Skip to main content

Advertisement

SpringerLink
Log in

Differentially expressed serum host proteins in hepatitis B and C viral infections

  • Original Article
  • Published:
VirusDisease Aims and scope Submit manuscript

Abstract

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection often lead to hepatocellular carcinoma (HCC), which is mostly detected in advanced stage. Hence, its early detection is of paramount importance using a biomarker having sensitivity and specificity both. The present study highlights differentially expressed host proteins in response to HBV/HCV infection at different stages. Comparative proteomic study was done by two-dimensional gel electrophoresis followed by mass spectrometry. Sera from each of chronically infected, liver cirrhosis and HCC in HBV or HCV infection along with controls were selected. Analysis of functional association between differentially expressed proteins with viral hepatitis was extensively carried out. Forty-three differentially expressed spots (≥ 1.5 fold; P < 0.05) on two-dimensional gel electrophoresis were corresponded to 28 proteins by mass spectrometry in variable liver diseases. Haptoglobin protein levels were decreased upon disease progression to HCC due to HBV infection. The other proteins expressed differentially are ceruloplasmin, serum paraoxonase 1, retinol binding protein and leucine rich alpha 2 proteins in plasma maybe associated to HBV HCC. Whereas, upregulation of C4a/C4b showed it as a reliable marker in patients with end stage liver disease related to HCV infection. ApolipoproteinA1 levels in liver diseases in both HBV and HCV infection corresponding to healthy controls may be a common marker for early diagnosis and disease monitoring. Protein interaction studies by extensive pathway analysis using bioinformatics tools such as EnrichNet application and STRING revealed significant associations with specific infections.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Acharya SK. Epidemiology of hepatocellular carcinoma in India. J Clin Exp Hepatol. 2014;4:S27–33.

    Article  Google Scholar 

  2. Andersen C, Murray K, Ragonesi N, Doerr A, Cintron-Rivera L, Dupree L. HDL-associated proteins and LDL differentially modulate chronic myelogenous leukemia cell viability. J Clin Lipidol. 2017;11:793–4.

    Article  Google Scholar 

  3. Awan FM, Naz A, Obaid A, Ali A, Ahmad J, Anjum S, et al. Identification of circulating biomarker candidates for hepatocellular carcinoma (HCC): an integrated prioritization approach. PLoS ONE (Internet). 2015;10. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586137/.

  4. Borlak J, Singh P, Gazzana G. Proteome mapping of epidermal growth factor induced hepatocellular carcinomas identifies novel cell metabolism targets and mitogen activated protein kinase signalling events. BMC Genom (Internet). 2015;16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357185/.

  5. Chaerkady R, Thuluvath PJ, Kim M-S, Nalli A, Vivekanandan P, Simmers J, et al. 18O labeling for a quantitative proteomic analysis of glycoproteins in hepatocellular carcinoma. Clin Proteomics. 2008;4:137–55.

    Article  CAS  Google Scholar 

  6. Corona. Differential proteomic analysis of hepatocellular carcinoma. Int J Oncol (Internet). 2009 [cited 2017 Dec 28];36. http://www.spandidos-publications.com/ijo/36/1/93.

  7. Derbyshire E, Hungin A, Nickerson C. UEG Week 2015 poster presentations. United Eur Gastroenterol J. 2015;2015(3):146–687.

    Google Scholar 

  8. Digre A, Nan J, Frank M, Li J-P. Heparin interactions with apoA1 and SAA in inflammation-associated HDL. Biochem Biophys Res Commun. 2016;474:309–14.

    Article  CAS  Google Scholar 

  9. Dillon ST, Bhasin MK, Feng X, Koh DW, Daoud SS. Quantitative proteomic analysis in HCV-induced HCC reveals sets of proteins with potential significance for racial disparity. J Transl Med. 2013;11:239.

    Article  Google Scholar 

  10. Ehsani Ardakani MJ, Safaei A, Arefi Oskouie A, Haghparast H, Haghazali M, Mohaghegh Shalmani H, et al. Evaluation of liver cirrhosis and hepatocellular carcinoma using protein–protein interaction networks. Gastroenterol Hepatol Bed Bench. 2016;9:S14–22.

    PubMed  PubMed Central  Google Scholar 

  11. European association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.

    Article  Google Scholar 

  12. Fang M, Zhao Y-P, Zhou F-G, Lu L-G, Qi P, Wang H, et al. N-glycan based models improve diagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma. Int J Cancer. 2010;127:148–59.

    Article  CAS  Google Scholar 

  13. Ferrín G, Ranchal I, Llamoza C, Rodríguez-Perálvarez ML, Romero-Ruiz A, Aguilar-Melero P, et al. Identification of candidate biomarkers for hepatocellular carcinoma in plasma of HCV-infected cirrhotic patients by 2-D DIGE. Liver Int. 2014;34:438–46.

    Article  Google Scholar 

  14. Ferrín G, Rodríguez-Perálvarez M, Aguilar-Melero P, Ranchal I, Llamoza C, Linares CI, et al. Plasma protein biomarkers of hepatocellular carcinoma in HCV-infected alcoholic patients with cirrhosis. PLoS ONE. 2015;10:e0118527.

    Article  Google Scholar 

  15. Gonçalves LDR, Campanhon IB, Domingues RR, Paes Leme AF, Soares da Silva MR. Comparative salivary proteome of hepatitis B- and C-infected patients. PLoS ONE (Internet). 2014;9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244100/.

  16. Xi D, Zhao J, Liu J, Xiong H, He W, Hu J, et al. The impact of serum amyloid P-component on gene expression in RAW264.7 mouse macrophages. BioMed Res Int (Internet). 2016;2016. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864538/.

  17. Huang C, Wang Y, Liu S, Ding G, Liu W, Zhou J, et al. Quantitative proteomic analysis identified paraoxonase 1 as a novel serum biomarker for microvascular invasion in hepatocellular carcinoma. J Proteome Res. 2013;12:1838–46.

    Article  CAS  Google Scholar 

  18. Katrinli S, Ozdil K, Sahin A, Ozturk O, Kir G, Baykal AT, et al. Proteomic profiling of HBV infected liver biopsies with different fibrotic stages. Proteome Sci (Internet). 2016 [cited 2017 Oct 5];15. http://proteomesci.biomedcentral.com/articles/10.1186/s12953-017-0114-4.

  19. Kawakami T, Hoshida Y, Kanai F, Tanaka Y, Tateishi K, Ikenoue T, et al. Proteomic analysis of sera from hepatocellular carcinoma patients after radiofrequency ablation treatment. Proteomics. 2005;5:4287–95.

    Article  CAS  Google Scholar 

  20. Kimhofer T, Fye H, Taylor-Robinson S, Thursz M, Holmes E. Proteomic and metabonomic biomarkers for hepatocellular carcinoma: a comprehensive review. Br J Cancer. 2015;112:1141–56.

    Article  CAS  Google Scholar 

  21. Li L, Gu X, Fang M, Ji J, Yi C, Gao C. The diagnostic value of serum fucosylated fetuin A in hepatitis B virus-related liver diseases. Clin Chem Lab Med CCLM [Internet]. 2016 [cited 2017 Dec 28];54. https://www.degruyter.com/view/j/cclm.2016.54.issue-4/cclm-2015-0307/cclm-2015-0307.xml.

  22. Ma X-L, Gao X-H, Gong Z-J, Wu J, Tian L, Zhang C-Y, et al. Apolipoprotein A1: a novel serum biomarker for predicting the prognosis of hepatocellular carcinoma after curative resection. Oncotarget. 2016;7:70654.

    PubMed  PubMed Central  Google Scholar 

  23. Mondal G, Saroha A, Bose PP, Chatterjee BP. Altered glycosylation, expression of serum haptoglobin and alpha-1-antitrypsin in chronic hepatitis C, hepatitis C induced liver cirrhosis and hepatocellular carcinoma patients. Glycoconj J. 2016;33:209–18.

    Article  CAS  Google Scholar 

  24. Ni X-C, Yi Y, Fu Y-P, He H-W, Cai X-Y, Wang J-X, et al. Serum amyloid A is a novel prognostic biomarker in hepatocellular carcinoma. Asian Pac J Cancer Prev APJCP. 2014;15:10713–8.

    Article  Google Scholar 

  25. Pousset D, Piller V, Bureaud N, Piller F. High levels of ceruloplasmin in the serum of transgenic mice developing hepatocellular carcinoma. Eur J Biochem. 2001;268:1491–9.

    Article  CAS  Google Scholar 

  26. Précourt L-P, Amre D, Denis M-C, Lavoie J-C, Delvin E, Seidman E, et al. The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis. 2011;214:20–36.

    Article  Google Scholar 

  27. Sarvari J, Mojtahedi Z, Taghavi SAR, Kuramitsu Y, Shamsi Shahrabadi M, Ghaderi A, et al. Differentially expressed proteins in chronic active hepatitis, cirrhosis, and HCC related to HCV infection in comparison with HBV infection: a proteomics study. Hepat Mon (Internet). 2013;13. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776151/.

  28. Sarvari J, Mojtahedi Z, Kuramitsu Y, Fattahi MR, Ghaderi A, Nakamura K, et al. Comparative proteomics of sera from HCC patients with different origins. Hepat Mon (Internet). 2014;14. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909643/.

  29. Shamsi Shahrabadi M. Differential expression of haptoglobin isoforms in chronic active hepatitis, cirrhosis and HCC related to HBV infection. Oncol Lett (Internet). 2011 [cited 2017 Dec 28]; http://www.spandidos-publications.com/10.3892/ol.2011.321.

  30. Shen Y, Li M, Ye X, Bi Q. Association of apolipoprotein E with the progression of hepatitis B virus-related liver disease. Int J Clin Exp Pathol. 2015;8:14749–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Sugimoto K, Shiraki K, Takei Y, Ito M, Nobori T, Suzuki H, et al. Serum protein isoform profiles indicate the progression of hepatitis C virus-induced liver diseases. Int J Mol Med. 2013;31:943–50.

    Article  CAS  Google Scholar 

  32. Sun W, Xing B, Sun Y, Du X, Lu M, Hao C, et al. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics. 2007;6:1798–808.

    Article  CAS  Google Scholar 

  33. Syed GH, Amako Y, Siddiqui A. Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab TEM. 2010;21:33–40.

    Article  CAS  Google Scholar 

  34. Targett-Adams P, Boulant S, Douglas MW, McLauchlan J. Lipid metabolism and HCV infection. Viruses. 2010;2:1195–217.

    Article  CAS  Google Scholar 

  35. Tsai T-H, Song E, Zhu R, Di Poto C, Wang M, Luo Y, et al. LC-MS/MS-based serum proteomics for identification of candidate biomarkers for hepatocellular carcinoma. Proteomics. 2015;15:2369–81.

    Article  CAS  Google Scholar 

  36. Voelkl J, Pakladok T, Lin Y, Viereck R, Lebedeva A, Kukuk D, et al. Up-regulation of hepatic alpha-2-HS-glycoprotein transcription by testosterone via androgen receptor activation. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2014;33:1911–20.

    Article  CAS  Google Scholar 

  37. Wang X, Zhang A, Sun H. Power of metabolomics in diagnosis and biomarker discovery of hepatocellular carcinoma. Hepatol Baltim Md. 2013;57:2072–7.

    Article  CAS  Google Scholar 

  38. Wang X, Abraham S, McKenzie JAG, Jeffs N, Swire M, Tripathi VB, et al. LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling. Nature. 2013;499:306–11.

    Article  CAS  Google Scholar 

  39. Wang C-H, Li M, Liu L-L, Zhou R-Y, Fu J, Zhang CZ, et al. LRG1 expression indicates unfavorable clinical outcome in hepatocellular carcinoma. Oncotarget. 2015;6:42118.

    PubMed  PubMed Central  Google Scholar 

  40. Wang Y, Hao J, Liu X, Wang H, Zeng X, Yang J, et al. The mechanism of apoliprotein A1 down-regulated by Hepatitis B virus. Lipids Health Dis. 2016;15:64.

    Article  Google Scholar 

  41. Wu W, Li J, Liu Y, Zhang C, Meng X, Zhou Z. Comparative proteomic studies of serum from patients with hepatocellular carcinoma. J Invest Surg. 2012;25:37–42.

    Article  CAS  Google Scholar 

  42. Zhang S, Jiang K, Zhang Q, Guo K, Liu Y. Serum fucosylated paraoxonase 1 as a potential glycobiomarker for clinical diagnosis of early hepatocellular carcinoma using ELISA Index. Glycoconj J. 2015;32:119–25.

    Article  Google Scholar 

  43. Zhang C, Peng L, Zhang Y, Liu Z, Li W, Chen S, et al. The identification of key genes and pathways in hepatocellular carcinoma by bioinformatics analysis of high-throughput data. Med Oncol Northwood Lond Engl (Internet). 2017;34. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400790/.

  44. Zhu RX, Seto W-K, Lai C-L, Yuen M-F. Epidemiology of hepatocellular carcinoma in the Asia–Pacific region. Gut Liver. 2016;10:332–9.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Lady Tata Memorial Trust, Mumbai for providing Research Scholarship to Ms. Kruti Dalal and Haffkine institute for utilization of proteomic setup. The study was supported by intramural funding of Indian Council of Medical Research (ICMR).

Author information

Author notes

  1. Akash Shukla & Aruna Shankarkumar

    Present address: Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital, Sion, Mumbai, 400 022, India

Authors and Affiliations

  1. Transfusion Transmitted Diseases Department, National Institute of Immunohaematology, 13th floor, New Multi-storeyed Bldg, KEM Hospital Campus, Parel, Mumbai, 400 012, India

    Kruti Dalal, Priyanka Khorate, Bhavik Dalal & Aruna Shankarkumar

  2. School of Chemical Sciences, UM-DAE Centre for Excellence in Basic Sciences, Mumbai University Campus, Vidyanagari, Kalina, Santacruz (East), Mumbai, 400098, India

    Rahul Chavan & Avinash Kale

  3. Department of Gastroenterology, Seth G S Medical College and K E M Hospital, Acharya Donde Marg, Parel, Mumbai, 400 012, India

    Shobna Bhatia & Akash Shukla

Authors
  1. Kruti Dalal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priyanka Khorate
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bhavik Dalal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rahul Chavan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shobna Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Avinash Kale
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akash Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aruna Shankarkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Avinash Kale or Aruna Shankarkumar.

Ethics declarations

Conflict of interest

Authors have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dalal, K., Khorate, P., Dalal, B. et al. Differentially expressed serum host proteins in hepatitis B and C viral infections. VirusDis. 29, 468–477 (2018). https://doi.org/10.1007/s13337-018-0484-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13337-018-0484-y

Keywords

Search

Navigation