2018

Review article

J of IMAB. 2018 Jul-Sep;24(3):2133-2141
Bushra al Hadra1, Elitsa Deliverska2ORCID logo Corresponding Autoremail, Hristo Stoianov2, Antoaneta Nedialkova3, Tsvetelin Lukanov1, Velizar Shivarov4, Dimitar Yovchev5, Elissaveta Naumova1, Milena Ivanova1.
1) Department of immunology, Medical University Sofia, Bulgaria.
2) Department of Oral and maxillofacial surgery, Faculty of Dental Medicine, Medical University, Sofia, Bulgaria.
3) Department of clinical immunology, University Hospital Alexandrovska, Sofia, Bulgaria.
4) Department of clinical immunology, University Hospital SofiaMed, Sofia, Bulgaria.
5) Department of Imaging and oral diagnostic, Faculty of Dental Medicine, Medical University, Sofia, Bulgaria.

Major histocompatibility complex class I-related chain A (MICA) is a ligand of Natural killer group 2, member D (NKG2D) receptor. Recent studies have shown that MICA is upregulated in tumors from the epithelial origin, playing a key role in immunological surveillance and different alleles are associated with diseases related to NK activity. The aim of our study was to analyse the associations of MICA polymorphism with oral squamous cell carcinoma (OSCC). Twenty seven patients with histologically proven OSCC were included in the study. The majority of patients had G2-G3 tumors according to Anneroth's classification. The control group included healthy subjects from the Bulgarian population. MICA genotyping was performed by PCR-SSO kit (LABType SSO MICA, OneLambda) and PCR-SBT. Our results showed a statistically significant protective association for MICA*12:01 allele (Pc<0.05, OR-0.07), encoding a full- length protein. Interestingly this allele had a higher frequency in the healthy Bulgarian population compared to other European populations. With the highest frequency in patients with OSCC was observed MICA*08:01 allele, encoding truncated protein. However, the difference with the control group was with a borderline significance (Pc=0.053). Although our data are preliminary considering the small number of patients analyzed, the associations observed support the model that alleles are encoding truncated, ectopic and soluble MICA molecules play an important role in OSCC by down- regulation of NKG2D on NK and CD8+ T cells leading to aberrant immunological surveillance.

Keywords: biomarkers, oral squamous cell carcinoma, HLA,

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Please cite this article as: al Hadra B, Deliverska E, Stoianov H, Nedialkova A, Lukanov T, Shivarov V, Yovchev D, Naumova E, Ivanova M. Investigation of HLA genes, HLA molecules and other factors in patients with oral squamous cell carcinoma. J of IMAB. 2018 Jul-Sep;24(3):2133-2141.
DOI: 10.5272/jimab.2018243.2133

Corresponding AutorCorrespondence to: Elitsa Georgieva Deliverska, Associate Professor, Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Medical University Sofia; 1, Georgi Sofiiski Blvd., 1431 Sofia, Bulgaria; E-mail: elitsadeliverska@yahoo.com,

1. Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6259-63. [PubMed] [CrossRef]
2. Leelayuwat C, Townend DC, Degli-Esposti MA, Abraham LJ, Dawkins RL. A new polymorphic and multicopy MHC gene family related to nonmammalian class I. Immunogenetics. 1994; 40(5):339-51. [PubMed]
3. Suresh PK. Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strate. J Cancer Res Ther. 2016;12(4):1224-33. [CrossRef]
4. Chen D, Gyllensten U. MICA polymorphism: biology and importance in cancer. Carcinogenesis. 2014 Dec;35(12):2633–42. [PubMed] [CrossRef]
5. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12445-50. [PubMed]
6. Tieng V, Le Bouguenec C, du Merle L, Bertheau P, Desreumaux P, Janin A, et al. Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA. Proc Natl Acad Sci U S A. 2002 Mar;99(5):2977–82. [PubMed] [CrossRef]
7. Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol. 2001 Mar;2(3):255–60. [PubMed] [CrossRef]
8. Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T, et al. MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function. Immunity. 2001 Jul;15(1):83-93. [PubMed]
9. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 2005 Aug 25;436(7054):1186-90. [PubMed] [CrossRef]
10. Choy M-K, Phipps ME. MICA polymorphism: biology and importance in immunity and disease. Trends Mol Med. 2010 Mar;16(3):97-106. [CrossRef]
11. Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9452-7. [PubMed] [CrossRef]
12. Caillat-Zucman S. How NKG2D ligands trigger autoimmunity? Hum Immunol. 2006 Mar;67(3):204-7.  [PubMed] [CrossRef]
13. Ullrich E, Koch J, Cerwenka A, Steinle A. New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology. 2013 Oct 1;2(10):e26097. [PubMed] [CrossRef]
14. Arreygue-Garcia NA, Daneri-Navarro A, del Toro-Arreola A, Cid-Arregui A, Gonzalez-Ramella O, Jave-Suarez LF, et al. Augmented serum level of major histocompatibility complex class I-related chain A (MICA) protein and reduced NKG2D expression on NK and T cells in patients with cervical cancer and precursor lesions. BMC Cancer. 2008 Jan 21;8:16. [PubMed] [CrossRef]
15. Kohga K, Takehara T, Tatsumi T, Ohkawa K, Miyagi T, Hiramatsu N, et al. Serum levels of soluble major histocompatibility complex (MHC) class I-related chain A in patients with chronic liver diseases and changes during transcatheter arterial embolization for hepatocellular carcinoma. Cancer Sci. 2008 Aug;99(8):1643-9. [PubMed] [CrossRef]
16. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet. 2011 May;43(5):455-8.  [PubMed] [CrossRef]
17. Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi A, Deng Z, et al. Soluble MICA and a MICA variation as possible prognostic biomarkers for HBV-induced hepatocellular carcinoma. PLoS One. 2012; 7(9):e44743.  [PubMed] [CrossRef]
18. Tong HV, Toan NL, Song LH, Bock CT, Kremsner PG, Velavan TP. Hepatitis B virus-induced hepatocellular carcinoma: functional roles of MICA variants. J Viral Hepat. 2013 Oct;20(10):687-98. [PubMed] [CrossRef]
19. Tamaki S1, Kawakami M, Yamanaka Y, Shimomura H, Imai Y, Ishida J, et al. Relationship between soluble MICA and the MICA A5.1 homozygous genotype in patients with oral squamous cell carcinoma. Clin Immunol. 2009 Mar;130(3):331-7. [PubMed] [CrossRef]
20. Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR. Soluble MICA in malignant diseases. Int J Cancer. 2006 Feb 1;118(3):684–7. [PubMed] [CrossRef]
21. Bahram S. MIC genes: from genetics to biology. Adv Immunol. 2000; 76:1-60. [PubMed]
22. Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nat Immunol. 2001 May;2(5):443-51. [PubMed] [CrossRef]
23. Steinle A, Li P, Morris DL, Groh V, Lanier LL, Strong RK, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics. 2001 May-Jun;53(4):279–87. [PubMed]
24. Steinle A, Groh V, Spies T. Diversification, expression, and gamma delta T cell recognition of evolutionarily distant members of the MIC family of major histocompatibility complex class I-related molecules. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12510-5. [PubMed] [CrossRef]
25. McFarland BJ, Strong RK. Thermodynamic Analysis of Degenerate Recognition by the NKG2D Immunoreceptor: Not Induced Fit but Rigid Adaptation. Immunity. 2003 Dec;19(6):803–12. [PubMed]
26. Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL, et al. An activating immunoreceptor complex formed by NKG2D and DAP10. Science. 1999 Jul 30;285(5428):730-2. [PubMed] [CrossRef]
27. Stephens HA. MICA and MICB genes: Can the enigma of their polymorphism be resolved? Trends Immunol. 2001 Jul;22(7):378–85. [PubMed]
28. Tang KF, Ren H, Cao J, Zeng GL, Xie J, Chen M, et al. Decreased Dicer expression elicits DNA damage and up-regulation of MICA and MICB. J Cell Biol. 2008 Jul 28;182(2):233–9. [PubMed] [CrossRef]
29. Groh V, Steinle A, Bauer S, Spies T. Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science. 1998 Mar 13;279(5357):1737-40. [PubMed] [CrossRef]
30. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science. 2001 Oct 19;294(5542):605-9. [PubMed] [CrossRef]
31. Mizutani K, Terasaki P, Rosen A, Esquenazi V, Miller J, Shih RN, et al. Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. Am J Transplant. 2005 Sep;5(9):2265-72. [PubMed] [CrossRef]
32. Zou Y, Mirbaha F, Lazaro A, Zhang Y, Lavingia B, Stastny P. MICA is a target for complement-dependent cytotoxicity with mouse monoclonal antibodies and human alloantibodies. Hum Immunol. 2002 Jan;63(1):30-9. [PubMed]
33. Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T. Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6879-84. [PubMed]
34. Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood. 2003 Aug 15;102(4):1389-96.  [PubMed] [CrossRef]
35. Wu JD, Higgins LM, Steinle A, Cosman D, Haugk K, Plymate SR. Prevalent expression of the immunostimulatory MHC class I chain – related molecule is counteracted by shedding in prostate cancer. J Clin Invest. 2004 Aug;114(4):560-8. [PubMed] [CrossRef]
36. Zwirner NW, Fernandez-Vina MA, Stastny P. MICA, a new polymorphic HLA-related antigen, is expressed mainly by keratinocytes, endothelial cells, and monocytes. Immunogenetics. 1998;47(2):139-48. [PubMed]
37. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol. 2013; 31:413-41. [PubMed] [CrossRef]
38.  Fernandez-Messina L, Reyburn HT, Vales-Gomez M. Human NKG2D-ligands: cell biology strategies to ensure immune recognition. Front Immunol. 2012 Sep 25;3:299. [PubMed] [CrossRef]
39. Schrambach S, Ardizzone M, Leymarie V, Sibilia J, Bahram S. In vivo expression pattern of MICA and MICB and its relevance to auto-immunity and cancer. PLoS One. 2007 Jun 13;2(6):e518. [PubMed] [CrossRef]
40. Kaiser BK, Yim D, Chow IT, Gonzalez S, Dai Z, Mann HH, et al. Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature. 2007 May 24;447(7143):482-6. [PubMed] [CrossRef]
41. Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A, et al. Tumor-associated MICA is shed by ADAM proteases. Cancer Res. 2008 Aug 1;68(15):6368-76. [PubMed] [CrossRef]
42. Suresh PK. Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strategies. J Can Res Ther. 2016; 12(4):1224-33. [CrossRef]
43. Baranwal AK, Mehra NK. Major Histocompatibility Complex Class I Chain-Related A (MICA) Molecules: Relevance in Solid Organ Transplantation. Front Immunol. 2017 Feb 28;8:182. [PubMed] [CrossRef]
44. Eissmann P, Evans JH, Mehrabi M, Rose EL, Nedvetzki S, Davis DM. Multiple Mechanisms Downstream of TLR-4 Stimulation Allow Expression of NKG2D Ligands To Facilitate Macrophage/NK Cell Crosstalk. J Immunol. 2010 Jun 15;184(12):6901-9. [PubMed] [CrossRef]
45. Ashiru O, Lopez-Cobo S, Fernandez-Messina L, Pontes-Quero S, Pandolfi R, Reyburn HT, et al. A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008. Biochem J. 2013;454(2):295-302. [PubMed] [CrossRef]
46. Kapoor S. sMICA and its emerging role as a prognostic and diagnostic indicator in systemic malignancies besides hepatocellular carcinoma. Chin J Cancer. 2013 Apr;32(4):224. [PubMed] [CrossRef]
47. Zou Y, Han M, Wang Z, Stastny P. MICA allele-level typing by sequence-based typing with computerized assignment of polymorphic sites and short tandem repeats within the transmembrane region. Hum Immunol. 2006 Mar;67(3):145-51. [PubMed] [CrossRef]
48. Isernhagen A, Schilling D, Monecke S, Shah P, Elsner L, Walter L, et al. The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA. Immunogenetics. 2016 Feb;68(2):109–23. [PubMed] [CrossRef]
49. Isernhagen A, Malzahn D, Viktorova E, Elsner L, Monecke S, von Bonin F, et al. The MICA 129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation. EMBO Mol Med. 2015 Nov;7(11):1480–502. [PubMed] [CrossRef]
50. Mizuki N, Ota M, Kimura M, Ohno S, Ando H, Katsuyama Y, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behзet disease. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1298-303. [PubMed] [CrossRef]
51. Suemizu H, Radosavljevic M, Kimura M, Sadahiro S, Yoshimura S, Bahram S, et al. A basolateral sorting motif in the MICA cytoplasmic tail. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2971-6. [PubMed] [CrossRef]
52. Binmadi NO, Basile JR. Perineural invasion in oral squamous cell carcinoma: a discussion of significance and review of the literature. Oral Oncol. 2011 Nov;47(11):1005-10. [PubMed] [CrossRef]
53. Slootweg PJ, de Pagter M, de Weger RA, de Wilde PC. Lymphocytes at tumor margins in patients with head and neck cancer. Relationship with tumor size, human lymphocyte antigen molecules, and metastasis. Int J Oral Maxillofac Surg. 1994 Oct;23(5):286-9. [PubMed]
54. Reinders J, Rozemuller EH, van der Ven KJ, Caillat-Zucman S, Slootweg PJ, de Weger RA, et al. MHC class I chain-related gene a diversity in head and neck squamous cell carcinoma. Hum Immunol. 2006 Mar;67(3):196-203. [PubMed] [CrossRef]
55. Zwirner NW, Dole K, Stastny P. Differential surface expression of MICA by endothelial cells, fibroblasts, keratinocytes, and monocytes. Hum Immunol. 1999 Apr;60(4):323-30. [PubMed] [CrossRef]
56. Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol. 2002 Oct 15;169(8):4098-102. [PubMed] [CrossRef]
57. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002 Oct 17;419(6908):734-8. [PubMed] [CrossRef]
58. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999 Jul 30;285(5428):727-9. [PubMed] [CrossRef]
59. Gonzalez-Gay MA, Rueda B, Vilchez JR, Lopez-Nevot MA, Robledo G, Ruiz MP, et al. Contribution of MHC class I region to genetic susceptibility for giant cell arteritis.Rheumatology (Oxford).2007 Mar;46(3):431-4. [PubMed] [CrossRef]
60. Yoshida K, Komai K, Shiozawa K, Mashida A, Horiuchi T, Tanaka Y, et al. Role of the MICA polymorphism in systemic lupus erythematosus. Arthritis Rheum. 2011 Oct;63(10):3058-66. [PubMed] [CrossRef]
61. Park YS, Sanjeevi CB, Robles D, Yu L, Rewers M, Gottlieb PA, et al. Additional association of intra-MHC genes, MICA and D6S273, with Addison's disease. Tissue Antigens. 2002 Aug;60(2):155-63. [PubMed]
62. Mok JW, Lee YJ, Kim JY, Lee EB, Song YW, Park MH, et al. Association of MICA polymorphism with rheumatoid arthritis patients in Koreans. Hum Immunol. 2003 Dec;64(12):1190-4. [PubMed]
63. Gonzalez S, Garcia-Fernandez S, Martinez-Borra J, Blanco-Gelaz MA, Rodrigo L, Sanchez Del Rio J, et al. High variability of HLA-B27 alleles in ankylosing spondylitis and related spondyloarthropathies in the population of Northern Spain. Hum Immunol. 2002 Aug;63(8):673–6. [PubMed]
64.  Chung-Ji L, Yann-Jinn L, Hsin-Fu L, Ching-Wen D, Che-Shoa C, Yi-Shing L, et al. The increase in the frequency of MICA gene A6 allele in oral squamous cell carcinoma. J Oral Pathol Med. 2002 Jul;31(6):323-8. [PubMed]
65. Tamaki S, Sanefuzi N, Ohgi K, Imai Y, Kawakami M, Yamamoto K, et al. An association between the MICA-A5.1 allele and an increased susceptibility to oral squamous cell carcinoma in Japanese patients. J Oral Pathol Med. 2007 Jul;36(6):351-6. [PubMed] [CrossRef]
66. Fan S, Tang QL, Lin YJ, Chen WL, Li JS, Huang ZQ, et al. A review of clinical and histological parameters associated with contralateral neck metastases in oral squamous cell carcinoma. Int J Oral Sci. 2011 Oct;3(4):180-91. [PubMed] [CrossRef]
67. Vallian S, Rad MJ, Tavallaei M, Tavassoli M. Correlation of major histocompatibility complex class i related A (MICA) polymorphism with the risk of developing breast cancer. Med Oncol. 2012 Mar;29(1):5–9. [PubMed] [CrossRef]
68. Tian W, Zeng XM, Li LX, Jin HK, Luo QZ, Wang F, et al. Gender-specific associations between MICA-STR and nasopharyngeal carcinoma in a southern Chinese Han population. Immunogenetics. 2006 Apr;58(2-3):113-21. [PubMed] [CrossRef]
69. Douik H, Ben Chaaben A, Attia Romdhane N, Romdhane HB, Mamoghli T, Fortier C, et al. Association of MICA-129 polymorphism with nasopharyngeal cancer risk in a Tunisian population. Hum Immunol. 2009 Jan;70(1):45-8. [PubMed] [CrossRef]
70. Kopp R, Glas J, Lau-Werner U, Albert ED, Weiss EH. Association of MICA-TM and MICB C1-2-A microsatellite polymorphisms with tumor progression in patients with colorectal cancer. J Clin Immunol. 2009 Jul;29(4):545-54. [PubMed] [CrossRef]
71. Luo QZ, Lin L, Gong Z, Mei B, Xu YJ, Huo Z, et al. Positive association of major histocompatibility complex class I chain-related gene A polymorphism with leukemia susceptibility in the people of Han nationality of Southern China. Tissue Antigens. 2011 Sep;78(3):178-84. [CrossRef]
72. Lo SS, Lee YJ, Wu CW, Liu CJ, Huang JW, Lui WY. The increase of MICA gene A9 allele associated with gastric cancer and less schirrous change. Br J Cancer. 2004 May 4;90(9):1809-13. [PubMed] [CrossRef]
73. Martinez-Chamorro A, Moreno A, Gуmez-Garcia M, Cabello MJ, Martin J, Lopez-Nevot MA. MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset. Clin Exp Immunol. 2016 Jun;184(3):323-31. [PubMed] [CrossRef]
74. Sugimura K, Ota M, Matsuzawa J, Katsuyama Y, Ishizuka K, Mochizuki T, Mizuki N, et al. A close relationship of triplet repeat polymorphism in MHC class I chain-related gene A (MICA) to the disease susceptibility and behavior in ulcerative colitis. Tissue Antigens. 2001 Jan;57(1):9-14. [PubMed]
75. McCarthy MI, Hirschhorn JN. Genome-wide association studies: Potential next steps on a genetic journey. Hum Mol Genet. 2008 Oct 15;17(R2):156–65. [PubMed]
76. Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9190-5. [PubMed] [CrossRef].

Received: 25 April 2018
Published online: 31 August 2018

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