Skip to main content

Advertisement

SpringerLink
Log in

Serum Markers of Hepatocellular Carcinoma

  • Review
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

The hepatocellular carcinoma is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains intricate.

Methods

A literature search identified potential markers for hepatocellular carcinoma. These markers were analysed and justification was provided for these factors’ inclusion to (or exclusion from) the markers of hepatocellular carcinoma (HCC). A search of the literature was made using cancer literature and the PubMed database for the following keywords: “markers and HCC,” “Lens culinaris agglutinin reactive AFP (AFP-L3) and HCC,” “Des-γ-carboxy prothrombin (DCP) and HCC,” “Glypican-3 and HCC,” “Chromogranin A and HCC,” “Transforming growth factor β1(TGF) and HCC,” “α-l-fucosidase (AFU) and HCC,” “Golgi protein-73 (GP73) and HCC,” “Hepatocyte growth factor (HGF) and HCC,” “Nervous growth factor (NGF) and HCC.”

Conclusions

Despite the large number of studies devoted to the immunohistochemistry of HCC, at the present time, the absolute positive and negative markers for HCC are still lacking, and even those characterized by very high sensitivity and specificity do not have an universal diagnostic usefulness. Given the poor response to current therapies, a better understanding of the molecular pathways active in this disease could potentially provide new targets for therapy. However, AFP shows a low sensitivity, therefore other biomarkers have been developed to make an early diagnosis and improve patients’ prognosis.

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

Similar content being viewed by others

References

  1. Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9:191–211.

    Article  PubMed  Google Scholar 

  2. Buck J, Miller RH, Kew MC, Purcell R. Hepatitis C virus RNA in southern African blacks with hepatocellular carcinoma. Proc Natl Acad Sci USA. 1993;90:1848–1851.

    Article  Google Scholar 

  3. Malaguarnera M, Di Fazio I, Laurino A, Pistone G, Restuccia S, Trovato BA. Decrease of interferon gamma serum levels in patients with chronic hepatitis C. Biomed Pharmacother. 1997;51:391–396.

    Article  PubMed  CAS  Google Scholar 

  4. Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L. Molecular mechanisms involved in NAFLD progression. J Mol Med. 2009;87:679–695.

    Article  PubMed  CAS  Google Scholar 

  5. Malaguarnera L, Madeddu R, Palio E, Arena N, Malaguarnera M. Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. J Hepatol. 2005;42:585–591.

    Article  PubMed  CAS  Google Scholar 

  6. Malaguarnera L, Rosa MD, Zambito AM, dell’Ombra N, Marco RD, Malaguarnera M. Potential role of chitotriosidase gene in non-alcoholic fatty liver disease evolution. Am J Gastroenterol. 2006;101:2060–2069.

    Article  PubMed  CAS  Google Scholar 

  7. Malaguarnera L, Di Rosa M, Zambito AM, dell’Ombra N, Nicoletti F, Malaguarnera M. Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut. 2006;55:1313–1320.

    Article  PubMed  CAS  Google Scholar 

  8. Malaguarnera M, Trovato G, Restuccia S, et al. Treatment of nonresectable hepatocellular carcinoma: review of the literature and meta-analysis. Adv Therapy. 1994;11:303–319.

    CAS  Google Scholar 

  9. Terentiev AA, Moldogazieva NT. Structural and functional mapping of alpha-fetoprotein. Biochemistry (Mosc). 2006;71:120–132.

    Article  CAS  Google Scholar 

  10. Mizejewski GJ. Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy. Expert Rev Anticancer Ther. 2002;2:709–735.

    Article  PubMed  CAS  Google Scholar 

  11. Saffroy R, Pham P, Reffas M, Takka M, Lemoine A, Debuire B. New perspectives and strategy research biomarkers for hepatocellular carcinoma. Clin Chem Lab Med. 2007;45:1169–1179.

    Article  PubMed  CAS  Google Scholar 

  12. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European association for the study of the liver. J Hepatol. 2001;35:421–430.

    Article  PubMed  CAS  Google Scholar 

  13. Han SJ, Yoo S, Choi SH, Hwang EH. Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors. Pediatr Surg Int. 1997;12:599–602.

    Article  PubMed  CAS  Google Scholar 

  14. Oka H, Saito A, Ito K, et al. Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein. J Gastroenterol Hepatol. 2001;16:1378–1383.

    Article  PubMed  CAS  Google Scholar 

  15. Sato Y, Nakata K, Kato Y, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med. 1993;328:1802–1806.

    Article  PubMed  CAS  Google Scholar 

  16. Miyaaki H, Nakashima O, Kurogi M, Eguchi K, Kojiro M. Lens culinaris agglutinin-reactive alpha-fetoprotein and protein induced by vitamin K absence II are potential indicators of a poor prognosis: a histopathological study of surgically resected hepatocellular carcinoma. J Gastroenterol. 2007;42:962–968.

    Article  PubMed  CAS  Google Scholar 

  17. Aoyagi Y, Suzuki Y, Isemura M, et al. The fucosylation index of alpha-fetoprotein and its usefulness in the early diagnosis of hepatocellular carcinoma. Cancer. 1988;61:769–774.

    Article  PubMed  CAS  Google Scholar 

  18. Taketa K. Alpha-fetoprotein: reevaluation in hepatology. Hepatology. 1990;12:1420–1432.

    Article  PubMed  CAS  Google Scholar 

  19. Sassa T, Kumada T, Nakano S, Uematsu T. Clinical utility of simultaneous measurement of serum high-sensitivity des-gamma-carboxy prothrombin and Lens culinaris agglutinin A-reactive alpha-fetoprotein in patients with small hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 1999;11:1387–1392.

    Article  PubMed  CAS  Google Scholar 

  20. Yamashita F, Tanaka M, Satomura S, Tanikawa K. Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas. Gastroenterology. 1996;111:996–1001.

    Article  PubMed  CAS  Google Scholar 

  21. Kuromatsu R, Tanaka M, Tanikawa K. Serum alpha-fetoprotein and lens culinaris agglutinin-reactive fraction of alpha-fetoprotein in patients with hepatocellular carcinoma. Liver. 1993;13:177–182.

    PubMed  CAS  Google Scholar 

  22. Hayashi K, Kumada T, Nakano S, et al. Usefulness of measurement of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein as a marker of prognosis and recurrence of small hepatocellular carcinoma. Am J Gastroenterol. 1999;94:3028–3033.

    PubMed  CAS  Google Scholar 

  23. Yamashita F, Tanaka M, Satomura S, Tanikawa K. Monitoring of lectin-reactive alpha-fetoproteins in patients with hepatocellular carcinoma treated using transcatheter arterial embolization. Eur J Gastroenterol Hepatol. 1995;7:627–633.

    PubMed  CAS  Google Scholar 

  24. Yamashiki N, Seki T, Wakabayashi M, et al. Usefulness of Lens culinaris agglutinin A-reactive fraction of alpha-fetoprotein (AFP-L3) as a marker of distant metastasis from hepatocellular carcinoma. Oncol Rep. 1999;6:1229–1232.

    PubMed  CAS  Google Scholar 

  25. Yamashita F, Tanaka M, Satomura S, Tanikawa K. Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinoma. Gastroenterology. 1996;111:996–1001.

    Article  PubMed  CAS  Google Scholar 

  26. Ono M, Ohat H, Ohhira M, et al. Measurement of immunoreactive prothrombin precursor and vitamin-K-dependent gamma-carboxylation in human hepatocellular tissues: decreased carboxylation of prothrombin precursor as a cause of des-gamma-carboxyprothrombin synthesis. Tumour Biol. 1990;11(6):319–326.

    Article  PubMed  CAS  Google Scholar 

  27. Grizzi F, Franceschini B, Hamrick C, Frezza EE, Cobos E, Chiriva-Internati M. Usefulness of cancer-testis antigens as biomarkers for the diagnosis and treatment of hepatocellular carcinoma. J Transl Med. 2007;5:3.

    Article  PubMed  CAS  Google Scholar 

  28. Nakagawa T, Seki T, Shiro T, et al. Clinicopathologic significance of protein induced by vitamin k absence or antagonistic II and alpha-fetoprotein in hepatocellular carcinoma. Int J Oncol. 1999;14:281–286.

    PubMed  CAS  Google Scholar 

  29. Fujiyama S, Tanaka M, Maeda S, et al. Tumormarkers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma. Oncology. 2002;62:57–63.

    Article  PubMed  CAS  Google Scholar 

  30. Suehiro T, Sugimachi K, Matsumata T, Itasaka H, Taketomi A, Maeda T. Protein induced by vitamin K absence or antagonist II (PIVKA-II) as a prognostic marker in hepatocellular carcinoma: comparison with a-fetoprotein. Cancer. 1994;73:2464–2471.

    Article  PubMed  CAS  Google Scholar 

  31. Toyosaka A, Okamoto E, Mitsunobu M, Oriyama T, Nakao N, Miura K. Intrahepatic metastases in hepatocellular carcinoma: evidence for spread via the portal vein as an efferent vessel. Am J Gastroenterol. 1996;91:1610–1615.

    PubMed  CAS  Google Scholar 

  32. Mitsunobu M, Toyosaka A, Oriyama T, Okamoto E, Nakao N. Intrahepatic metastases in hepatocellular carcinoma: the role of the portal vein as an efferent vessel. Clin Exp Metastasis. 1996;14:520–529.

    Article  PubMed  CAS  Google Scholar 

  33. Fujikawa T, Shiraha H, Ueda N, et al. Des-gamma-carboxyl prothrombin-promoted vascular endothelial cell proliferation and migration. J Biol Chem. 2007;282:8741–8748.

    Article  PubMed  CAS  Google Scholar 

  34. Suzuki M, Shiraha H, Fujikawa T, et al. Des-gamma-carboxyl prothrombin is a potential autologous growth factor for hepatocellular carcinoma. J Biol Chem. 2005;280:6409–6415.

    Article  PubMed  CAS  Google Scholar 

  35. Bernfield M, Götte M, Park PW, et al. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem. 1999;68:729–777.

    Article  PubMed  CAS  Google Scholar 

  36. Song HH, Shi W, Filmus J. OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2. J Biol Chem. 1997;272:7574–7577.

    Article  PubMed  CAS  Google Scholar 

  37. Reich-Slotky R, Bonneh-Barkay D, Shaoul E, Bluma B, Svahn CM, Ron D. Differential effect of cell-associated heparan sulfates on the binding of keratinocyte growth factor (KGF) and acidic fibroblast growth factor to the KGF receptor. J Biol Chem. 1994;269:32279–32285.

    PubMed  CAS  Google Scholar 

  38. Pilia G, Hughes-Benzie RM, MacKenzie A, et al. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet. 1996;12:241.

    Article  PubMed  CAS  Google Scholar 

  39. Hsue HC, Cheng W, Pl Lai. Cloning and expression of a developmentally regulated transcripts MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. Cancer Res. 1997;57:5179–5184.

    Google Scholar 

  40. Zhu ZW, Friess H, Wang L, et al. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut. 2001;48:558–564.

    Article  PubMed  CAS  Google Scholar 

  41. Hagihara K, Watanabe K, Yamaguchi J. Glypican-4 is an FGF2-binding heparan sulfate proteoglycans expressed in neural precursor cells. Dev Dyn. 2000;219:353–367.

    Article  PubMed  CAS  Google Scholar 

  42. Gengrinovitch S, Berman B, David G, Witte L, Neufeld G, Ron D. Glypican-1 is a VEGF165 binding proteoglycan that acts as an extracellular chaperone for VEGF 165. J Biol Chem. 1999;274:10816–10822.

    Article  PubMed  CAS  Google Scholar 

  43. Knapp LT, Klann E. Superoxide- induced stimulation of protein kinase C via thiol modification and modulation of zinc content. J Biol Chem. 2000;275:24136–24145.

    Article  PubMed  CAS  Google Scholar 

  44. Suzuki A, Hirata M, Kamimura K, et al. aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Curr Biol. 2004;14:1425–1435.

    Article  PubMed  CAS  Google Scholar 

  45. Eder AM, Sui X, Rosen DG, et al. Atypical PKCiota contributes to poor prognosis through loss of apical–basal polarity and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:12519–12524.

    Article  PubMed  CAS  Google Scholar 

  46. Regala RP, Weems C, Jamieson L, Copland JA, Thompson EA, Fields AP. Atypical protein kinase C iota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem. 2005;280:31109–31115.

    Article  PubMed  CAS  Google Scholar 

  47. Ikeguchi M, Makino M, Kaibara N. Clinical significance of E-cadherin-catenin complex expression in metastatic foci of colorectal carcinoma. J Surg Oncol. 2001;77:201–207.

    Article  PubMed  CAS  Google Scholar 

  48. Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg. 2000;87:992–1005.

    Article  PubMed  CAS  Google Scholar 

  49. Shiozaki H, Oka H, Inoue M, Tamura S, Monden M. E-cadherin mediated adhesion system in cancer cells. Cancer. 1996;77:1605–1613.

    PubMed  CAS  Google Scholar 

  50. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspots in the p53 gene in human hepatocellular carcinomas. Nature. 1991;350:427–428.

    Article  PubMed  CAS  Google Scholar 

  51. Liu S, Ma L, Huang W, et al. Decreased expression of the human carbonyl reductase 2 Gene HCR2 in hepatocellular carcinoma. Cell Mol Biol Lett. 2006;11:230–241.

    Article  PubMed  CAS  Google Scholar 

  52. Haidon GH, Hayes PC. Screening for hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 1996;8:856–860.

    Google Scholar 

  53. Deugnier Y, David V, Bressot P, et al. Serum α-L-fucosidase: a new marker for the diagnosis of primary hepatic carcinoma? Hepatology. 1984;4:889–892.

    Article  PubMed  CAS  Google Scholar 

  54. Leray G, Deugnier Y, Jouanolle AM, et al. Biochemical aspects of α-L-fucosidase in hepatocellular carcinoma. Hepatology. 1989;9:249–252.

    Article  PubMed  CAS  Google Scholar 

  55. Giardina MG, Matarazzo M, Varriale A, Morante R, Napoli A, Martino R. Serum alpha-L-fucosidase. A useful marker in the diagnosis of hepatocellular carcinoma. Cancer. 1992;70:1044–1048.

    Article  PubMed  CAS  Google Scholar 

  56. Ishizuka H, Nakayama T, Matsuoka S, et al. Prediction of the development of hepato-cellular-carcinoma in patients with liver cirrhosis by the serial determinations of serum alpha-L-fucosidase activity. Intern Med. 1999;38:927–931.

    Article  PubMed  CAS  Google Scholar 

  57. Mattern J, Koomagi R, Volm M. Association of vascular endothelial growth factor expression with intratumoural microvessel density and tumor cell proliferation in human epidermoid lung carcinoma. Br J Cancer. 1996;73:931–934.

    PubMed  CAS  Google Scholar 

  58. Brown LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinoma of gastrointestinal tract. Cancer Res. 1993;53:4727–4735.

    PubMed  CAS  Google Scholar 

  59. Toi M, Hoshina S, Takayanagi T, et al. Association of vascular endothelial growth factor expression with tumour angiogenesis and early relapse in primary breast cancer. Jpn J Cancer Res. 1994;85:1045–1049.

    PubMed  CAS  Google Scholar 

  60. Suzuki K, Hayashi M, Miyamaoto Y, et al. Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res. 1996;56:3004–3009.

    PubMed  CAS  Google Scholar 

  61. Mise M, Arii S, Higashituji H, Furutani M, et al. Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology. 1996;23:455–464.

    Article  PubMed  CAS  Google Scholar 

  62. Mohle R, Green D, Moore MAS, et al. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA. 1997;94:663–668.

    Article  PubMed  CAS  Google Scholar 

  63. Li XM, Tang ZY, Qin LX, Zhou J, Sun HC. Serum vascular endothelial growth factor is a predictor of invasion and metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res. 1999;18:511–517.

    PubMed  CAS  Google Scholar 

  64. Suminami Y, Kishi F, Sekiguchi K, Kato H. Squamous cell carcinoma antigen is a new member of the serine protease inhibitors. Biochem Biophys Res Commun. 1991;181:51–58.

    Article  PubMed  CAS  Google Scholar 

  65. Kato H, Suehiro Y, Morioka H, et al. Heterogeneous distribution of acidic TA-4 in cervical squamous cell carcinoma: immunohistochemical demonstration with monoclonal antibodies. Jpn J Cancer Res. 1987;78:1246–1250.

    PubMed  CAS  Google Scholar 

  66. Giannelli G, Marinosci F, Sgarra C, Lupo L, Dentico P, Antonaci S. Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma. Int J Cancer. 2005;10(116):579–583.

    Article  CAS  Google Scholar 

  67. Uemura Y, Pak SC, Luke C, Cataltepe S, Tsu C, Schick C, Kamachi Y, Pomeroy SL, Perlmutter DH, Silverman GA. Circulating serpin tumor markers SCCA1 and SCCA2 are not actively secreted but reside in the cytosol of squamous carcinoma cells. Int J Cancer. 2000;89:368–377.

    Article  PubMed  CAS  Google Scholar 

  68. Deftos LJ. Chromogranin A: its role in endocrine function and as an endocrine and neuroendocrine tumor marker. Endocr Rev. 1991;12:181–187.

    Article  PubMed  CAS  Google Scholar 

  69. Leone N, Pellicano R, Brunello F, Rizzetto M, Ponzetto A. Elevated serum chromogranin A in patients with hepatocellular carcinoma. Clin Exp Med. 2002;2:119–123.

    Article  PubMed  CAS  Google Scholar 

  70. Ranno S, Motta M, Rampello E, Risino C, Bennati E, Malaguarnera M. The chromogranin-A(CgA) in prostate cancer. Arch Gerontol Geriatr. 2006;43:117–126.

    Article  PubMed  CAS  Google Scholar 

  71. Malaguarnera M, Cristaldi E, Cammalleri L, et al. Elevated chromogranin A (CgA) serum levels in the patients with advanced pancreatic cancer. Arch Gerontol Geriatr. 2009;48:213–217.

    Article  PubMed  CAS  Google Scholar 

  72. Spadaro A, Ajello A, Morace C, et al. Serum chromogranin-A in hepatocellular carcinoma: diagnostic utility and limits. World J Gastroenterol. 2005;11:1987–1990.

    PubMed  Google Scholar 

  73. Malaguarnera M, Vacante M, Fichera R, Cappellani A, Cristaldi E, Motta M. Chromogranin A (CgA) serum level as a marker of progression in hepatocellular carcinoma (HCC) of elderly patients. Arch Gerontol Geriatr. 2009;PMID 19766330 (in press).

    Google Scholar 

  74. Wilander E, Lundqvist M, Oberg K. Gastrointestinal carcinoid tumours. Histogenetic, histochemical, immunohistochemical, clinical and therapeutic aspects. Prog Histochem Cytochem. 1989;19:1–88.

    PubMed  CAS  Google Scholar 

  75. Hsiao RJ, Parmer RJ, Takiyyuddin MA, O’Connor DT. Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma. Medicine. 1991;70:33–45.

    Article  PubMed  CAS  Google Scholar 

  76. Malaguarnera L, Pignatelli S, Simporè J, Malaguarnera M, Musumeci S. Plasma levels of interleukin-12 (IL-12), interleukin-18 (IL-18) and transforming growth factor beta (TGF-beta) in Plasmodium falciparum malaria. Eur Cytokine Netw. 2002;13:425–430.

    PubMed  CAS  Google Scholar 

  77. Bedossa P, Peltier E, Terries B, Franco D, Poynard T. Transforming growth factor -β1 (TGF-β1) and TGF-β1 receptors in normal, cirrhotic and neoplastic human livers. Hepatology. 1995;21:760–766.

    PubMed  CAS  Google Scholar 

  78. Ito N, Kawata S, Tamura S, et al. Expression of transforming growth factor β1 mRNA in human hepatocellular carcinoma. Jpn J Cancer Res. 1990;81:1202–1205.

    PubMed  CAS  Google Scholar 

  79. Grizzi F, Franceschini B, Hamrick C, et al. Usefulness of cancer-testis antigens as biomarkers for the diagnosis and treatment of hepatocellular carcinoma. J Transl Med. 2007;5:3.

    Article  PubMed  CAS  Google Scholar 

  80. Mann CD, Neal CP, Garcea G, et al. Prognostic molecular markers in hepatocellular carcinoma: a systematic review. Eur J Cancer. 2007;43:979–992.

    Article  PubMed  CAS  Google Scholar 

  81. Ko TC, Tu W, Sakai T, et al. TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression. Oncogene. 1998;16:3445–3454.

    Article  PubMed  CAS  Google Scholar 

  82. Izzo JG, Papadimitrakopoulou VA, Li XQ, et al. Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification. Oncogene. 1998;17:2313–2322.

    Article  PubMed  CAS  Google Scholar 

  83. Seewaldt VL, Kim JH, Parker MB, Dietze EC, Vasan KV, Caldwell LE. Dysregulated expression of cyclin D1 in normal human mammary epithelial cells inhibits all-trans-retinoic acid-mediated G0/G1-phase arrest and differentiation in vitro. Exp Cell Res. 1999;249:70–85.

    Article  PubMed  CAS  Google Scholar 

  84. Kladney RD, Bulla GA, Guo L, et al. GP73, a novel Golgi-localized protein upregulated by viral infection. Gene. 2000;249:53–65.

    Article  PubMed  CAS  Google Scholar 

  85. Kladney RD, Cui X, Bulla GA, Brunt EM, Fimmel CJ. Expression of GP73, a resident membrane protein, in viral and non-viral liver disease. Hepatology. 2002;35:1431–1440.

    Article  PubMed  CAS  Google Scholar 

  86. Block TM, Comunale MA, Lowman M, et al. Use of targeted glycoproteins that correlated with liver cancer in woodchucks and humans. Proc Natl Acad Sci USA. 2005;102:779–784.

    Article  PubMed  CAS  Google Scholar 

  87. Comunale MA, Mattu TS, Lowman MA, et al. Comparative proteomic analysis of de-N-glycosylated serum from hepatitis B carriers reveals polypeptides that correlate with disease status. Proteomics. 2004;4:826–838.

    Article  PubMed  CAS  Google Scholar 

  88. Nakamura T. Hepatocyte growth factor as mitogen, motogen and morphogen and its roles in organ regeneration. Princess Takamatsu Symp. 1994;24:195–213.

    PubMed  CAS  Google Scholar 

  89. Birchmeier C, Gherardi E. Development roles of HGF/SF and its receptor c-Met tyrosine kinase. Trends Cell Biol. 1998;8:404–410.

    Article  PubMed  CAS  Google Scholar 

  90. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750.

    Article  PubMed  CAS  Google Scholar 

  91. Schneider PD. Preoperative assessment of liver function. Surg Clin North Am. 2004;84:355–373.

    Article  PubMed  Google Scholar 

  92. Breuhan K, Longerich T, Schirmacher P. Dysregulation of growth factor signalling in human hepatocellular carcinoma. Oncogene. 2006;25:3787–3800.

    Article  CAS  Google Scholar 

  93. Yamagamim H, Moriyana M, Matsumura H, et al. Serum concentrations of human hepatocyte growth factor is a useful indicator for predicting the occurrence of hepatocellular carcinomas in C-viral chronic liver diseases. Cancer. 2002;95:824–834.

    Article  PubMed  CAS  Google Scholar 

  94. Mizuguchi T, Katsuramachi T, Nobuoka T, et al. Serum hyaluronate level for predicting subclinical liver dysfunction after hepatectomy. World J Surg. 2004;28:971–976.

    Article  PubMed  Google Scholar 

  95. Wu FS, Zheng SS, Wu LJ, et al. Study on the prognostic value of hepatocyte growth factor and c-met for patients with hepatocellular carcinoma. Zhongua Wai Ke Za Zhi. 2006;44:603–608.

    Google Scholar 

  96. Vogelstein B, Kinzler KW. p53 function and dysfunction. Cell. 1992;70:523–526.

    Article  PubMed  CAS  Google Scholar 

  97. Gannon JV, Greaves R, Iggo R, Lane DP. Activating mutations in p53 produce a common conformational effect-a monoclonal antibody specific for the mutant form. EMBO J. 1990;9:1595–1602.

    PubMed  CAS  Google Scholar 

  98. Hsu H-C, Tseng H-J, Lai P-L, Lee P-H, Peng S-Y. Expression of p53 gene in 184 unifocal hepatocellular carcinoma: association with tumor growth and invasiveness. Cancer Res. 1993;53:4691–4694.

    PubMed  CAS  Google Scholar 

  99. Hayashi H, Sugio K, Matsumata T, Adachi E, Takenaka K, Sugimachi K. The clinical significance of p53 gene mutation in hepatocellular carcinomas from Japan. Hepatology. 1995;22:1702–1707.

    PubMed  CAS  Google Scholar 

  100. Crawford LV, Pim DC, Bulbrook RD. Detection of antibodies against cellular protein p53 in sera from patients with breast cancer. Int J Cancer. 1982;30:403–408.

    Article  PubMed  CAS  Google Scholar 

  101. Winter SF, Minna JD, Johnson BE, Takahashi T, Gazdar AF, Carbone DP. Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation. Cancer Res. 1992;52:4168–4174.

    PubMed  CAS  Google Scholar 

  102. Schlichtholz RLB, Bengoufa D, Zalcman BG, et al. Analysis of p53 antibodies in patients with various cancer define B-cell epitopes of human p53: distribution on primary structure and exposure on protein surface. Cancer Res. 1993;53:5872–5876.

    PubMed  Google Scholar 

  103. Bressac B, Kew M, Wands J, Ozturk M. Selective G to mutations of p53 gene in HCC from southern Africa. Nature. 1991;350:429–431.

    Article  PubMed  CAS  Google Scholar 

  104. Bothwell M. Functional interactions of neurotrophins and neurotrophin receptors. Annu Rev Neurosci. 1995;18:223–253.

    Article  PubMed  CAS  Google Scholar 

  105. Gregor LM, McCune BK, Graff JR, et al. Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression. Proc Natl Acad Sci USA. 1990;96:4540–4545.

    Article  Google Scholar 

  106. Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol. 2002;67:203–233.

    Article  PubMed  CAS  Google Scholar 

  107. Chapman BS. A region of the 75-kDa neurotrophin receptor homologous to the death domains of TNFR-I and Fas. FEBS Lett. 1995;374:216–220.

    Article  PubMed  CAS  Google Scholar 

  108. Tokusashi Y, Asai K, Tamakawa S, et al. Expression of NGF in hepatocellular carcinoma cells with its receptors in non-tumor cell components. Int J Cancer. 2005;114:39–45.

    Article  PubMed  CAS  Google Scholar 

  109. Trim N, Morgan S, Evans M, et al. Hepatic stellate cells express the low affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation. Am J Pathol. 2000;156:1235–1243.

    PubMed  CAS  Google Scholar 

  110. Cassiman D, Roskams TJ. Beauty is in the eye of the beholder: emerging concepts and pitfalls in hepatic stellate cell research. Hepatol. 2002;37:527–535.

    Article  Google Scholar 

  111. Rasi G, Serafino A, Bellis L, et al. Nerve growth factor involvement in liver cirrhosis and hepatocellular carcinoma. World J Gastroenterol. 2007;13:4986–4995.

    PubMed  CAS  Google Scholar 

  112. Preissner KT, Jenne D. Vitronectin: a new molecular connection in haemostasis. Thromb Haemost. 1991;66:189–194.

    PubMed  CAS  Google Scholar 

  113. Musso O, Theret N, Campion SP, et al. In situ detection of matrix metalloproteinase-2 (MMP2) and metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. J Hepatol. 1997;26:593–605.

    Article  PubMed  CAS  Google Scholar 

  114. Malaguarnera L, Ferlito L, Di Mauro S, Imbesi RM, Scalia G, Malaguarnera M. Immunosenescence and cancer: a review. Arch Gerontol Geriatrics. 2001;32:77–93.

    Article  CAS  Google Scholar 

  115. Evrin PE, Wibell L. Serum β-2 microglobulin in various disorders. Clin Chim Acta. 1973;43:183–186.

    Article  PubMed  CAS  Google Scholar 

  116. Weistal R, Norkrans G, Weiland O, et al. Lymphocyte subsets and β2-microglobulin expression in chronic hepatitis C/non-A. non-B. Effects of interferon-alpha treatment. Clin Exp Immunol. 1992;87:340–345.

    Article  Google Scholar 

  117. Malaguarnera M, Restuccia S, Di Fazio I, Zoccolo AM, Trovato BA, Pistone G. Serum beta-2 microglobulin in chronic hepatitis C. Dig Dis Sci. 1997;42:762–766.

    Article  PubMed  CAS  Google Scholar 

  118. Motta M, Giugno I, Ruello P, Pistone G, Di Fazio I, Malaguarnera M. Lipoprotein (a) behaviour in patients with hepatocellular carcinoma. Minerva Medica. 2001;92:301–305.

    PubMed  CAS  Google Scholar 

  119. Malaguarnera M, Di Fazio I, Laurino A, Motta M, Giugno I, Trovato B. A Ròle de interleukine-6 dans le carcinome hèpatocellulaire. Bull Cancer. 1996;83:379–384.

    PubMed  CAS  Google Scholar 

  120. Malaguarnera M, Di Fazio I, Ferlito L, et al. Increase of serum β-2 microglobulin in patients affected by HCV correlated hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2000;12:1–3.

    Article  Google Scholar 

  121. Ni RZ, Huang JF, Xiao MB, et al. Glycylproline dipeptidyl aminopeptidase isoenzyme in diagnosis of primary hepatocellular carcinoma. World J Gastroenterol. 2003;9:710–713.

    PubMed  CAS  Google Scholar 

  122. Vinci E, Rampello E, Zanoli L, Oreste G, Pistone G, Malaguarnera M. Serum carnitine levels in patients with tumoral cachexia. Eur J Intern Med. 2005;16:419–423.

    Article  PubMed  CAS  Google Scholar 

  123. Malaguarnera M, Laurino A, Di Mauro S, Motta M, Di Fazio I, Maugeri D. The comorbidities of elderly oncologic patients. Arch Gerontol Geriatr. 2000;30:237–244.

    Article  Google Scholar 

  124. Motta M, Ferlito L, Malaguarnera L, et al. Alterations of the lymphocytic set-up in elderly patients with cancer. Arch Gerontol Geriatr. 2003;36:7–14.

    Article  PubMed  CAS  Google Scholar 

  125. Motta M, Pistone G, Franzone AM, et al. Antibodies against ox-LDL serum levels in patients with hepatocellular carcinoma. Panminerva Med. 2003;45:69–73.

    PubMed  CAS  Google Scholar 

  126. Malaguarnera L, Cristaldi E, Malaguarnera M (2009) The role of immunity in elderly cancer. Crit Rev Oncol Hematol. PMID 19577481.

  127. Liaw YF, Tai DI, Chen TJ, Chu CM, Huang MJ. Alpha-fetoprotein changes in the course of chronic hepatitis: relation to bridging hepatic necrosis and hepatocellular carcinoma. Liver. 1986;6:133–137.

    PubMed  CAS  Google Scholar 

  128. Malaguarnera M, Gargante MP, Fricia T, Rampello E, Risino C, Romano M. Hepatitis C virus in elderly cancer patients. Eur J Intern Med. 2006;17:325–329.

    Article  PubMed  Google Scholar 

  129. Noda K, Miyoshi E, Uozumi N, et al. Gene expression of alpha1–6 fucosyltransferase in human hepatoma tissues: a possible implication for increased fucosylation of alpha-fetoprotein. Hepatology. 1998;28:944–952.

    Article  PubMed  CAS  Google Scholar 

  130. Guido M, Roskams T, Pontisso P, et al. Squamous cell carcinoma antigen in human liver carcinogenesis. J Clin Pathol. 2008;61:445–447.

    Article  PubMed  CAS  Google Scholar 

  131. Wu TT, Hsieh YH, Wu CC, Hsieh YS, Huang CY, Liu JY. Overexpression of protein kinase C alpha mRNA in human hepatocellular carcinoma: a potential marker of disease prognosis. Clin Chim Acta. 2007;382:54–58.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Miss Paola Favetta, for her expert assistant in the preparation and correction of the manuscript.

Conflict of interest statement

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. Department of Biomedical Science, University of Catania, Via Androne 83, 95124, Catania, Italy

    Giulia Malaguarnera

  2. Senescence, Urological, and Neurological Sciences, University of Catania, Via Messina 829, 95126, Catania, Italy

    Maria Giordano, Isabella Paladina, Massimiliano Berretta & Mariano Malaguarnera

  3. Department of Medical Oncology, National Cancer Institute, Via Franco Gallini 2, 33081, Aviano (PN), Italy

    Massimiliano Berretta

  4. Section of General Surgery and Oncology, Department of General Surgery, University Medical School of Catania, Ospedale Vittorio Emanuele Via Plebiscito 628, 95100, Catania, Italy

    Alessandro Cappellani

Authors
  1. Giulia Malaguarnera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabella Paladina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Massimiliano Berretta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alessandro Cappellani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mariano Malaguarnera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giulia Malaguarnera.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Malaguarnera, G., Giordano, M., Paladina, I. et al. Serum Markers of Hepatocellular Carcinoma. Dig Dis Sci 55, 2744–2755 (2010). https://doi.org/10.1007/s10620-010-1184-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-010-1184-7

Keywords

Search

Navigation