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BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

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

Authors: Naela A Arreygue-Garcia, Adrian Daneri-Navarro, Alicia del Toro-Arreola, Angel Cid-Arregui, Oscar Gonzalez-Ramella, Luis F Jave-Suarez, Adriana Aguilar-Lemarroy, Rogelio Troyo-Sanroman, Alejandro Bravo-Cuellar, Vidal Delgado-Rizo, Trinidad Garcia-Iglesias, Georgina Hernandez-Flores, Susana del Toro-Arreola

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

Cervical cancer is the second most common cancer in women worldwide. NK and cytotoxic T cells play an important role in the elimination of virus-infected and tumor cells through NKG2D activating receptors, which can promote the lysis of target cells by binding to the major histocompatibility complex class I-related chain A (MICA) proteins. Increased serum levels of MICA have been found in patients with epithelial tumors. The aim of this study was to compare the levels of soluble MICA (sMICA) and NKG2D-expressing NK and T cells in blood samples from patients with cervical cancer or precursor lesions with those from healthy donors.

Methods

Peripheral blood with or without heparin was collected to obtain mononuclear cells or sera, respectively. Serum sMICA levels were measured by ELISA and NKG2D-expressing immune cells were analyzed by flow cytometry. Also, a correlation analysis was performed to associate sMICA levels with either NKG2D expression or with the stage of the lesion.

Results

Significant amounts of sMICA were detected in sera from nearly all patients. We found a decrease in the number of NKG2D-expressing NK and T cells in both cervical cancer and lesion groups when compared to healthy donors. Pearson analysis showed a negative correlation between sMICA and NKG2D-expressing T cells; however, we did not find a significant correlation when the analysis was applied to sMICA and NKG2D expression on NK cells.

Conclusion

Our results show for the first time that high sMICA levels are found in sera from patients with both cervical cancer and precursor lesions when compared with healthy donors. We also observed a diminution in the number of NKG2D-expressing NK and T cells in the patient samples; however, a significant negative correlation between sMICA and NKG2D expression was only seen in T cells.
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Literature
1.
2.
Sankaranarayanan R, Ferlay J: Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol. 2006, 20 (2): 207-225. 10.1016/j.bpobgyn.2005.10.007.CrossRefPubMed
3.
Lazcano-Ponce EC, Moss S, Alonso de Ruiz P, Salmeron Castro J, Hernandez Avila M: Cervical cancer screening in developing countries: why is it ineffective? The case of Mexico. Arch Med Res. 1999, 30 (3): 240-250. 10.1016/S0188-0128(99)00006-8.CrossRefPubMed
4.
zur Hausen H: Papillomavirus infections--a major cause of human cancers. Biochim Biophys Acta. 1996, 1288 (2): F55-78.PubMed
5.
Munoz N: Human papillomavirus and cancer: the epidemiological evidence. J Clin Virol. 2000, 19 (1-2): 1-5. 10.1016/S1386-6532(00)00125-6.CrossRefPubMed
6.
Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV: The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002, 55 (4): 244-265.CrossRefPubMedPubMedCentral
7.
Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S: Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003, 88 (1): 63-73. 10.1038/sj.bjc.6600688.CrossRefPubMedPubMedCentral
8.
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999, 189 (1): 12-19. 10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F.CrossRefPubMed
9.
Richardson H, Kelsall G, Tellier P, Voyer H, Abrahamowicz M, Ferenczy A, Coutlee F, Franco EL: The natural history of type-specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev. 2003, 12 (6): 485-490.PubMed
10.
Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD: Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998, 338 (7): 423-428. 10.1056/NEJM199802123380703.CrossRefPubMed
11.
Sellors JW, Karwalajtys TL, Kaczorowski J, Mahony JB, Lytwyn A, Chong S, Sparrow J, Lorincz A: Incidence, clearance and predictors of human papillomavirus infection in women. Cmaj. 2003, 168 (4): 421-425.PubMedPubMedCentral
12.
Richardson H, Abrahamowicz M, Tellier PP, Kelsall G, du Berger R, Ferenczy A, Coutlee F, Franco EL: Modifiable risk factors associated with clearance of type-specific cervical human papillomavirus infections in a cohort of university students. Cancer Epidemiol Biomarkers Prev. 2005, 14 (5): 1149-1156. 10.1158/1055-9965.EPI-04-0230.CrossRefPubMed
13.
Dalstein V, Riethmuller D, Pretet JL, Le Bail Carval K, Sautiere JL, Carbillet JP, Kantelip B, Schaal JP, Mougin C: Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. Int J Cancer. 2003, 106 (3): 396-403. 10.1002/ijc.11222.CrossRefPubMed
14.
Cuschieri KS, Cubie HA, Whitley MW, Gilkison G, Arends MJ, Graham C, McGoogan E: Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study. J Clin Pathol. 2005, 58 (9): 946-950. 10.1136/jcp.2004.022863.CrossRefPubMedPubMedCentral
15.
Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ: HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol. 2006, 208 (2): 152-164. 10.1002/path.1866.CrossRefPubMed
16.
Brummer O, Hollwitz B, Bohmer G, Kuhnle H, Petry KU: Human papillomavirus-type persistence patterns predict the clinical outcome of cervical intraepithelial neoplasia. Gynecol Oncol. 2006
17.
Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, Takeda K, van Dommelen SL, Degli-Esposti MA, Hayakawa Y: Activation of NK cell cytotoxicity. Mol Immunol. 2005, 42 (4): 501-510. 10.1016/j.molimm.2004.07.034.CrossRefPubMed
18.
Moretta L, Bottino C, Pende D, Castriconi R, Mingari MC, Moretta A: Surface NK receptors and their ligands on tumor cells. Semin Immunol. 2006, 18 (3): 151-158. 10.1016/j.smim.2006.03.002.CrossRefPubMed
19.
Glienke J, Sobanov Y, Brostjan C, Steffens C, Nguyen C, Lehrach H, Hofer E, Francis F: The genomic organization of NKG2C, E, F, and D receptor genes in the human natural killer gene complex. Immunogenetics. 1998, 48 (3): 163-173. 10.1007/s002510050420.CrossRefPubMed
20.
Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH: The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity. 2002, 17 (1): 19-29. 10.1016/S1074-7613(02)00333-3.CrossRefPubMed
21.
Diefenbach A, Jensen ER, Jamieson AM, Raulet DH: Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 2001, 413 (6852): 165-171. 10.1038/35093109.CrossRefPubMedPubMedCentral
22.
Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A: Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res. 2002, 62 (21): 6178-6186.PubMed
23.
Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D, Groh V, Spies T, Pollio G, Cosman D, Catalano L, Tassone P, Rotoli B, Venuta S: HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005, 105 (1): 251-258. 10.1182/blood-2004-04-1422.CrossRefPubMed
24.
Robinson J, Perez-Rodriguez M, Waller MJ, Cuillerier B, Bahram S, Yao Z, Albert ED, Madrigal JA, Marsh SG: MICA sequences 2000. Immunogenetics. 2001, 53 (2): 150-169. 10.1007/s002510100303.CrossRefPubMed
25.
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, 91 (14): 6259-6263. 10.1073/pnas.91.14.6259.CrossRefPubMedPubMedCentral
26.
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, 93 (22): 12445-12450. 10.1073/pnas.93.22.12445.CrossRefPubMedPubMedCentral
27.
Vetter CS, Groh V, thor Straten P, Spies T, Brocker EB, Becker JC: Expression of stress-induced MHC class I related chain molecules on human melanoma. J Invest Dermatol. 2002, 118 (4): 600-605. 10.1046/j.1523-1747.2002.01700.x.CrossRefPubMed
28.
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, 96 (12): 6879-6884. 10.1073/pnas.96.12.6879.CrossRefPubMedPubMedCentral
29.
Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, Kimura R, Miyagi T, Mochizuki K, Sasaki Y, Hayashi N: Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer. 2003, 104 (3): 354-361. 10.1002/ijc.10966.CrossRefPubMed
30.
Watson NF, Spendlove I, Madjd Z, McGilvray R, Green AR, Ellis IO, Scholefield JH, Durrant LG: Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer. 2006, 118 (6): 1445-1452. 10.1002/ijc.21510.CrossRefPubMed
31.
Pende D, Cantoni C, Rivera P, Vitale M, Castriconi R, Marcenaro S, Nanni M, Biassoni R, Bottino C, Moretta A, Moretta L: Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. Eur J Immunol. 2001, 31 (4): 1076-1086. 10.1002/1521-4141(200104)31:4<1076::AID-IMMU1076>3.0.CO;2-Y.CrossRefPubMed
32.
Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L: Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol. 2001, 19: 197-223. 10.1146/annurev.immunol.19.1.197.CrossRefPubMed
33.
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T: Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999, 285 (5428): 727-729. 10.1126/science.285.5428.727.CrossRefPubMed
34.
Jinushi M, Takehara T, Tatsumi T, Hiramatsu N, Sakamori R, Yamaguchi S, Hayashi N: Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J Hepatol. 2005, 43 (6): 1013-1020. 10.1016/j.jhep.2005.05.026.CrossRefPubMed
35.
Doubrovina ES, Doubrovin MM, Vider E, Sisson RB, O'Reilly RJ, Dupont B, Vyas YM: Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol. 2003, 171 (12): 6891-6899.CrossRefPubMed
36.
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, 114 (4): 560-568. 10.1172/JCI200422206.CrossRefPubMedPubMedCentral
37.
Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR: Soluble MICA in malignant diseases. Int J Cancer. 2006, 118 (3): 684-687. 10.1002/ijc.21382.CrossRefPubMed
38.
Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, Steinle A: Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood. 2003, 102 (4): 1389-1396. 10.1182/blood-2003-01-0019.CrossRefPubMed
39.
Groh V, Wu J, Yee C, Spies T: Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002, 419 (6908): 734-738. 10.1038/nature01112.CrossRefPubMed
40.
Creasman WT: New gynecologic cancer staging. Gynecol Oncol. 1995, 58 (2): 157-158. 10.1006/gyno.1995.1203.CrossRefPubMed
41.
42.
Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright T, Young N: The 2001 Bethesda System: terminology for reporting results of cervical cytology. Jama. 2002, 287 (16): 2114-2119. 10.1001/jama.287.16.2114.CrossRefPubMed
43.
Crothers BA: The Bethesda System 2001: update on terminology and application. Clin Obstet Gynecol. 2005, 48 (1): 98-107. 10.1097/01.grf.0000151572.99437.a5.CrossRefPubMed
44.
Salih HR, Rammensee HG, Steinle A: Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol. 2002, 169 (8): 4098-4102.CrossRefPubMed
45.
Daneri-Navarro A, Del Toro-Arreola S, Bravo-Cuellar A, Cabrera N, Orbach-Arbouys S, Perez-Montfort R: Proteolytic activity in extracts of invasive cervical carcinoma and precursor lesions. Biomed Pharmacother. 1995, 49 (6): 304-310. 10.1016/0753-3322(96)82648-5.CrossRefPubMed
46.
Kaiser BK, Yim D, Chow IT, Gonzalez S, Dai Z, Mann HH, Strong RK, Groh V, Spies T: Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature. 2007, 447 (7143): 482-486. 10.1038/nature05768.CrossRefPubMed
47.
Torres LM, Cabrera T, Concha A, Oliva MR, Ruiz-Cabello F, Garrido F: HLA class I expression and HPV-16 sequences in premalignant and malignant lesions of the cervix. Tissue Antigens. 1993, 41 (2): 65-71.CrossRefPubMed
48.
Ryu KS, Lee YS, Kim BK, Park YG, Kim YW, Hur SY, Kim TE, Kim IK, Kim JW: Alterations of HLA class I and II antigen expression in preinvasive, invasive and metastatic cervical cancers. Exp Mol Med. 2001, 33 (3): 136-144.CrossRefPubMed
49.
Lanier LL: NK cell receptors. Annu Rev Immunol. 1998, 16: 359-393. 10.1146/annurev.immunol.16.1.359.CrossRefPubMed
50.
Lanier LL: NK cell recognition. Annu Rev Immunol. 2005, 23: 225-274. 10.1146/annurev.immunol.23.021704.115526.CrossRefPubMed
51.
Lee JC, Lee KM, Kim DW, Heo DS: Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004, 172 (12): 7335-7340.CrossRefPubMed
52.
Friese MA, Wischhusen J, Wick W, Weiler M, Eisele G, Steinle A, Weller M: RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res. 2004, 64 (20): 7596-7603. 10.1158/0008-5472.CAN-04-1627.CrossRefPubMed
53.
Tervahauta A, Syrjanen S, Yliskoski M, Gold LI, Syrjanen K: Expression of transforming growth factor-beta 1 and -beta 2 in human papillomavirus (HPV)-associated lesions of the uterine cervix. Gynecol Oncol. 1994, 54 (3): 349-356. 10.1006/gyno.1994.1222.CrossRefPubMed
54.
Shier MK, Neely EB, Ward MG, Richards ME, Manders EC, Meyers C, Howett MK: Correlation of TGF beta 1 overexpression with down-regulation of proliferation-inducing molecules in HPV-11 transformed human tissue xenografts. Anticancer Res. 1999, 19 (6B): 4969-4976.PubMed
55.
Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS: Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood. 2004, 103 (8): 3065-3072. 10.1182/blood-2003-06-2125.CrossRefPubMed
56.
Allez M, Tieng V, Nakazawa A, Treton X, Pacault V, Dulphy N, Caillat-Zucman S, Paul P, Gornet JM, Douay C, Ravet S, Tamouza R, Charron D, Lemann M, Mayer L, Toubert A: CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology. 2007, 132 (7): 2346-2358. 10.1053/j.gastro.2007.03.025.CrossRefPubMed
57.
Osaki T, Saito H, Yoshikawa T, Matsumoto S, Tatebe S, Tsujitani S, Ikeguchi M: Decreased NKG2D expression on CD8+ T cell is involved in immune evasion in patients with gastric cancer. Clin Cancer Res. 2007, 13 (2 Pt 1): 382-387. 10.1158/1078-0432.CCR-06-1454.CrossRefPubMed
58.
Hunt JS, Petroff MG, McIntire RH, Ober C: HLA-G and immune tolerance in pregnancy. Faseb J. 2005, 19 (7): 681-693. 10.1096/fj.04-2078rev.CrossRefPubMed
59.
Ugurel S, Rebmann V, Ferrone S, Tilgen W, Grosse-Wilde H, Reinhold U: Soluble human leukocyte antigen--G serum level is elevated in melanoma patients and is further increased by interferon-alpha immunotherapy. Cancer. 2001, 92 (2): 369-376. 10.1002/1097-0142(20010715)92:2<369::AID-CNCR1332>3.0.CO;2-U.CrossRefPubMed
60.
Rebmann V, Regel J, Stolke D, Grosse-Wilde H: Secretion of sHLA-G molecules in malignancies. Semin Cancer Biol. 2003, 13 (5): 371-377. 10.1016/S1044-579X(03)00028-2.CrossRefPubMed
61.
Morandi F, Levreri I, Bocca P, Galleni B, Raffaghello L, Ferrone S, Prigione I, Pistoia V: Human neuroblastoma cells trigger an immunosuppressive program in monocytes by stimulating soluble HLA-G release. Cancer Res. 2007, 67 (13): 6433-6441. 10.1158/0008-5472.CAN-06-4588.CrossRefPubMed
62.
Fournel S, Aguerre-Girr M, Huc X, Lenfant F, Alam A, Toubert A, Bensussan A, Le Bouteiller P: Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J Immunol. 2000, 164 (12): 6100-6104.CrossRefPubMed
63.
Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, Puppo F: Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol. 2003, 33 (1): 125-134. 10.1002/immu.200390015.CrossRefPubMed
Metadata
Title
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
Authors
Naela A Arreygue-Garcia
Adrian Daneri-Navarro
Alicia del Toro-Arreola
Angel Cid-Arregui
Oscar Gonzalez-Ramella
Luis F Jave-Suarez
Adriana Aguilar-Lemarroy
Rogelio Troyo-Sanroman
Alejandro Bravo-Cuellar
Vidal Delgado-Rizo
Trinidad Garcia-Iglesias
Georgina Hernandez-Flores
Susana del Toro-Arreola
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-16

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