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BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: A systematic expression analysis

Authors: Alexander Hamm, Juergen Veeck, Nuran Bektas, Peter J Wild, Arndt Hartmann, Uwe Heindrichs, Glen Kristiansen, Tamra Werbowetski-Ogilvie, Rolando Del Maestro, Ruth Knuechel, Edgar Dahl

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

The inter-alpha-trypsin inhibitors (ITI) are a family of plasma protease inhibitors, assembled from a light chain – bikunin, encoded by AMBP – and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), contributing to extracellular matrix stability by covalent linkage to hyaluronan. So far, ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis.

Methods

We systematically investigated differential gene expression of the ITIH gene family, as well as AMBP and the interacting partner TNFAIP6 in 13 different human tumor entities (of breast, endometrium, ovary, cervix, stomach, small intestine, colon, rectum, lung, thyroid, prostate, kidney, and pancreas) using cDNA dot blot analysis (Cancer Profiling Array, CPA), semiquantitative RT-PCR and immunohistochemistry.

Results

We found that ITIH genes are clearly downregulated in multiple human solid tumors, including breast, colon and lung cancer. Thus, ITIH genes may represent a family of putative tumor suppressor genes that should be analyzed in greater detail in the future. For an initial detailed analysis we chose ITIH2 expression in human breast cancer. Loss of ITIH2 expression in 70% of cases (n = 50, CPA) could be confirmed by real-time PCR in an additional set of breast cancers (n = 36). Next we studied ITIH2 expression on the protein level by analyzing a comprehensive tissue micro array including 185 invasive breast cancer specimens. We found a strong correlation (p < 0.001) between ITIH2 expression and estrogen receptor (ER) expression indicating that ER may be involved in the regulation of this ECM molecule.

Conclusion

Altogether, this is the first systematic analysis on the differential expression of ITIH genes in human cancer, showing frequent downregulation that may be associated with initiation and/or progression of these malignancies.
Appendix
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Literature
1.
Bost F, Diarra-Mehrpour M, Martin JP: Inter-alpha-trypsin inhibitor proteoglycan family--a group of proteins binding and stabilizing the extracellular matrix. Eur J Biochem. 1998, 252 (3): 339-346. 10.1046/j.1432-1327.1998.2520339.x.CrossRefPubMed
2.
Zhuo L, Hascall VC, Kimata K: Inter-alpha-trypsin inhibitor, a covalent protein-glycosaminoglycan-protein complex. J Biol Chem. 2004, 279 (37): 38079-38082. 10.1074/jbc.R300039200.CrossRefPubMed
3.
Salier JP, Rouet P, Raguenez G, Daveau M: The inter-alpha-inhibitor family: from structure to regulation. Biochem J. 1996, 315 ( Pt 1): 1-9.CrossRef
4.
Gebhard W, Schreitmuller T, Hochstrasser K, Wachter E: Two out of the three kinds of subunits of inter-alpha-trypsin inhibitor are structurally related. Eur J Biochem. 1989, 181 (3): 571-576. 10.1111/j.1432-1033.1989.tb14762.x.CrossRefPubMed
5.
Diarra-Mehrpour M, Bourguignon J, Sesboue R, Mattei MG, Passage E, Salier JP, Martin JP: Human plasma inter-alpha-trypsin inhibitor is encoded by four genes on three chromosomes. Eur J Biochem. 1989, 179 (1): 147-154. 10.1111/j.1432-1033.1989.tb14532.x.CrossRefPubMed
6.
Diarra-Mehrpour M, Sarafan N, Bourguignon J, Bonnet F, Bost F, Martin JP: Human inter-alpha-trypsin inhibitor heavy chain H3 gene. Genomic organization, promoter analysis, and gene linkage. J Biol Chem. 1998, 273 (41): 26809-26819. 10.1074/jbc.273.41.26809.CrossRefPubMed
7.
Himmelfarb M, Klopocki E, Grube S, Staub E, Klaman I, Hinzmann B, Kristiansen G, Rosenthal A, Durst M, Dahl E: ITIH5, a novel member of the inter-alpha-trypsin inhibitor heavy chain family is downregulated in breast cancer. Cancer Lett. 2004, 204 (1): 69-77. 10.1016/j.canlet.2003.09.011.CrossRefPubMed
8.
Heron A, Bourguignon J, Calle A, Borghi H, Sesboue R, Diarra-Mehrpour M, Martin JP: Post-translational processing of the inter-alpha-trypsin inhibitor in the human hepatoma HepG2 cell line. Biochem J. 1994, 302 ( Pt 2): 573-580.CrossRef
9.
Zhuo L, Salustri A, Kimata K: A physiological function of serum proteoglycan bikunin: the chondroitin sulfate moiety plays a central role. Glycoconj J. 2002, 19 (4-5): 241-247. 10.1023/A:1025331929373.CrossRefPubMed
10.
Huang L, Yoneda M, Kimata K: A serum-derived hyaluronan-associated protein (SHAP) is the heavy chain of the inter alpha-trypsin inhibitor. J Biol Chem. 1993, 268 (35): 26725-26730.PubMed
11.
Jessen TE, Odum L: Role of tumour necrosis factor stimulated gene 6 (TSG-6) in the coupling of inter-alpha-trypsin inhibitor to hyaluronan in human follicular fluid. Reproduction. 2003, 125 (1): 27-31. 10.1530/rep.0.1250027.CrossRefPubMed
12.
Wisniewski HG, Hua JC, Poppers DM, Naime D, Vilcek J, Cronstein BN: TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo. J Immunol. 1996, 156 (4): 1609-1615.PubMed
13.
Rugg MS, Willis AC, Mukhopadhyay D, Hascall VC, Fries E, Fulop C, Milner CM, Day AJ: Characterization of complexes formed between TSG-6 and inter-alpha-inhibitor that act as intermediates in the covalent transfer of heavy chains onto hyaluronan. J Biol Chem. 2005, 280 (27): 25674-25686. 10.1074/jbc.M501332200.CrossRefPubMed
14.
Sanggaard KW, Karring H, Valnickova Z, Thogersen IB, Enghild JJ: The TSG-6 and I alpha I interaction promotes a transesterification cleaving the protein-glycosaminoglycan-protein (PGP) cross-link. J Biol Chem. 2005, 280 (12): 11936-11942. 10.1074/jbc.M409016200.CrossRefPubMed
15.
Mukhopadhyay D, Asari A, Rugg MS, Day AJ, Fulop C: Specificity of the tumor necrosis factor-induced protein 6-mediated heavy chain transfer from inter-alpha-trypsin inhibitor to hyaluronan: implications for the assembly of the cumulus extracellular matrix. J Biol Chem. 2004, 279 (12): 11119-11128. 10.1074/jbc.M313471200.CrossRefPubMed
16.
Jessen TE, Odum L: TSG-6 and calcium ions are essential for the coupling of inter-alpha-trypsin inhibitor to hyaluronan in human synovial fluid. Osteoarthritis Cartilage. 2004, 12 (2): 142-148. 10.1016/j.joca.2003.10.004.CrossRefPubMed
17.
Milner CM, Day AJ: TSG-6: a multifunctional protein associated with inflammation. J Cell Sci. 2003, 116 (Pt 10): 1863-1873. 10.1242/jcs.00407.CrossRefPubMed
18.
Hess KA, Chen L, Larsen WJ: Inter-alpha-inhibitor binding to hyaluronan in the cumulus extracellular matrix is required for optimal ovulation and development of mouse oocytes. Biol Reprod. 1999, 61 (2): 436-443. 10.1095/biolreprod61.2.436.CrossRefPubMed
19.
Medetognon-Benissan J, Tardivel S, Hennequin C, Daudon M, Drueke T, Lacour B: Inhibitory effect of bikunin on calcium oxalate crystallization in vitro and urinary bikunin decrease in renal stone formers. Urol Res. 1999, 27 (1): 69-75. 10.1007/s002400050091.CrossRefPubMed
20.
21.
Ohnishi H, Kosuzume H, Ashida Y, Kato K, Honjo I: Effects of urinary trypsin inhibitor on pancreatic enzymes and experimental acute pancreatitis. Dig Dis Sci. 1984, 29 (1): 26-32. 10.1007/BF01296858.CrossRefPubMed
22.
Kikuchi H, Tanaka S, Matsuo O: Plasminogen activator in synovial fluid from patients with rheumatoid arthritis. J Rheumatol. 1987, 14 (3): 439-445.PubMed
23.
Pineiro M, Alava MA, Gonzalez-Ramon N, Osada J, Lasierra P, Larrad L, Pineiro A, Lampreave F: ITIH4 serum concentration increases during acute-phase processes in human patients and is up-regulated by interleukin-6 in hepatocarcinoma HepG2 cells. Biochem Biophys Res Commun. 1999, 263 (1): 224-229. 10.1006/bbrc.1999.1349.CrossRefPubMed
24.
de la Motte CA, Hascall VC, Drazba J, Bandyopadhyay SK, Strong SA: Mononuclear leukocytes bind to specific hyaluronan structures on colon mucosal smooth muscle cells treated with polyinosinic acid:polycytidylic acid: inter-alpha-trypsin inhibitor is crucial to structure and function. Am J Pathol. 2003, 163 (1): 121-133.CrossRefPubMedPubMedCentral
25.
Yang S, Lim YP, Zhou M, Salvemini P, Schwinn H, Josic D, Koo DJ, Chaudry IH, Wang P: Administration of human inter-alpha-inhibitors maintains hemodynamic stability and improves survival during sepsis. Crit Care Med. 2002, 30 (3): 617-622. 10.1097/00003246-200203000-00021.CrossRefPubMed
26.
Opal SM, Lim YP, Siryaporn E, Moldawer LL, Pribble JP, Palardy JE, Souza S: Longitudinal studies of inter-alpha inhibitor proteins in severely septic patients: a potential clinical marker and mediator of severe sepsis. Crit Care Med. 2007, 35 (2): 387-392. 10.1097/01.CCM.0000253810.08230.83.CrossRefPubMed
27.
Lim YP, Bendelja K, Opal SM, Siryaporn E, Hixson DC, Palardy JE: Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis. J Infect Dis. 2003, 188 (6): 919-926. 10.1086/377642.CrossRefPubMed
28.
Opal SM, Artenstein AW, Cristofaro PA, Jhung JW, Palardy JE, Parejo NA, Lim YP: Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication. Infect Immun. 2005, 73 (8): 5101-5105. 10.1128/IAI.73.8.5101-5105.2005.CrossRefPubMedPubMedCentral
29.
Fries E, Blom AM: Bikunin--not just a plasma proteinase inhibitor. Int J Biochem Cell Biol. 2000, 32 (2): 125-137. 10.1016/S1357-2725(99)00125-9.CrossRefPubMed
30.
Kobayashi H, Sugino D, She MY, Ohi H, Hirashima Y, Shinohara H, Fujie M, Shibata K, Terao T: A bifunctional hybrid molecule of the amino-terminal fragment of urokinase and domain II of bikunin efficiently inhibits tumor cell invasion and metastasis. Eur J Biochem. 1998, 253 (3): 817-826. 10.1046/j.1432-1327.1998.2530817.x.CrossRefPubMed
31.
Kobayashi H, Suzuki M, Kanayama N, Terao T: Genetic down-regulation of phosphoinositide 3-kinase by bikunin correlates with suppression of invasion and metastasis in human ovarian cancer HRA cells. J Biol Chem. 2004, 279 (8): 6371-6379. 10.1074/jbc.M305749200.CrossRefPubMed
32.
Ossowski L: Plasminogen activator dependent pathways in the dissemination of human tumor cells in the chick embryo. Cell. 1988, 52 (3): 321-328. 10.1016/S0092-8674(88)80025-4.CrossRefPubMed
33.
Rakic JM, Maillard C, Jost M, Bajou K, Masson V, Devy L, Lambert V, Foidart JM, Noel A: Role of plasminogen activator-plasmin system in tumor angiogenesis. Cell Mol Life Sci. 2003, 60 (3): 463-473. 10.1007/s000180300039.CrossRefPubMed
34.
Kobayashi H, Gotoh J, Hirashima Y, Fujie M, Sugino D, Terao T: Inhibitory effect of a conjugate between human urokinase and urinary trypsin inhibitor on tumor cell invasion in vitro. J Biol Chem. 1995, 270 (14): 8361-8366. 10.1074/jbc.270.14.8361.CrossRefPubMed
35.
Kobayashi H, Shinohara H, Fujie M, Gotoh J, Itoh M, Takeuchi K, Terao T: Inhibition of metastasis of Lewis lung carcinoma by urinary trypsin inhibitor in experimental and spontaneous metastasis models. Int J Cancer. 1995, 63 (3): 455-462. 10.1002/ijc.2910630326.CrossRefPubMed
36.
Paris S, Sesboue R, Delpech B, Chauzy C, Thiberville L, Martin JP, Frebourg T, Diarra-Mehrpour M: Inhibition of tumor growth and metastatic spreading by overexpression of inter-alpha-trypsin inhibitor family chains. Int J Cancer. 2002, 97 (5): 615-620. 10.1002/ijc.10120.CrossRefPubMed
37.
Veeck J, Chorovicer M, Naami A, Breuer E, Zafrakas M, Bektas N, Durst M, Kristiansen G, Wild P, Hartmann A, Knuchel R, Dahl E: The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation. Oncogene. 2007, 10.1038/sj.onc.1210669
38.
Kasper G, Weiser AA, Rump A, Sparbier K, Dahl E, Hartmann A, Wild P, Schwidetzky U, Castanos-Velez E, Lehmann K: Expression levels of the putative zinc transporter LIV-1 are associated with a better outcome of breast cancer patients. Int J Cancer. 2005, 117 (6): 961-973. 10.1002/ijc.21235.CrossRefPubMed
39.
Dahl E, Kristiansen G, Gottlob K, Klaman I, Ebner E, Hinzmann B, Hermann K, Pilarsky C, Durst M, Klinkhammer-Schalke M, Blaszyk H, Knuechel R, Hartmann A, Rosenthal A, Wild PJ: Molecular profiling of laser-microdissected matched tumor and normal breast tissue identifies karyopherin alpha2 as a potential novel prognostic marker in breast cancer. Clin Cancer Res. 2006, 12 (13): 3950-3960. 10.1158/1078-0432.CCR-05-2090.CrossRefPubMed
40.
41.
Sers C, Tchernitsa OI, Zuber J, Diatchenko L, Zhumabayeva B, Desai S, Htun S, Hyder K, Wiechen K, Agoulnik A, Scharff KM, Siebert PD, Schafer R: Gene expression profiling in RAS oncogene-transformed cell lines and in solid tumors using subtractive suppression hybridization and cDNA arrays. Adv Enzyme Regul. 2002, 42: 63-82. 10.1016/S0065-2571(01)00024-3.CrossRefPubMed
42.
Zafrakas M, Petschke B, Donner A, Fritzsche F, Kristiansen G, Knuchel R, Dahl E: Expression analysis of mammaglobin A (SCGB2A2) and lipophilin B (SCGB1D2) in more than 300 human tumors and matching normal tissues reveals their co-expression in gynecologic malignancies. BMC Cancer. 2006, 6: 88-10.1186/1471-2407-6-88.CrossRefPubMedPubMedCentral
43.
Zhumabayeva B, Chang C, McKinley J, Diatchenko L, Siebert PD: Generation of full-length cDNA libraries enriched for differentially expressed genes for functional genomics. Biotechniques. 2001, 30 (3): 512-6, 518-20.PubMed
44.
Zafrakas M, Chorovicer M, Klaman I, Kristiansen G, Wild PJ, Heindrichs U, Knuchel R, Dahl E: Systematic characterisation of GABRP expression in sporadic breast cancer and normal breast tissue. Int J Cancer. 2006, 118 (6): 1453-1459. 10.1002/ijc.21517.CrossRefPubMed
45.
Fink L, Seeger W, Ermert L, Hanze J, Stahl U, Grimminger F, Kummer W, Bohle RM: Real-time quantitative RT-PCR after laser-assisted cell picking. Nat Med. 1998, 4 (11): 1329-1333. 10.1038/3327.CrossRefPubMed
46.
Werbowetski-Ogilvie TE, Agar NY, Waldkircher de Oliveira RM, Faury D, Antel JP, Jabado N, Del Maestro RF: Isolation of a natural inhibitor of human malignant glial cell invasion: inter alpha-trypsin inhibitor heavy chain 2. Cancer Res. 2006, 66 (3): 1464-1472. 10.1158/0008-5472.CAN-05-1913.CrossRefPubMed
47.
Remmele W, Stegner HE: [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. Pathologe. 1987, 8 (3): 138-140.PubMed
48.
49.
Mizushima S, Nii A, Kato K, Uemura A: Gene expression of the two heavy chains and one light chain forming the inter-alpha-trypsin-inhibitor in human tissues. Biol Pharm Bull. 1998, 21 (2): 167-169.CrossRefPubMed
50.
Dahl E, Sadr-Nabavi A, Klopocki E, Betz B, Grube S, Kreutzfeld R, Himmelfarb M, An HX, Gelling S, Klaman I, Hinzmann B, Kristiansen G, Grutzmann R, Kuner R, Petschke B, Rhiem K, Wiechen K, Sers C, Wiestler O, Schneider A, Hofler H, Nahrig J, Dietel M, Schafer R, Rosenthal A, Schmutzler R, Durst M, Meindl A, Niederacher D: Systematic identification and molecular characterization of genes differentially expressed in breast and ovarian cancer. J Pathol. 2005, 205 (1): 21-28. 10.1002/path.1687.CrossRefPubMed
51.
Rochefort H, Platet N, Hayashido Y, Derocq D, Lucas A, Cunat S, Garcia M: Estrogen receptor mediated inhibition of cancer cell invasion and motility: an overview. J Steroid Biochem Mol Biol. 1998, 65 (1-6): 163-168. 10.1016/S0960-0760(98)00010-7.CrossRefPubMed
52.
Cox DA, Helvering LM: Extracellular matrix integrity: a possible mechanism for differential clinical effects among selective estrogen receptor modulators and estrogens?. Mol Cell Endocrinol. 2006, 247 (1-2): 53-59. 10.1016/j.mce.2005.12.020.CrossRefPubMed
53.
54.
Klein-Hitpass L, Schorpp M, Wagner U, Ryffel GU: An estrogen-responsive element derived from the 5' flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells. Cell. 1986, 46 (7): 1053-1061. 10.1016/0092-8674(86)90705-1.CrossRefPubMed
55.
Stender JD, Frasor J, Komm B, Chang KC, Kraus WL, Katzenellenbogen BS: Estrogen-regulated gene networks in human breast cancer cells: involvement of E2F1 in the regulation of cell proliferation. Mol Endocrinol. 2007, 21 (9): 2112-2123. 10.1210/me.2006-0474.CrossRefPubMed
56.
Yousef GM, Diamandis EP: The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev. 2001, 22 (2): 184-204. 10.1210/er.22.2.184.PubMed
57.
Matrisian LM, Sledge GW, Mohla S: Extracellular proteolysis and cancer: meeting summary and future directions. Cancer Res. 2003, 63 (19): 6105-6109.PubMed
58.
Kobayashi H, Suzuki M, Hirashima Y, Terao T: The protease inhibitor bikunin, a novel anti-metastatic agent. Biol Chem. 2003, 384 (5): 749-754. 10.1515/BC.2003.083.CrossRefPubMed
59.
West DC, Kumar S: Hyaluronan and angiogenesis. Ciba Found Symp. 1989, 143: 187-201; discussion 201-7, 281-5.PubMed
60.
Kovacs G, Erlandsson R, Boldog F, Ingvarsson S, Muller-Brechlin R, Klein G, Sumegi J: Consistent chromosome 3p deletion and loss of heterozygosity in renal cell carcinoma. Proc Natl Acad Sci U S A. 1988, 85 (5): 1571-1575. 10.1073/pnas.85.5.1571.CrossRefPubMedPubMedCentral
61.
Brauch H, Tory K, Kotler F, Gazdar AF, Pettengill OS, Johnson B, Graziano S, Winton T, Buys CH, Sorenson GD, et al: Molecular mapping of deletion sites in the short arm of chromosome 3 in human lung cancer. Genes Chromosomes Cancer. 1990, 1 (3): 240-246. 10.1002/gcc.2870010309.CrossRefPubMed
62.
Maestro R, Gasparotto D, Vukosavljevic T, Barzan L, Sulfaro S, Boiocchi M: Three discrete regions of deletion at 3p in head and neck cancers. Cancer Res. 1993, 53 (23): 5775-5779.PubMed
63.
Kato M, Seki N, Sugano S, Hashimoto K, Masuho Y, Muramatsu M, Kaibuchi K, Nakafuku M: Identification of sonic hedgehog-responsive genes using cDNA microarray. Biochem Biophys Res Commun. 2001, 289 (2): 472-478. 10.1006/bbrc.2001.5976.CrossRefPubMed
64.
Villavicencio EH, Walterhouse DO, Iannaccone PM: The sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet. 2000, 67 (5): 1047-1054. 10.1086/321187.CrossRefPubMedPubMedCentral
65.
Sobin LH WC: TNM classification of malignant tumors. 1997, New York , Wiley-Liss, 227-5th
Metadata
Title
Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: A systematic expression analysis
Authors
Alexander Hamm
Juergen Veeck
Nuran Bektas
Peter J Wild
Arndt Hartmann
Uwe Heindrichs
Glen Kristiansen
Tamra Werbowetski-Ogilvie
Rolando Del Maestro
Ruth Knuechel
Edgar Dahl
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-25

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