Hepatocellular carcinoma: Review of disease and tumor biomarkers

World Journal of Hepatology

Volumn 8, Issue 10, 2016, Pages 471-484

  Kim, Jin Un ^a   Shariff, Mohamed I F ^a   Crossey, Mary M E ^a   Gomez Romero, Maria ^a   Holmes, Elaine ^a   Jane Cox, I ^b   Fye, Haddy K S ^c   Njie, Ramou ^c   Taylor Robinson, Simon D ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

^b INSTITUTE OF HEPATOLOGY   (United Kingdom)

^c MRC The Gambia   (Gambia)

Author keywords

Biomarker; Hepatocellular carcinoma; Metabonomics; Plasma; Serum; Urine; Warburg hypothesis

Indexed keywords

EID: 84962719796     PISSN: None     EISSN: 19485182     Source Type: Journal    
DOI: 10.4254/wjh.v8.i10.471     Document Type: Review

References (129)

1. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142: 1264-1273.e1 [PMID: 22537432 DOI: 10.1053/j.gastro.2011.12.061]
2. Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC. Increase in primary liver cancer in the UK, 1979-94. Lancet 1997; 350: 1142-1143 [PMID: 9343506]
3. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: 2557-2576 [PMID: 17570226]
4. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329-338 [PMID: 10518312 DOI: 10.1055/s-2007-1007122]
5. Stravitz RT, Heuman DM, Chand N, Sterling RK, Shiffman ML, Luketic VA, Sanyal AJ, Habib A, Mihas AA, Giles HC, Maluf DG, Cotterell AH, Posner MP, Fisher RA. Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome. Am J Med 2008; 121: 119-126 [PMID: 18261500 DOI: 10.1016/j.amjmed.2007.09.020]
6. International Agency for Research on Cancer. World cancer report 2014. Geneva: WHO, 2014
7. Warburg O, Posener K, Negelein E. Ueber den stoffwechsel der tumoren. Biochem Z 1924; 152: 319-344
8. Warburg O. [The effect of hydrogen peroxide on cancer cells and on embryonic cells]. Acta Unio Int Contra Cancrum 1958; 14: 55-57 [PMID: 13533023]
9. Ariff B, Lloyd CR, Khan S, Shariff M, Thillainayagam AV, Bansi DS, Khan SA, Taylor-Robinson SD, Lim AK. Imaging of liver cancer. World J Gastroenterol 2009; 15: 1289-1300 [PMID: 19294758 DOI: 10.3748/wjg.15.1289]
10. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008; 13: 472-482 [PMID: 18538731 DOI: 10.1016/j.ccr.2008.05.005]
11. López-Ríos F, Sánchez-Aragó M, García-García E, Ortega AD, Berrendero JR, Pozo-Rodríguez F, López-Encuentra A, Ballestín C, Cuezva JM. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res 2007; 67: 9013-9017 [PMID: 17909002]
12. Weinberg F, Chandel NS. Mitochondrial metabolism and cancer. Ann N Y Acad Sci 2009; 1177: 66-73 [PMID: 19845608 DOI: 10.1111/j.1749-6632.2009.05039.x]
13. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029-1033 [PMID: 19460998 DOI: 10.1126/ science.1160809]
14. Harris AL. Hypoxia- a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38-47 [PMID: 11902584 DOI: 10.1038/ nrc704]
15. Griffiths JR, McSheehy PM, Robinson SP, Troy H, Chung YL, Leek RD, Williams KJ, Stratford IJ, Harris AL, Stubbs M. Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia- inducible factor-1beta (HIF-1beta): evidence of an anabolic role for the HIF-1 pathway. Cancer Res 2002; 62: 688-695 [PMID: 11830521]
16. Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007; 39: 231-234 [PMID: 17551816 DOI: 10.1007/s10863-007-9081-2]
17. Amann T, Maegdefrau U, Hartmann A, Agaimy A, Marienhagen J, Weiss TS, Stoeltzing O, Warnecke C, Schölmerich J, Oefner PJ, Kreutz M, Bosserhoff AK, Hellerbrand C. GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol 2009; 174: 1544-1552 [PMID: 19286567 DOI: 10.23 53/ajpath.2009.080596]
18. Wang W, Xu GL, Jia WD, Wang ZH, Li JS, Ma JL, Ge YS, Xie SX, Yu JH. Expression and correlation of hypoxia-inducible factor- 1alpha, vascular endothelial growth factor and microvessel density in experimental rat hepatocarcinogenesis. J Int Med Res 2009; 37: 417-425 [PMID: 19383236 DOI: 10.1177/147323000903700217]
19. Yao DF, Jiang H, Yao M, Li YM, Gu WJ, Shen YC, Qiu LW, Wu W, Wu XH, Sai WL. Quantitative analysis of hepatic hypoxia- inducible factor-1alpha and its abnormal gene expression during the formation of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2009; 8: 407-413 [PMID: 19666411]
20. Luo D, Wang Z, Wu J, Jiang C, Wu J. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int 2014; 2014: 409272 [PMID: 25101278 DOI: 10.1155/2014/409272]
21. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. p53 regulates mitochondrial respiration. Science 2006; 312: 1650-1653 [PMID: 16728594 DOI: 10.1126/science. 1126863]
22. Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D. Glycolytic enzymes can modulate cellular life span. Cancer Res 2005; 65: 177-185 [PMID: 15665293]
23. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006; 126: 107-120 [PMID: 16839880 DOI: 10.1016/j.cell.2006.05.036]
24. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008; 134: 703-707 [PMID: 18775299 DOI: 10.1016/ j.cell.2008.08.021]
25. Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 2006; 66: 632-637 [PMID: 16423989 DOI: 10.1158/0008-5472.CAN-05-3260]
26. Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 2007; 26: 299-310 [PMID: 17415526 DOI: 10.1007/s10555-007-9 064-0]
27. Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 2005; 5: 857-866 [PMID: 16327764]
28. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009; 457: 910-914 [PMID: 19212411 DOI: 10.1038/nature07762]
29. Mínguez B, Tovar V, Chiang D, Villanueva A, Llovet JM. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 2009; 25: 186-194 [PMID: 19387255 DOI: 10.1097/MOG.0b013e32832962a1]
30. Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009; 50: 604-620 [PMID: 19157625 DOI: 10.1016/j.jhep.2008.12.011]
31. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Yamamoto J, Shimada K, Kosuge T, Okada S, Takayasu K, Yamasaki S. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology 1998; 28: 1241-1246 [PMID: 9794907 DOI: 10.1002/hep.510280511]
32. Armengol C, Tarafa G, Boix L, Solé M, Queralt R, Costa D, Bachs O, Bruix J, Capellá G. Orthotopic implantation of human hepatocellular carcinoma in mice: analysis of tumor progression and establishment of the BCLC-9 cell line. Clin Cancer Res 2004; 10: 2150-2157 [PMID: 15041736 DOI: 10.1158/1078-0432. CCR-03-1028]
33. Poon RT, Ho JW, Tong CS, Lau C, Ng IO, Fan ST. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg 2004; 91: 1354-1360 [PMID: 15376182 DOI: 10.1002/bjs.4594]
34. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10: 789-799 [DOI: 10.1038/nm1087]
35. Fraisl P, Baes M, Carmeliet P. Hungry for blood vessels: linking metabolism and angiogenesis. Dev Cell 2008; 14: 313-314 [PMID: 18331707 DOI: 10.1016/j.devcel.2008.02.009]
36. Vizán P, Sánchez-Tena S, Alcarraz-Vizán G, Soler M, Messeguer R, Pujol MD, Lee WN, Cascante M. Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets. Carcinogenesis 2009; 30: 946-952 [PMID: 19369582 DOI: 10.1093/carcin/ bgp083]
37. Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest 2013; 123: 1911-1918 [PMID: 23635789 DOI: 10.1172/JCI66024]
38. Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, Morgan TR, Kim HY, Lee WM, Bonkovsky HL, Dienstag JL. Des-gamma-carboxy prothrombin and alphafetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology 2010; 138: 493-502 [PMID: 19852963 DOI: 10.1053/j.gastro.2009.10.031]
39. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020-1022 [PMID: 21374666 DOI: 10.1002/hep.24199]
40. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208-1236 [PMID: 16250051 DOI: 10.1002/ hep.20933]
41. Nicholson JK, Lindon JC. Systems biology: Metabonomics. Nature 2008; 455: 1054-1056 [PMID: 18948945 DOI: 10.1038/4551054a]
42. Fiehn O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comp Funct Genomics 2001; 2: 155-168 [PMID: 18628911 DOI: 10.1002/cfg.82]
43. Want EJ, Cravatt BF, Siuzdak G. The expanding role of mass spectrometry in metabolite profiling and characterization. Chem- biochem 2005; 6: 1941-1951 [PMID: 16206229 DOI: 10.1002/ cbic.200500151]
44. Want EJ, Nordström A, Morita H, Siuzdak G. From exogenous to endogenous: the inevitable imprint of mass spectrometry in 59 metabolomics. JProteome Res 2007; 6: 459-468 [PMID: 17269703 DOI: 10.1021/pr060505]
45. Holmes E, Loo RL, Stamler J, Bictash M, Yap IK, Chan Q, Ebbels T, De Iorio M, Brown IJ, Veselkov KA, Daviglus ML, Kesteloot H, Ueshima H, Zhao L, Nicholson JK, Elliott P. Human metabolic phenotype diversity and its association with diet and blood pressure. Nature 2008; 453: 396-400 [PMID: 18425110 DOI: 10.1038/nature06882]
46. Williams HR, Cox IJ, Walker DG, North BV, Patel VM, Marshall 61 SE, Jewell DP, Ghosh S, Thomas HJ, Teare JP, Jakobovits S, Zeki S, Welsh KI, Taylor-Robinson SD, Orchard TR. Characterization of inflammatory bowel disease with urinary metabolic profiling. Am J Gastroenterol 2009; 104: 1435-1444 [PMID: 19491857 DOI: 10.1038/ajg.2009.175]
47. Bertini I, Calabrò A, De Carli V, Luchinat C, Nepi S, Porfirio B, Renzi D, Saccenti E, Tenori L. The metabonomic signature of celiac disease. J Proteome Res 2009; 8: 170-177 [PMID: 19072164 DOI: 10.1021/pr800548z]
48. Gao H, Dong B, Liu X, Xuan H, Huang Y, Lin D. Metabonomic profiling of renal cell carcinoma: high-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis. Anal Chim Acta 2008; 624: 269-277 [PMID: 18706333 DOI: 10.1016/j.aca.2008.06.051]
49. Gao H, Lu Q, Liu X, Cong H, Zhao L, Wang H, Lin D. Application of 1H NMR-based metabonomics in the study of metabolic profiling of human hepatocellular carcinoma and liver cirrhosis. Cancer Sci 2009; 100: 782-785 [PMID: 19469021 DOI: 10.1111/65 j.1349-7006.2009.01086.x]
50. Nicholson JK, Foxall PJ, Spraul M, Farrant RD, Lindon JC. 750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. Anal Chem 1995; 67: 793-811 [PMID: 7762816 DOI: 10.1021/ac00101a004]
51. Khan SA, Cox IJ, Thillainayagam AV, Bansi DS, Thomas HC, Taylor-Robinson SD. Proton and phosphorus-31 nuclear magnetic resonance spectroscopy of human bile in hepatopancreaticobiliary cancer. Eur J Gastroenterol Hepatol 2005; 17: 733-738 [PMID: 15947550]
52. Yang Y, Li C, Nie X, Feng X, Chen W, Yue Y, Tang H, Deng F. Metabonomic studies of human hepatocellular carcinoma using 67 high-resolution magic-angle spinning 1H NMR spectroscopy in conjunction with multivariate data analysis. J Proteome Res 2007; 6: 2605-2614 [PMID: 17564425 DOI: 10.1021/pr070063h]
53. Pauling L, Robinson AB, Teranishi R, Cary P. Quantitative analysis of urine vapor and breath by gas-liquid partition chroma- 68 tography. Proc Natl Acad Sci USA 1971; 68: 2374-2376 [PMID: 5289873 DOI: 10.1073/pnas.68.10.2374]
54. Gomaa AI, Khan SA, Leen EL, Waked I, Taylor-Robinson SD. Diagnosis of hepatocellular carcinoma. World J Gastro- 69 enterol 2009; 15: 1301-1314 [PMID: 19294759 DOI: 10.3748/ wjg.15.1301]
55. Sell S. Alpha-fetoprotein, stem cells and cancer: how study of 70 the production of alpha-fetoprotein during chemical hepatocar- cinogenesis led to reaffirmation of the stem cell theory of cancer. Tumour Biol 2008; 29: 161-180 [PMID: 18612221 DOI: 10.1159/000143402]
56. Daniele B, Bencivenga A, Megna AS, Tinessa V. Alpha-fetoprotein 71 and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 2004; 127: S108-S112 [PMID: 15508073 DOI: 10.1053/j.gastro.2004.09.023]
57. Sherman M, Peltekian KM, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and 72 prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 1995; 22: 432-438 [PMID: 7543434 DOI: 10.1002/hep. 1840220210]
58. Trevisani F, D'Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, Domenicali M, De Notariis S, Roda E, Bernardi M. Serum a-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 2001; 34: 570-575 [DOI: 10.1016/S0168-8278(00)00053-2]
59. Lok AS, Lai C. a-fetoprotein monitoring in chinese patients with chronic hepatitis B virus infection: Role in the early detection of hepatocellular carcinoma. Hepatology 1989; 9: 110-115 [DOI: 10.1002/hep. 1840090119]
60. Khien VV, Mao HV, Chinh TT, Ha PT, Bang MH, Lac BV, Hop TV, Tuan NA, Don LV, Taketa K, Satomura S. Clinical evaluation of lentil lectin-reactive alpha-fetoprotein-L3 in histology-proven hepatocellular carcinoma. Int J Biol Markers 2001; 16: 105-111 [PMID: 11471892]
61. Kumada T, Nakano S, Takeda I, Kiriyama S, Sone Y, Hayashi K, Katoh H, Endoh T, Sassa T, Satomura S. Clinical utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in small hepatocellular carcinoma: special reference to imaging diagnosis. J Hepatol 1999; 30: 125-130 [PMID: 9927159]
62. 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 [PMID: 17244360]
63. Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, Lok AS. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients. Hepatology 2003; 37: 1114-1121 [PMID: 12717392 DOI: 10.1053/jhep.2003.50195]
64. Volk ML, Hernandez JC, Su GL, Lok AS, Marrero JA. Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3. Cancer Biomark 2007; 3: 79-87 [PMID: 17522429]
65. Nakamura S, Nouso K, Sakaguchi K, Ito YM, Ohashi Y, Kobayashi Y, Toshikuni N, Tanaka H, Miyake Y, Matsumoto E, Shiratori Y. Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol 2006; 101: 2038-2043 [PMID: 16848811]
66. Ishizuka H, Nakayama T, Matsuoka S, Gotoh I, Ogawa M, Suzuki K, Tanaka N, Tsubaki K, Ohkubo H, Arakawa Y, Okano T. 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 [PMID: 10628928 DOI: 10.2169/internalmedicine.38.927]
67. Tangkijvanich P, Tosukhowong P, Bunyongyod P, Lertmaharit S, Hanvivatvong O, Kullavanijaya P, Poovorawan Y. Alpha-L- fucosidase as a serum marker of hepatocellular carcinoma in Thailand. Southeast Asian J Trop Med Public Health 1999; 30: 110-114 [PMID: 10695798]
68. Wang JJ, Cao EH. Rapid kinetic rate assay of the serum alpha- L-fucosidase in patients with hepatocellular carcinoma by using a novel substrate. Clin Chim Acta 2004; 347: 103-109 [PMID: 15313147 DOI: 10.1016/j.cccn.2004.04.007]
69. El-Houseini ME, Mohammed MS, Elshemey WM, Hussein TD, Desouky OS, Elsayed AA. Enhanced detection of hepatocellular carcinoma. Cancer Control 2005; 12: 248-253 [PMID: 16258497]
70. Moon WS, Rhyu KH, Kang MJ, Lee DG, Yu HC, Yeum JH, Koh GY, Tarnawski AS. Overexpression of VEGF and angiopoietin 2: a key to high vascularity of hepatocellular carcinoma? Mod Pathol 2003; 16: 552-557 [PMID: 12808060 DOI: 10.1097/01. MP.0000071841.17900.69]
71. Liu Z, Yan L, Xiang T, Jiang L, Yang B. Expression of vascular endothelial growth factor and matrix metalloproteinase-2 correlates with the invasion and metastasis of hepatocellular carcinoma. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2003; 20: 249-250, 254 [PMID: 12856590]
72. Huang GW, Yang LY, Lu WQ. Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: Impact on neovascularization and survival. World J Gastroenterol 2005; 11: 1705-1708 [PMID: 15786555 DOI: 10.3748/ wjg.v11.i11.1705]
73. Ren Y, Poon RT, Tsui HT, Chen WH, Li Z, Lau C, Yu WC, Fan ST. Interleukin-8 serum levels in patients with hepatocellular carcinoma: correlations with clinicopathological features and prognosis. Clin Cancer Res 2003; 9: 5996-6001 [PMID: 14676125]
74. Akiba J, Yano H, Ogasawara S, Higaki K, Kojiro M. Expression and function of interleukin-8 in human hepatocellular carcinoma. Int J Oncol 2001; 18: 257-264 [PMID: 11172590 DOI: 10.3892/ ijo.18.2.257]
75. Song BC, Chung YH, Kim JA, Choi WB, Suh DD, Pyo SI, Shin JW, Lee HC, Lee YS, Suh DJ. Transforming growth factor-beta1 as a useful serologic marker of small hepatocellular carcinoma. Cancer 2002; 94: 175-180 [PMID: 11815974 DOI: 10.1002/cncr.10170]
76. Sacco R, Leuci D, Tortorella C, Fiore G, Marinosci F, Schiraldi O, Antonaci S. Transforming growth factor beta1 and soluble Fas serum levels in hepatocellular carcinoma. Cytokine 2000; 12: 811-814 [PMID: 10843770 DOI: 10.1006/cyto.1999.0650]
77. Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol 2006; 12: 1175-1181 [PMID: 16534867]
78. Murakami A, Fukushima C, Yositomi K, Sueoka K, Nawata S, Fujimoto M, Nakamura K, Sugino N. Tumor-related protein, the squamous cell carcinoma antigen binds to the intracellular protein carbonyl reductase. Int J Oncol 2010; 36: 1395-1400 [PMID: 20428762 DOI: 10.3892/ijo_00000624]
79. Hussein MM, Ibrahim AA, Abdella HM, Montasser IF, Hassan MI. Evaluation of serum squamous cell carcinoma antigen as a novel biomarker for diagnosis of hepatocellular carcinoma in Egyptian patients. Indian J Cancer 2008; 45: 167-172 [PMID: 19112206 DOI: 10.4103/0019-509X.44666]
80. Abu El Makarem M. An overview of biomarkers for the diagnosis of hepatocellular carcinoma. HepatMon 2012; 12: e6122 [PMID: 23162601 DOI: 10.5812/hepatmon.6122]
81. Chuma M, Sakamoto M, Yamazaki K, Ohta T, Ohki M, Asaka M, Hirohashi S. Expression profiling in multistage hepatocar- cinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology 2003; 37: 198-207 [PMID: 12500205 DOI: 10.1053/jhep.2003.50022]
82. Nahon P, Amathieu R, Triba MN, Bouchemal N, Nault JC, Ziol M, Seror O, Dhonneur G, Trinchet JC, Beaugrand M, Le Moyec L. Identification of serum proton NMR metabolomic fingerprints associated with hepatocellular carcinoma in patients with alcoholic cirrhosis. Clin Cancer Res 2012; 18: 6714-6722 [PMID: 23136190 DOI: 10.115 8/1078-0432.CCR-12-1099]
83. Wei S, Suryani Y, Gowda GA, Skill N, Maluccio M, Raftery D. Differentiating hepatocellular carcinoma from hepatitis C using metabolite profiling. Metabolites 2012; 2: 701-716 [PMID: 24957758 DOI: 10.3390/metabo2040701]
84. Liu Y, Hong Z, Tan G, Dong X, Yang G, Zhao L, Chen X, Zhu Z, Lou Z, Qian B, Zhang G, Chai Y. NMR and LC/MS-based global metabolomics to identify serum biomarkers differentiating hepatocellular carcinoma from liver cirrhosis. Int J Cancer 2014; 135: 658-668 [PMID: 24382646 DOI: 10.1002/ijc.28706]
85. Assi N, Fages A, Vineis P, Chadeau-Hyam M, Stepien M, Duarte-Salles T, Byrnes G, Boumaza H, Knüppel S, Kühn T, Palli D, Bamia C, Boshuizen H, Bonet C, Overvad K, Johansson M, Travis R, Gunter MJ, Lund E, Dossus L, Elena-Herrmann B, Riboli E, Jenab M, Viallon V, Ferrari P. A statistical framework to model the meeting-in-the-middle principle using metabolomic data: application to hepatocellular carcinoma in the EPIC study. Mutagenesis 2015; 30: 743-753 [PMID: 26130468]
86. Baniasadi H, Gowda GA, Gu H, Zeng A, Zhuang S, Skill N, Maluccio M, Raftery D. Targeted metabolic profiling of hepatocellular carcinoma and hepatitis C using LC-MS/MS. Electrophoresis 2013; 34: 2910-2917 [PMID: 23856972 DOI: 10.1002/elps.201300029]
87. Chen F, Xue J, Zhou L, Wu S, Chen Z. Identification of serum biomarkers of hepatocarcinoma through liquid chromatography/ mass spectrometry-based metabonomic method. Anal Bioanal Chem 2011; 401: 1899-1904 [PMID: 21833635 DOI: 10.1007/ s00216-011-5245-3]
88. Chen S, Kong H, Lu X, Li Y, Yin P, Zeng Z, Xu G. Pseudotargeted metabolomics method and its application in serum biomarker discovery for hepatocellular carcinoma based on ultra highperformance liquid chromatography/triple quadrupole mass spectrometry. Anal Chem 2013; 85: 8326-8333 [PMID: 23889541 DOI: 10.1021/ac4016787]
89. Chen S, Yin P, Zhao X, Xing W, Hu C, Zhou L, Xu G. Serum lipid profiling of patients with chronic hepatitis B, cirrhosis, and hepatocellular carcinoma by ultra fast LC/IT-TOF MS. Electrophoresis 2013; 34: 2848-2856 [PMID: 24228263 DOI: 10.1002/elps.201200629]
90. Huang Q, Tan Y, Yin P, Ye G, Gao P, Lu X, Wang H, Xu G. Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics. Cancer Res 2013; 73: 4992-5002 [PMID: 23824744 DOI: 10.1158/0008-5472.CAN-13-0308]
91. Patterson AD, Maurhofer O, Beyoglu D, Lanz C, Krausz KW, Pabst T, Gonzalez FJ, Dufour JF, Idle JR. Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling. Cancer Res 2011; 71: 6590-6600 [PMID: 21900402 DOI: 10.1158/0008-5472.CAN-11-0885]
92. Ressom HW, Xiao JF, Tuli L, Varghese RS, Zhou B, Tsai TH, Ranjbar MR, Zhao Y, Wang J, Di Poto C, Cheema AK, Tadesse MG, Goldman R, Shetty K. Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis. Anal Chim Acta 2012; 743: 90-100 [PMID: 22882828 DOI: 10.1016/j.aca.2012.07.013]
93. Wang B, Chen D, Chen Y, Hu Z, Cao M, Xie Q, Chen Y, Xu J, Zheng S, Li L. Metabonomic profiles discriminate hepatocellular carcinoma from liver cirrhosis by ultraperformance liquid chromatography-mass spectrometry. J Proteome Res 2012; 11: 1217-1227 [PMID: 22200553 DOI: 10.1021/pr2009252]
94. Xiao JF, Varghese RS, Zhou B, Nezami Ranjbar MR, Zhao Y, Tsai TH, Di Poto C, Wang J, Goerlitz D, Luo Y, Cheema AK, Sarhan N, Soliman H, Tadesse MG, Ziada DH, Ressom HW. LC- MS based serum metabolomics for identification of hepatocellular carcinoma biomarkers in Egyptian cohort. J Proteome Res 2012; 11: 5914-5923 [PMID: 23078175 DOI: 10.1021/pr300673x]
95. 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 CommunMass Spectrom 2008; 22: 3061-3068 [PMID: 18767022 DOI: 10.1002/rcm.3708]
96. Yin P, Wan D, Zhao C, Chen J, Zhao X, Wang W, Lu X, Yang S, Gu J, Xu G. A metabonomic study of hepatitis B-induced liver cirrhosis and hepatocellular carcinoma by using RP-LC and HILIC coupled with mass spectrometry. Mol Biosyst 2009; 5: 868-876 [PMID: 19603122 DOI: 10.1039/b820224a]
97. Zhou L, Ding L, Yin P, Lu X, Wang X, Niu J, Gao P, Xu G. Serum metabolic profiling study of hepatocellular carcinoma infected with hepatitis B or hepatitis C virus by using liquid chromatography- mass spectrometry. J Proteome Res 2012; 11: 5433-5442 [PMID: 22946841 DOI: 10.1021/pr300683a]
98. Zhou L, Wang Q, Yin P, Xing W, Wu Z, Chen S, Lu X, Zhang Y, Lin X, Xu G. Serum metabolomics reveals the deregulation of fatty acids metabolism in hepatocellular carcinoma and chronic liver diseases. Anal Bioanal Chem 2012; 403: 203-213 [PMID: 22349331 DOI: 10.1007/s00216-012-5782-4]
99. Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology 2012; 55: 483-490 [DOI: 10.1002/hep.24703]
100. Linkous AG, Yazlovitskaya EM, Hallahan DE. Cytosolic phospholipase A2 and lysophospholipids in tumor angiogenesis. J Natl Cancer Inst 2010; 102: 1398-1412 [PMID: 20729478 DOI: 10.1093/jnci/djq290]
101. Morita Y, Sakaguchi T, Ikegami K, Goto-Inoue N, Hayasaka T, Hang VT, Tanaka H, Harada T, Shibasaki Y, Suzuki A, Fukumoto K, Inaba K, Murakami M, Setou M, Konno H. Lysopho- sphatidylcholine acyltransferase 1 altered phospholipid composition and regulated hepatoma progression. J Hepatol 2013; 59: 292-299 [PMID: 23567080 DOI: 10.1016/j.jhep.2013.02.030]
102. Chen T, Xie G, Wang X, Fan J, Qiu Y, Zheng X, Qi X, Cao Y, Su M, Wang X, Xu LX, Yen Y, Liu P, Jia W. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Mol Cell Proteomics 2011; 10: M110.004945 [PMID: 21518826 DOI: 10.1074/mcp.M110.004945]
103. Wu H, Xue R, Dong L, Liu T, Deng C, Zeng H, Shen X. Metabo- lomic profiling of human urine in hepatocellular carcinoma patients using gas chromatography/mass spectrometry. Anal Chim Acta 2009; 648: 98-104 [PMID: 19616694 DOI: 10.1016/ j.aca.2009.06.033]
104. Neale G, Lewis B, Weaver V, Panveliwalla D. Serum bile acids in liver disease. Gut 1971; 12: 145-152 [PMID: 5548561 DOI: 10.1136/gut. 12.2.145]
105. Chen Y, Xu Z, Kong H, Chen N, Chen J, Zhou L, Wang F, Dong Y, Zheng S, Chen Z. Differences between the metabolic profiles of decompensated and compensated cirrhosis patients with Hepatitis B virus infections under high-performance liquid chromatography- mass spectrometry. Metabolomics 2012; 8: 845-853 [DOI: 10.1007/s11306-011-0379-z]
106. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008; 7: 678-693 [PMID: 18670431 DOI: 10.1038/ nrd2619]
107. Baptissart M, Vega A, Maqdasy S, Caira F, Baron S, Lobaccaro JM, Volle DH. Bile acids: from digestion to cancers. Biochimie 2013; 95: 504-517 [PMID: 22766017 DOI: 10.1016/j.biochi.2012.06.022]
108. LaRusso NF, Hoffman NE, Korman MG, Hofmann AF, Cowen AE. Determinants of fasting and postprandial serum bile acid levels in healthy man. Am J Dig Dis 1978; 23: 385-391 [PMID: 677089 DOI: 10.1007/BF01072919]
109. Criss WE, Murad F. Urinary excretion of cyclic guanosine 3': 5'-monophosphate and cyclic adenosine 3': 5'-monophosphate in rats bearing transplantable liver and kidney tumors. Cancer Res 1976; 36: 1714-1716 [PMID: 178429]
110. Dusheiko GM, Levin J, Kew MC. Cyclic nucleotides in biological fluids in hepatocellular carcinoma. Cancer 1981; 47: 113-118 [PMID: 6257369]
111. Tamura S, Amuro Y, Nakano T, Fujii J, Moriwaki Y, Yamamoto T, Hada T, Higashino K. Urinary excretion of pseudouridine in patients with hepatocellular carcinoma. Cancer 1986; 57: 1571-1575 [PMID: 2418945]
112. Jeng LB, Lo WY, Hsu WY, Lin WD, Lin CT, Lai CC, Tsai FJ. Analysis of urinary nucleosides as helper tumor markers in hepatocellular carcinoma diagnosis. Rapid Commun Mass Spectrom 2009; 23: 1543-1549 [PMID: 19399767 DOI: 10.1002/rcm.4034]
113. Katoh M, Inagaki H, Kurosawa-Ohsawa K, Katsuura M, Tanaka S. Detection of transforming growth factor alpha in human urine and plasma. Biochem Biophys Res Commun 1990; 167: 1065-1072 [PMID: 2157422]
114. Chuang LY, Tsai JH, Yeh YC, Chang CC, Yeh HW, Guh JY, Tsai JF. Epidermal growth factor-related transforming growth factors in the urine of patients with hepatocellular carcinoma. Hepatology 1991; 13: 1112-1116 [PMID: 1646759]
115. Tsai JF, Jeng JE, Chuang LY, Yang ML, Ho MS, Chang WY, Hsieh MY, Lin ZY, Tsai JH. Clinical evaluation of urinary transforming growth factor-beta1 and serum alpha-fetoprotein as tumour markers of hepatocellular carcinoma. Br J Cancer 1997; 75: 1460-1466 [PMID: 9166938 DOI: 10.1038/bjc.1997.250]
116. Daito K, Suou T, Kawasaki H. Clinical significance of serum and urinary neopterin levels in patients with various liver diseases. Am J Gastroenterol 1992; 87: 471-476 [PMID: 1313206]
117. Kawasaki H, Watanabe H, Yamada S, Watanabe K, Suyama A. Prognostic significance of urinary neopterin levels in patients with hepatocellular carcinoma. Tohoku J Exp Med 1988; 155: 311-318 [PMID: 2852855 DOI: 10.1620/tjem.155.311]
118. Sucher R, Schroecksnadel K, Weiss G, Margreiter R, Fuchs D, Brandacher G. Neopterin, a prognostic marker in human malignancies. Cancer Lett 2010; 287: 13-22 [PMID: 19500901 DOI: 10.1016/j.canlet.2009.05.008]
119. Wishart DS, Tzur D, Knox C, Eisner R, Guo AC, Young N, Cheng D, Jewell K, Arndt D, Sawhney S, Fung C, Nikolai L, Lewis M, Coutouly MA, Forsythe I, Tang P, Shrivastava S, Jeroncic K, Stothard P, Amegbey G, Block D, Hau DD, Wagner J, Miniaci J, Clements M, Gebremedhin M, Guo N, Zhang Y, Duggan GE, Macinnis GD, Weljie AM, Dowlatabadi R, Bamforth F, Clive D, Greiner R, Li L, Marrie T, Sykes BD, Vogel HJ, Querengesser L. HMDB: the Human Metabolome Database. Nucleic Acids Res 2007; 35: D521-D526 [PMID: 17202168]
120. Antoniello S, Auletta M, Magri P, Pardo F. Urinary excretion of free and acetylated polyamines in hepatocellular carcinoma. Int J Biol Markers 1998; 13: 92-97 [PMID: 9803357]
121. Lin SD, Endo R, Kuroda H, Kondo K, Miura Y, Takikawa Y, Kato A, Suzuki K. Plasma and urine levels of urinary trypsin inhibitor in patients with chronic liver diseases and hepatocellular carcinoma. J Gastroenterol Hepatol 2004; 19: 327-332 [PMID: 14748881]
122. Kikuchi I, Uchinami H, Nanjo H, Hashimoto M, Nakajima A, Kume M, Mencin A, Yamamoto Y. Clinical and prognostic significance of urinary trypsin inhibitor in patients with hepatocellular carcinoma after hepatectomy. Ann Surg Oncol 2009; 16: 2805-2817 [PMID: 19636634 DOI: 10.1245/s10434-009-0622 -2]
123. Chen J, Wang W, Lv S, Yin P, Zhao X, Lu X, Zhang F, Xu G. Metabonomics study of liver cancer based on ultra performance liquid chromatography coupled to mass spectrometry with HILIC and RPLC separations. Anal Chim Acta 2009; 650: 3-9 [PMID: 19720165 DOI: 10.1016/j.aca.2009.03.039]
124. Shariff MI, Ladep NG, Cox IJ, Williams HR, Okeke E, Malu A, Thillainayagam AV, Crossey MM, Khan SA, Thomas HC, Taylor-Robinson SD. Characterization of urinary biomarkers of hepatocellular carcinoma using magnetic resonance spectroscopy in a Nigerian population. J Proteome Res 2010; 9: 1096-1103 [PMID: 19968328 DOI: 10.1021/pr901058t]
125. Shariff MI, Gomaa AI, Cox IJ, Patel M, Williams HR, Crossey MM, Thillainayagam AV, Thomas HC, Waked I, Khan SA, Taylor-Robinson SD. Urinary metabolic biomarkers of hepatocellular carcinoma in an Egyptian population: a validation study. J Proteome Res 2011; 10: 1828-1836 [PMID: 21275434 DOI: 10.1021/pr101096f]
126. Ladep NG, Dona AC, Lewis MR, Crossey MM, Lemoine M, Okeke E, Shimakawa Y, Duguru M, Njai HF, Fye HK, Taal M, Chetwood J, Kasstan B, Khan SA, Garside DA, Wijeyesekera A, Thillainayagam AV, Banwat E, Thursz MR, Nicholson JK, Njie R, Holmes E, Taylor-Robinson SD. Discovery and validation of urinary metabotypes for the diagnosis of hepatocellular carcinoma in West Africans. Hepatology 2014; 60: 1291-1301 [PMID: 24923488 DOI: 10.1002/hep.27264]
127. Oterdoom LH, Gansevoort RT, Schouten JP, de Jong PE, Gans RO, Bakker SJ. Urinary creatinine excretion, an indirect measure of muscle mass, is an independent predictor of cardiovascular disease and mortality in the general population. Atherosclerosis 2009; 207: 534-540 [PMID: 19535078 DOI: 10.1016/j.atheroscler osis.2009.05.010]
128. Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q. Role of carnitine in disease. NutrMetab (Lond) 2010; 7: 30 [PMID: 20398344 DOI: 10.1186/1743-7075-7-30]
129. Nguyen MH, Garcia RT, Simpson PW, Wright TL, Keeffe EB. Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis. Hepatology 2002; 36: 410-417 [PMID: 12143050]