Editorial Open Access
Copyright ©2010 Baishideng. All rights reserved.
World J Hepatol. Feb 27, 2010; 2(2): 55-57
Published online Feb 27, 2010. doi: 10.4254/wjh.v2.i2.55
Can proteomics lead to the discovery of real biomarkers for HCC?
Yasuhiro Kuramitsu, Yamaguchi University Graduate School of Medicine, Department of Biochemistry and Functional Proteomics, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan
Author contributions: Kuramitsu Y solely contributed to this work.
Correspondence to: Dr. Yasuhiro Kuramitsu, MD, PhD, Yamaguchi University Graduate School of Medicine, Department of Biochemistry and Functional Proteomics 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan. climates@yamaguchi-u.ac.jp
Telephone: +81-836-222213 Fax: +81-836-222212
Received: September 4, 2009
Revised: January 9, 2010
Accepted: January 16, 2010
Published online: February 27, 2010


The development of proteomics technologies has lead to a great deal of effort being focused on the identification of biomarkers for cancers. Although many papers have reported candidate biomarkers for hepatocellular carcinomas (HCCs) in particular, so far none of these candidate biomarkers have been used either for diagnosis or therapy intreating patients. The question remains: Can proteomics identify real biomarkers for HCCs?

Key Words: Hepatocellular carcinoma, Proteomics, Mass spectrometry, Two-dimensional polyacrylamide gel electrophoresis, Biomarker


During the past decade, proteomic technologies, including mass spectrometry, have developed considerably, and have been extensively applied to many fields of science, including medicine and pharmacy, as well as industry and agriculture. In the field of medicine in particular, a huge number of reports on the topic have been published. Above all, much effort has gone into proteomic analyses of tissues, cells and sera from cancer patients. The purpose of these studies has been the identification of biomarkers which could provide the development and identification of diagnostic and therapeutic targets for cancers. Many research labs and large pharmaceutical companies have been actively searching for new and effective biomarkers of cancers. Most applications use expression proteomics to determine expression profiles of proteins in tissues, cells and sera during normal or diseased states.


Hepatocellular carcinoma (HCC) is the third most deadly cancer, and about one million patients with HCC die each year. Despite remarkable advances in diagnostic and therapeutic techniques, the incidence of HCC continues to increase. While some papers on the proteomic analysis and discovery of molecular diagnostic markers for the diagnoses against HCC have been reported[1-9], no complete molecular diagnostic markers specific to HCC have been revealed by proteomics.

So far, many proteins have been reported as candidates for new diagnostic biomarkers, and as therapeutic targets for HCC by proteomics from HCC tissues[10-20]. They are classified as (1) digestive enzymes, (2) growth factors, (3) cell adhesion molecules, (4) calcium-binding proteins, (5) proteases, (6) protease inhibitors, (7) transporter proteins, (8) structural molecules, (9) proteins related to cell growth, (10) proteins related to cell differentiation, (11) proteins related to cell transformation, (12) proteins related to tumor invasion, (13) apoptosis inhibitors, (14) proteins related to carcinogen metabolism, (15) molecular chaperone, and (16) others. However, up to now, unfortunately none of them have been able to be used for diagnostic purposes because of their sensitivity and specificity.


Although detection for autoantibodies as diagnostic markers in cancer patients’ sera is useful, not many reports associating them with HCC have been published. Le Naour et al[21] identified autoantibodies reaction to calreticulin isoforms, cytokeratin 8, cytokeratin 18, creatine kinase B, HSP60, nucleoside diphosphate kinase A and F1-ATP synthase beta-subunit. Takashima et al[22] identified their reaction to HSP70, peroxiredoxin and Mn-SOD. Their sensitivity seems to be high, but their specificity is still not great enough.


Nowadays, in order to identify dramatically increased or decreased metabolites in cancer tissues, metabolomic profiling analyses have been used. Wu et al[23] and Xue et al[24] assayed endogenous metabolome in urine and sera from HCC patients using chemical derivatization followed by gas chromatography/mass spectrometry respectively, and many metabolites were shown to be significantly different between the HCC and control groups.


To exclude false positive biomarkers for hepatocellular carcinomas (HCCs), we need high specific biomarkers which show as increased biomarkers solely in HCCs, and not in hepatitis as well. Many reports have shown such high specific biomarker candidates, unfortunately they are still not enough.

Much time may still be needed for the identification of real biomarkers for HCC.


Peer reviewers: Yusuf Yilmaz, MD, Department of Gastroenterology, Marmara University School of Medicine, Tophanelioglu cad. No:13/15, Altunizade, Istanbul 34662, Turkey; Xiu-Jie Wang, Professor, Laborotary of Geritrics, Laborotary of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No.37 Guoxue Xiang, Chengdu 610041, Sichuan Province, China

S- Editor Zhang HN L- Editor Herholdt A E- Editor Liu N

1.  Chambers G, Lawrie L, Cash P, Murray GI. Proteomics: a new approach to the study of disease. J Pathol. 2000;192:280-288.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Alaiya AA, Franzén B, Auer G, Linder S. Cancer proteomics: from identification of novel markers to creation of artifical learning models for tumor classification. Electrophoresis. 2000;21:1210-1217.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Xu L, Hui L, Wang S, Gong J, Jin Y, Wang Y, Ji Y, Wu X, Han Z, Hu G. Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma. Cancer Res. 2001;61:3176-3181.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Hanash SM. Biomedical applications of two-dimensional electrophoresis using immobilized pH gradients: current status. Electrophoresis. 2000;21:1202-1209.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Beretta L. Comparative analysis of the liver and plasma proteomes as a novel and powerful strategy for hepatocellular carcinoma biomarker discovery. Cancer Lett. 2009;286:134-139.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Sun W, Zhong F, Zhi L, Zhou G, He F. Systematic-omics analysis of HBV-associated liver diseases. Cancer Lett. 2009;286:89-95.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Orimo T, Ojima H, Hiraoka N, Saito S, Kosuge T, Kakisaka T, Yokoo H, Nakanishi K, Kamiyama T, Todo S. Proteomic profiling reveals the prognostic value of adenomatous polyposis coli-end-binding protein 1 in hepatocellular carcinoma. Hepatology. 2008;48:1851-1863.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Chaerkady R, Harsha HC, Nalli A, Gucek M, Vivekanandan P, Akhtar J, Cole RN, Simmers J, Schulick RD, Singh S. A quantitative proteomic approach for identification of potential biomarkers in hepatocellular carcinoma. J Proteome Res. 2008;7:4289-4298.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Lee NP, Chen L, Lin MC, Tsang FH, Yeung C, Poon RT, Peng J, Leng X, Beretta L, Sun S. Proteomic expression signature distinguishes cancerous and nonmalignant tissues in hepatocellular carcinoma. J Proteome Res. 2009;8:1293-1303.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Park KS, Kim H, Kim NG, Cho SY, Choi KH, Seong JK, Paik YK. Proteomic analysis and molecular characterization of tissue ferritin light chain in hepatocellular carcinoma. Hepatology. 2002;35:1459-1466.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Park KS, Cho SY, Kim H, Paik YK. Proteomic alterations of the variants of human aldehyde dehydrogenase isozymes correlate with hepatocellular carcinoma. Int J Cancer. 2002;97:261-265.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Kim J, Kim SH, Lee SU, Ha GH, Kang DG, Ha NY, Ahn JS, Cho HY, Kang SJ, Lee YJ. Proteome analysis of human liver tumor tissue by two-dimensional gel electrophoresis and matrix assisted laser desorption/ionization-mass spectrometry for identification of disease-related proteins. Electrophoresis. 2002;23:4142-4156.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Lim SO, Park SJ, Kim W, Park SG, Kim HJ, Kim YI, Sohn TS, Noh JH, Jung G. Proteome analysis of hepatocellular carcinoma. Biochem Biophys Res Commun. 2002;291:1031-1037.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Li C, Tan YX, Zhou H, Ding SJ, Li SJ, Ma DJ, Man XB, Hong Y, Zhang L, Li L. Proteomic analysis of hepatitis B virus-associated hepatocellular carcinoma: Identification of potential tumor markers. Proteomics. 2005;5:1125-1139.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Fujii K, Kondo T, Yokoo H, Yamada T, Iwatsuki K, Hirohashi S. Proteomic study of human hepatocellular carcinoma using two-dimensional difference gel electrophoresis with saturation cysteine dye. Proteomics. 2005;5:1411-1422.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Zeindl-Eberhart E, Haraida S, Liebmann S, Jungblut PR, Lamer S, Mayer D, Jäger G, Chung S, Rabes HM. Detection and identification of tumor-associated protein variants in human hepatocellular carcinomas. Hepatology. 2004;39:540-549.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Kim W, Oe Lim S, Kim JS, Ryu YH, Byeon JY, Kim HJ, Kim YI, Heo JS, Park YM, Jung G. Comparison of proteome between hepatitis B virus- and hepatitis C virus-associated hepatocellular carcinoma. Clin Cancer Res. 2003;9:5493-5500.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Takashima M, Kuramitsu Y, Yokoyama Y, Iizuka N, Toda T, Sakaida I, Okita K, Oka M, Nakamura K. Proteomic profiling of heat shock protein 70 family members as biomarkers for hepatitis C virus-related hepatocellular carcinoma. Proteomics. 2003;3:2487-2493.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Yokoyama Y, Kuramitsu Y, Takashima M, Iizuka N, Toda T, Terai S, Sakaida I, Oka M, Nakamura K, Okita K. Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus. Proteomics. 2004;4:2111-2116.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Takashima M, Kuramitsu Y, Yokoyama Y, Iizuka N, Fujimoto M, Nishisaka T, Okita K, Oka M, Nakamura K. Overexpression of alpha enolase in hepatitis C virus-related hepatocellular carcinoma: association with tumor progression as determined by proteomic analysis. Proteomics. 2005;5:1686-1692.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Le Naour F, Brichory F, Misek DE, Bréchot C, Hanash SM, Beretta L. A distinct repertoire of autoantibodies in hepatocellular carcinoma identified by proteomic analysis. Mol Cell Proteomics. 2002;1:197-203.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Takashima M, Kuramitsu Y, Yokoyama Y, Iizuka N, Harada T, Fujimoto M, Sakaida I, Okita K, Oka M, Nakamura K. Proteomic analysis of autoantibodies in patients with hepatocellular carcinoma. Proteomics. 2006;6:3894-3900.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Wu H, Xue R, Dong L, Liu T, Deng C, Zeng H, Shen X. Metabolomic profiling of human urine in hepatocellular carcinoma patients using gas chromatography/mass spectrometry. Anal Chim Acta. 2009;648:98-104.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Xue R, Lin Z, Deng C, Dong L, Liu T, Wang J, Shen X. A serum metabolomic investigation on hepatocellular carcinoma patients by chemical derivatization followed by gas chromatography/mass spectrometry. Rapid Commun Mass Spectrom. 2008;22:3061-3068.  [PubMed]  [DOI]  [Cited in This Article: ]