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Identification of a high molecular weight kininogen fragment as a marker for early gastric cancer by serum proteome analysis

  • Original Article—Alimentary Tract
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Abstract

Background

Serum biomarkers currently available for gastric cancers are not sufficiently sensitive and specific.

Methods

We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS) to generate comparative peptide profiles of serum samples obtained from gastric cancer patients (n = 81) and age- and sex-matched healthy controls (n = 66).

Results

Because of initial screening and further validation, we found that the intensities of a 2209 m/z MS peak were increased in the preoperative sera obtained from gastric cancer patients, and we identified this peak, a 2209 Da peptide, as a high molecular weight (HMW) kininogen fragment. Receiver operating characteristic analyses showed that the area under the curve (AUC) for the 2209 Da peptide (AUC = 0.715) was greater than those for conventional tumor markers (carcinoembryonic antigen AUC = 0.593, carbohydrate antigen 19-9 AUC = 0.527) used for the detection of stage I gastric cancers. Inverse correlations were observed between the levels of intact HMW kininogen and the 2209 Da peptide, suggesting that the upregulation of some protease activities is responsible for the overproduction of a kininogen fragment in gastric cancer patients.

Conclusions

Serum levels of the 2209 Da peptide identified in this study have a greater diagnostic ability than those of conventional tumor markers used for the early detection of gastric cancer.

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References

  1. Goodman KJ, Cockburn M. The role of epidemiology in understanding the health effects of Helicobacter pylori. Epidemiology. 2001;12:266–71.

    Article  PubMed  CAS  Google Scholar 

  2. Wobbes T, Thomas CM, Segers MF, Nagengast FM. Evaluation of seven tumor markers (CA 50, CA 19–9, CA 19–9 TruQuant, CA 72–4, CA 195, carcinoembryonic antigen, and tissue polypeptide antigen) in the pretreatment sera of patients with gastric carcinoma. Cancer. 1992;69:2036–41.

    Article  PubMed  CAS  Google Scholar 

  3. Fernandez-Fernandez L, Tejero E, Tieso A, Rabadan L, Munoz M, Santos I. Receiver operating characteristic (ROC) curve analysis of the tumor markers CEA, CA 19–9 and CA 72–4 in gastric cancer. Int Surg. 1996;81:400–2.

    PubMed  CAS  Google Scholar 

  4. Kochi M, Fujii M, Kanamori N, Kaiga T, Kawakami T, Aizaki K, et al. Evaluation of serum CEA and CA19–9 levels as prognostic factors in patients with gastric cancer. Gastric Cancer. 2000;3:177–86.

    Article  PubMed  Google Scholar 

  5. Wulfkuhle JD, Liotta LA, Petricoin EF. Proteomic applications for the early detection of cancer. Nat Rev Cancer. 2003;3:267–75.

    Article  PubMed  CAS  Google Scholar 

  6. Petricoin EF, Belluco C, Araujo RP, Liotta LA. The blood peptidome: a higher dimension of information content for cancer biomarker discovery. Nat Rev Cancer. 2006;6:961–7.

    Article  PubMed  CAS  Google Scholar 

  7. Hortin GL. The MALDI-TOF mass spectrometric view of the plasma proteome and peptidome. Clin Chem. 2006;52:1223–37.

    Article  PubMed  CAS  Google Scholar 

  8. Davies HA. The ProteinChip System from Ciphergen: a new technique for rapid, micro-scale protein biology. J Mol Med. 2000;78:B29.

    PubMed  CAS  Google Scholar 

  9. Kanmura S, Uto H, Sato Y, Kumagai K, Sasaki F, Moriuchi A, et al. The complement component C3a fragment is a potential biomarker for hepatitis C virus-related hepatocellular carcinoma. J Gastroenterol. 2010;45:459–67.

    Article  PubMed  CAS  Google Scholar 

  10. Nomura F, Tomonaga T, Sogawa K, Ohashi T, Nezu M, Sunaga M, et al. Identification of novel and downregulated biomarkers for alcoholism by surface enhanced laser desorption/ionization-mass spectrometry. Proteomics. 2004;4:1187–94.

    Article  PubMed  CAS  Google Scholar 

  11. Takano S, Yoshitomi H, Togawa A, Sogawa K, Shida T, Kimura F, et al. Apolipoprotein C-1 maintains cell survival by preventing from apoptosis in pancreatic cancer cells. Oncogene. 2008;27:2810–22.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang X, Leung SM, Morris CR, Shigenaga MK. Evaluation of a novel, integrated approach using functionalized magnetic beads, bench-top MALDI-TOF-MS with prestructured sample supports, and pattern recognition software for profiling potential biomarkers in human plasma. J Biomol Tech. 2004;15:167–75.

    PubMed  Google Scholar 

  13. Sogawa K, Satoh M, Kodera Y, Tomonaga T, Iyo M, Nomura F. A search for novel markers of alcohol abuse using magnetic beads and MALDI-TOF/TOF mass spectrometry. Proteomics Clin Appl. 2009;3:821–8.

    Article  PubMed  CAS  Google Scholar 

  14. Kulasingam V, Diamandis EP. Strategies for discovering novel cancer biomarkers through utilization of emerging technologies. Nat Clin Pract Oncol. 2008;5:588–99.

    Article  PubMed  CAS  Google Scholar 

  15. Umemura H, Nezu M, Kodera Y, Satoh M, Kimura A, Tomonaga T, et al. Effects of the time intervals between venipuncture and serum preparation for serum peptidome analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Clin Chim Acta. 2009;406:179–80.

    Article  PubMed  CAS  Google Scholar 

  16. Umemura H, Kodera Y, Nomura F. Effects of humidity on the dried-droplet sample preparation for MALDI-TOF MS peptide profiling. Clin Chim Acta. 2010;411:2109–11.

    Article  PubMed  CAS  Google Scholar 

  17. Ebert MP, Meuer J, Wiemer JC, Schulz HU, Reymond MA, Traugott U, et al. Identification of gastric cancer patients by serum protein profiling. J Proteome Res. 2004;3:1261–6.

    Article  PubMed  CAS  Google Scholar 

  18. Ebert MP, Lamer S, Meuer J, Malfertheiner P, Reymond M, Buschmann T, et al. Identification of the thrombin light chain a as the single best mass for differentiation of gastric cancer patients from individuals with dyspepsia by proteome analysis. J Proteome Res. 2005;4:586–90.

    Article  PubMed  CAS  Google Scholar 

  19. Ebert MP, Niemeyer D, Deininger SO, Wex T, Knippig C, Hoffmann J, et al. Identification and confirmation of increased fibrinopeptide a serum protein levels in gastric cancer sera by magnet bead assisted MALDI-TOF mass spectrometry. J Proteome Res. 2006;5:2152–8.

    Article  PubMed  CAS  Google Scholar 

  20. Su Y, Shen J, Qian H, Ma H, Ji J, Ma H, et al. Diagnosis of gastric cancer using decision tree classification of mass spectral data. Cancer Sci. 2007;98:37–43.

    Article  PubMed  CAS  Google Scholar 

  21. Inoue M, Tsugane S. Epidemiology of gastric cancer in Japan. Postgrad Med J. 2005;81:419–24.

    Article  PubMed  CAS  Google Scholar 

  22. Hatakeyama M. Helicobacter pylori and gastric carcinogenesis. J Gastroenterol. 2009;44:239–48.

    Article  PubMed  CAS  Google Scholar 

  23. Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H, et al. Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer. 2004;109:138–43.

    Article  PubMed  CAS  Google Scholar 

  24. Mukoubayashi C, Yanaoka K, Ohata H, Arii K, Tamai H, Oka M, et al. Serum pepsinogen and gastric cancer screening. Intern Med. 2007;46:261–6.

    Article  PubMed  Google Scholar 

  25. Villanueva J, Shaffer DR, Philip J, Chaparro CA, Erdjument-Bromage H, Olshen AB, et al. Differential exoprotease activities confer tumor-specific serum peptidome patterns. J Clin Invest. 2006;116:271–84.

    Article  PubMed  CAS  Google Scholar 

  26. Schaub NP, Jones KJ, Nyalwidhe JO, Cazares LH, Karbassi ID, Semmes OJ, et al. Serum proteomic biomarker discovery reflective of stage and obesity in breast cancer patients. J Am Coll Surg. 2009;208:970–8.

    Article  PubMed  Google Scholar 

  27. Roeise O, Sivertsen S, Ruud TE, Bouma BN, Stadaas JO, Aasen AO. Studies on components of the contact phase system in patients with advanced gastrointestinal cancer. Cancer. 1990;65:1355–9.

    Article  PubMed  CAS  Google Scholar 

  28. Colman RW, Jameson BA, Lin Y, Johnson D, Mousa SA. Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood. 2000;95:543–50.

    PubMed  CAS  Google Scholar 

  29. Zhang JC, Donate F, Qi X, Ziats NP, Juarez JC, Mazar AP, et al. The antiangiogenic activity of cleaved high molecular weight kininogen is mediated through binding to endothelial cell tropomyosin. Proc Natl Acad Sci USA. 2002;99:12224–9.

    Article  PubMed  CAS  Google Scholar 

  30. Asakura S, Hurley RW, Skorstengaard K, Ohkubo I, Mosher DF. Inhibition of cell adhesion by high molecular weight kininogen. J Cell Biol. 1992;116:465–76.

    Article  PubMed  CAS  Google Scholar 

  31. Kawasaki M, Maeda T, Hanasawa K, Ohkubo I, Tani T. Effect of His-Gly-Lys motif derived from domain 5 of high molecular weight kininogen on suppression of cancer metastasis both in vitro and in vivo. J Biol Chem. 2003;278:49301–7.

    Article  PubMed  CAS  Google Scholar 

  32. Liu Y, Pixley R, Fusaro M, Godoy G, Kim E, Bromberg ME, et al. Cleaved high-molecular-weight kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway. Oncogene. 2009;28:2756–65.

    Article  PubMed  CAS  Google Scholar 

  33. Fortin T, Salvador A, Charrier JP, Lenz C, Bettsworth F, Lacoux X, et al. Multiple reaction monitoring cubed for protein quantification at the low nanogram/milliliter level in nondepleted human serum. Anal Chem. 2009;81:9343–52.

    Article  PubMed  CAS  Google Scholar 

  34. Baechle D, Sparbier K, Dihazi H, Blaschke S, Mueller GA, et al. Towards stable diagnostic setups in clinical proteomics: absolute quantitation of peptide biomarkers using MALDI-TOF-MS. Proteomics Clin Appl. 2007;1:1280–4.

    Article  CAS  Google Scholar 

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Acknowledgments

We thank Masumi Ishibashi and Satomi Tojo Nishimura for their technical assistance. We also thank members of the clinical laboratory staff of Kimitsu Chuo Hospital and PortSquare Kashiwado Clinic for collecting serum samples. This work was supported in part by Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (Nos. 19390154 and 20790411).

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Authors and Affiliations

  1. Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan

    Hiroshi Umemura, Kazuyuki Sogawa, Mamoru Satoh, Motoi Nishimura, Kazuyuki Matsushita & Fumio Nomura

  2. Department of Surgery, Kimitsu Chuo Hospital, Kisarazu, Japan

    Akira Togawa

  3. Information Center for Medical Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Kaoru Mogushi & Hiroshi Tanaka

  4. Kashiwado Memorial Foundation, PortSquare Kashiwado Clinic, Chiba, Japan

    Hirotaka Takizawa

  5. Laboratory of Biomolecular Dynamics, Department of Physics, School of Science, Kitasato University, Sagamihara, Japan

    Yoshio Kodera

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  1. Hiroshi Umemura
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Correspondence to Fumio Nomura.

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Umemura, H., Togawa, A., Sogawa, K. et al. Identification of a high molecular weight kininogen fragment as a marker for early gastric cancer by serum proteome analysis. J Gastroenterol 46, 577–585 (2011). https://doi.org/10.1007/s00535-010-0369-3

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  • DOI: https://doi.org/10.1007/s00535-010-0369-3

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