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Molecular Medicine

, Volume 17, Issue 1–2, pp 70–78 | Cite as

Identification of Treatment Efficacy-Related Host Factors in Chronic Hepatitis C by ProteinChip Serum Analysis

  • Naoki Fujita
  • Mamoru Nakanishi
  • Jun Mukai
  • Yuuji Naito
  • Takafumi Ichida
  • Masahiko Kaito
  • Toshikazu Yoshikawa
  • Yoshiyuki Takei
Research Article

Abstract

Recent development of proteomic array technology, including protein profiling coupling ProteinChip array with surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF/MS), provides a potentially powerful tool for discovery of new biomarkers by comparison of its profiles according to patient phenotypes. We used this approach to identify the host factors associated with treatment response in patients with chronic hepatitis C (CHC) receiving a 48-wk course of pegylated interferon (PEG-IFN) alpha 2b plus ribavirin (RBV). Protein profiles of pretreatment serum samples from 32 patients with genotype 1b and high viral load were conducted by SELDI-TOF/MS by using the three different ProteinChip arrays (CM10, Q10, IMAC30). Proteins showed significantly different peak intensities between sustained virological responders (SVRs), and non-SVRs were identified by chromatography, SDS-PAGE, TOF/MS and tandem mass spectrometry (MS/MS) assay. Eleven peak intensities were significantly different between SVRs and non-SVRs. The three SVR-increased peaks could be identified as two apolipoprotein (Apo) fragments and albumin and, among the eight non-SVR-increased proteins, four peaks identified as two iron-related and two fibrogenesis-related protein fragments, respectively. Multivariate analysis showed that the serum ferritin and three peak intensity values (Apo A1, hemopexin and transferrin) were independent variables associated with SVRs, and the area under the receiver operating characteristic (ROC) curves for SVR prediction by using the Apo A1/hemopexin and hemopexin/transferrin were 0.964 and 0.936. In conclusion, pretreatment serum protein profiling by SELDI-TOF/MS is variable for identification of response-related host factors, which are useful for treatment efficacy prediction in CHC receiving PEG-IFN plus RBV. Our data also may help us understand the mechanism for treatment resistance and development of more effective antiviral therapy targeted toward the modulation of lipogenesis or iron homeostasis in CHC patients.

Notes

Acknowledgments

We thank K. Mihara and Y. Yanohara for excellent technical suggestions and assistance.

References

  1. 1.
    Poynard T, Yuen MF, Ratziu V, Lai CL. (2003) Viral hepatitis C. Lancet. 362:2095–100.CrossRefGoogle Scholar
  2. 2.
    Seeff LB. (2002) Natural history of chronic hepatitis C. Hepatology. 36 Suppl 1:S35–46.PubMedGoogle Scholar
  3. 3.
    Manns MP, et al. (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 358:958–65.CrossRefGoogle Scholar
  4. 4.
    Fried MW, et al. (2002) Pegintereron alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347:975–82.CrossRefGoogle Scholar
  5. 5.
    Berg T, et al. (2006) Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology. 130:1086–97.CrossRefGoogle Scholar
  6. 6.
    Paweletz CP, et al. (2000) Rapid protein display profiling of cancer progression directly from human tissue using a protein biochip. Drug Dev. Res. 49:34–42.CrossRefGoogle Scholar
  7. 7.
    Issaq HJ, Veenstra TD, Conrads TP, Helshow D. (2002) The SELDI-TOF MS approach to proteomics: protein profiling and biomarker identification. Biochem. Biophys. Res. Commun. 292:587–92.CrossRefGoogle Scholar
  8. 8.
    Wiesner A. (2004) Detection of tumor markers with ProteinChip technology. Curr. Pharm. Biotechnol. 5:45–67.CrossRefGoogle Scholar
  9. 9.
    Xiao Z, et al. (2001) Quantification of serum prostate-specific membrane antigen by a novel protein biochip immunoassay discriminates benign from malignant prostate disease. Cancer Res. 15:6029–33.Google Scholar
  10. 10.
    Petricoin EF, et al. (2002) Use of proteomic patterns in serum to identify ovarian cancer. Lancet. 359:572–7.CrossRefGoogle Scholar
  11. 11.
    Paradis V, et al. (2005) Identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases. Hepatology. 41:40–7.CrossRefGoogle Scholar
  12. 12.
    Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 19:1513–20.CrossRefGoogle Scholar
  13. 13.
    Shevchenko A, Wilm M, Vorm O, Mann M. (1996) Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal. Chem. 68:850–8.CrossRefGoogle Scholar
  14. 14.
    Fujita N, et al. (2007) Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol. Med. 13:97–104.CrossRefGoogle Scholar
  15. 15.
    Smith A, Morgan WT. (1979) Haem transport to the liver by haemopexin: receptor-mediated uptake with recycling of the protein. Biochem. J. 182:47–54.CrossRefGoogle Scholar
  16. 16.
    Tolosano E, Altruda F. (2002) Hemopexin: structure, function, and regulation. DNA Cell Biol. 21:297–306.CrossRefGoogle Scholar
  17. 17.
    National Institutes of Health. (2002) National Institutes of Health. Consensus Development Statement: management of hepatitis. Hepatology. 36 Suppl 1:S3–20.Google Scholar
  18. 18.
    Neumann AU, et al. (1998) Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-a therapy. Science. 282:103–6.CrossRefGoogle Scholar
  19. 19.
    Enomoto N, et al. (1996) Mutations in the non-structural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N. Engl. J. Med. 334:77–81.CrossRefGoogle Scholar
  20. 20.
    Akuta N, et al. (2007) Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J. Hepatol. 46:403–10.CrossRefGoogle Scholar
  21. 21.
    Gao B, Hong F, Radaeva S. (2004) Host factors and failure of interferon-alpha treatment in hepatitis C virus. Hepatology. 39:880–90.CrossRefGoogle Scholar
  22. 22.
    Fujita N, et al. (2007) Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J. Gastroenterol. Hepatol. 22:1886–93.CrossRefGoogle Scholar
  23. 23.
    Tanaka Y, et al. (2009) Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat. Genet. 41:1105–9.CrossRefGoogle Scholar
  24. 24.
    Suppiah V, et al. (2009) IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat. Genet. 41:1100–4.CrossRefGoogle Scholar
  25. 25.
    Popescu CI, Dubuisson J. (2009) Role of lipid metabolism in hepatitis C virus assembly and entry. Biol. Cell. 28;102:63–74.Google Scholar
  26. 26.
    Voisset C, et al. (2006) High-density lipoproteins reduce the neutralizing effect of hepatitis C virus (HCV)-infected patient antibodies by promoting HCV entry. J. Gen. Virol. 87:2577–81.CrossRefGoogle Scholar
  27. 27.
    Voisset C, et al. (2005) High density lipoproteins facilitate hepatitis C virus entry through the scavenger receptor class B type I. J. Biol. Chem. 280:7793–9.CrossRefGoogle Scholar
  28. 28.
    Dreux M, et al. (2007) The exchangeable apolipo-protein ApoC-I promotes membrane fusion of hepatitis C virus. J. Biol. Chem. 282:32357–69.CrossRefGoogle Scholar
  29. 29.
    Pumeechockchai W, et al. (2002) Hepatitis C virus particles of different density in the blood of chronically infected immunocompetent and immunodeficient patients: implications for virus clearance by antibody. J. Med. Virol. 68:335–42.CrossRefGoogle Scholar
  30. 30.
    Di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR. (1992) Measurements of iron status in patients with chronic hepatitis. Gastroenterolgy. 102:2108–13.CrossRefGoogle Scholar
  31. 31.
    Haque S, Chandra B, Gerber MA, Lok ASF. (1996) Iron overload in patients with chronic hepatitis C: a clinicopathologic study. Hum. Pathol. 27:1277–81.CrossRefGoogle Scholar
  32. 32.
    Van Thiel DH, et al. (1994) Response to interferon a therapy is influenced by the iron content of the liver. J. Hepatol. 20:410–5.CrossRefGoogle Scholar
  33. 33.
    Olynyk JK, et al. (1995) Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology. 108:1104–9.CrossRefGoogle Scholar
  34. 34.
    Fontana RJ, et al. (2000) Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology. 31:730–6.CrossRefGoogle Scholar
  35. 35.
    Fargion S, et al. (2002) Iron reduction and sustained response to interferon-a therapy in patients with chronic hepatitis C: results of Italian multicenter randomized study. Am. J. Gastroenterol. 97:1204–10.PubMedGoogle Scholar
  36. 36.
    Guyader D, et al. (1999) A pilot study of iron depletion as adjuvant therapy in chronic hepatitis C patients not responding to interferon. Am. J. Gas-troenterol. 94:1696–8.CrossRefGoogle Scholar
  37. 37.
    Di Bisceglie AM, et al. (2000) Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon: a multicenter, prospective, randomized, controlled trial. Hepatology. 32:135–8.CrossRefGoogle Scholar
  38. 38.
    Gutteridge JM, Smith A. (1988) Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation. Biochem. J. 256:861–5.CrossRefGoogle Scholar
  39. 39.
    Tolosano E, et al. (1999) Defective recovery and severe renal damage after acute hemolysis in hemopexin-deficient mice. Blood. 94:3906–14.PubMedGoogle Scholar
  40. 40.
    Tolosano E, et al. (2002) Enhanced splenomegaly and severe liver inflammation in hepatoglobin/hemopexin double-null mice after acute hemolysis. Blood. 100:4201–8.CrossRefGoogle Scholar
  41. 41.
    Sumida Y, et al. (2000) Serum thioredoxin levels as an indicator of oxidative stress in patients with hepatitis C virus infection. J. Hepatol. 33:616–22.CrossRefGoogle Scholar
  42. 42.
    Horiike S, et al. (2005) Accumulation of 8-nitroguanine in the liver of patients with chronic hepatitis C. J. Hepatol. 43:403–10.CrossRefGoogle Scholar
  43. 43.
    Fujita N, et al. (2007) Hepatic oxidative DNA damage correlates with iron overload in chronic hepatitis C. Free Radic. Biol. Med. 42:353–62.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Naoki Fujita
    • 1
  • Mamoru Nakanishi
    • 2
  • Jun Mukai
    • 2
  • Yuuji Naito
    • 3
  • Takafumi Ichida
    • 4
  • Masahiko Kaito
    • 5
  • Toshikazu Yoshikawa
    • 3
  • Yoshiyuki Takei
    • 1
  1. 1.Department of Gastroenterology and Hepatology, Division of Clinical Medicine and Biomedical Science, Institute of Medical SciencesMie University Graduate School of MedicineTsu, MieJapan
  2. 2.Biomarker ScienceOsakaJapan
  3. 3.Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  4. 4.Department of Gastroenterology and HepatologyJuntendo University School of Medicine, Shizuoka HospitalShizuokaJapan
  5. 5.Mie Gastroenterological ClinicMieJapan

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