Advertisement

Hepatocellular carcinoma patients with increased oxidative stress levels are prone to recurrence after curative treatment: a prospective case series study using the d-ROM test

  • Yusuke Suzuki
  • Kenji Imai
  • Koji Takai
  • Tatsunori Hanai
  • Hideki Hayashi
  • Takafumi Naiki
  • Yoichi Nishigaki
  • Eiichi Tomita
  • Masahito ShimizuEmail author
  • Hisataka Moriwaki
Original Paper

Abstract

Purpose

Oxidative stress plays an important role in liver carcinogenesis. To determine the impact of oxidative stress on the recurrence of stage I/II hepatocellular carcinoma (HCC) after curative treatment, we conducted a prospective case series analysis.

Methods

This study included 45 consecutive patients with stage I/II HCC, who underwent curative treatment by surgical resection or radiofrequency ablation at Gifu Municipal Hospital from 2006 to 2007. In these 45 cases, recurrence-free survival was estimated using the Kaplan–Meier method. The factors contributing to HCC recurrence, including the serum levels of derivatives of reactive oxygen metabolites (d-ROM) as an index of oxidative stress, were subjected to univariate and multivariate analyses using the Cox proportional hazards model.

Results

The serum levels of d-ROM (P = 0.0231), α-fetoprotein (AFP, P = 0.0274), and fasting plasma glucose (P = 0.0400) were significantly associated with HCC recurrence in the univariate analysis. Multivariate analysis showed that the serum levels of d-ROM (hazard ratio [HR] 1.0038, 95 % confidence interval [CI] 1.0002–1.0071, P = 0.0392) and AFP (HR 1.0002, 95 % CI 1.0000–1.0003, P = 0.0316) were independent predictors of HCC recurrence. Kaplan–Meier analysis showed that recurrence-free survival was low in patients with high serum d-ROM (≥570 Carr U, P = 0.0036) and serum AFP (≥40 ng/dL, P = 0.0185) levels.

Conclusions

The serum levels of d-ROM and AFP can be used for screening patients with a high risk for HCC recurrence. Patients who show increased levels of these factors require careful surveillance.

Keywords

Hepatocellular carcinoma Oxidative stress d-ROM Carcinogenesis 

Notes

Acknowledgments

This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (No. 22790638 to M. S. and No. 21590838 to H. M.) and by Grant-in-Aid for the 3rd Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

432_2013_1389_MOESM1_ESM.pptx (75 kb)
Supplementary material 1 (PPTX 75 kb)

References

  1. Abel S, De Kock M, van Schalkwyk DJ, Swanevelder S, Kew MC, Gelderblom WC (2009) Altered lipid profile, oxidative status and hepatitis B virus interactions in human hepatocellular carcinoma. Prostaglandins Leukot Essent Fat Acids 81(5–6):391–399. doi: 10.1016/j.plefa.2009.08.003 CrossRefGoogle Scholar
  2. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6(4):389–395. doi: 10.1038/74651 PubMedCrossRefGoogle Scholar
  3. Chuma M, Hige S, Nakanishi M, Ogawa K, Natsuizaka M, Yamamoto Y, Asaka M (2008) 8-Hydroxy-2′-deoxy-guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 23(9):1431–1436. doi: 10.1111/j.1440-1746.2008.05502.x PubMedCrossRefGoogle Scholar
  4. Chung JS, Park S, Park SH, Park ER, Cha PH, Kim BY, Chung YM, Woo SR, Han CJ, Kim SB, Suh KS, Jang JJ, Lee K, Choi DW, Lee S, Lee GY, Hahm KB, Shin JA, Kim BS, Noh KH, Kim TW, Lee KH, Yoo YD (2012) Overexpression of Romo1 promotes production of reactive oxygen species and invasiveness of hepatic tumor cells. Gastroenterology 143(4):1084–1094 e1087. doi: 10.1053/j.gastro.2012.06.038 Google Scholar
  5. Clemente C, Elba S, Buongiorno G, Guerra V, D’Attoma B, Orlando A, Russo F (2007) Manganese superoxide dismutase activity and incidence of hepatocellular carcinoma in patients with Child-Pugh class A liver cirrhosis: a 7-year follow-up study. Liver Int Off J Int Assoc Study Liver 27(6):791–797. doi: 10.1111/j.1478-3231.2007.01485.x CrossRefGoogle Scholar
  6. Clinical Practice Guidelines for Hepatocellular Carcinoma (2010) The Japan Society of Hepatology 2009 update. Hepatol Res Off J Jpn Soc Hepatol 40(Suppl 1):2–144. doi: 10.1111/j.1872-034X.2010.00650.x Google Scholar
  7. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842–845PubMedCrossRefGoogle Scholar
  8. Dreher D, Junod AF (1996) Role of oxygen free radicals in cancer development. Eur J Cancer 32A(1):30–38PubMedCrossRefGoogle Scholar
  9. El-Serag HB (2002) Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 35(5 Suppl 2):S72–S78PubMedCrossRefGoogle Scholar
  10. Fontana RJ, Israel J, LeClair P, Banner BF, Tortorelli K, Grace N, Levine RA, Fiarman G, Thiim M, Tavill AS, Bonkovsky HL (2000) Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology 31(3):730–736. doi: 10.1002/hep.510310325 PubMedCrossRefGoogle Scholar
  11. Glauert HP, Calfee-Mason K, Stemm DN, Tharappel JC, Spear BT (2010) Dietary antioxidants in the prevention of hepatocarcinogenesis: a review. Mol Nutr Food Res 54(7):875–896. doi: 10.1002/mnfr.200900482 PubMedCrossRefGoogle Scholar
  12. Hirose H, Kawabe H, Komiya N, Saito I (2009) Relations between serum reactive oxygen metabolites (ROMs) and various inflammatory and metabolic parameters in a Japanese population. J Atheroscler Thromb 16(2):77–82PubMedCrossRefGoogle Scholar
  13. Hu CT, Wu JR, Cheng CC, Wang S, Wang HT, Lee MC, Wang LJ, Pan SM, Chang TY, Wu WS (2011) Reactive oxygen species-mediated PKC and integrin signaling promotes tumor progression of human hepatoma HepG2. Clin Exp Metastasis 28(8):851–863. doi: 10.1007/s10585-011-9416-6 PubMedCrossRefGoogle Scholar
  14. Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3(4):276–285. doi: 10.1038/nrc1046 PubMedCrossRefGoogle Scholar
  15. Ikeda K, Saitoh S, Tsubota A, Arase Y, Chayama K, Kumada H, Watanabe G, Tsurumaru M (1993) Risk factors for tumor recurrence and prognosis after curative resection of hepatocellular carcinoma. Cancer 71(1):19–25PubMedCrossRefGoogle Scholar
  16. Imai K, Takai K, Nishigaki Y, Shimizu S, Naiki T, Hayashi H, Uematsu T, Sugihara J, Tomita E, Shimizu M, Nagaki M, Moriwaki H (2010) Insulin resistance raises the risk for recurrence of stage I hepatocellular carcinoma after curative radiofrequency ablation in hepatitis C virus-positive patients: a prospective, case series study. Hepatol Res Off J Jpn Soc Hepatol 40(4):376–382. doi: 10.1111/j.1872-034X.2009.00616.x CrossRefGoogle Scholar
  17. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi: 10.3322/caac.20107 PubMedCrossRefGoogle Scholar
  18. Kato J, Kobune M, Nakamura T, Kuroiwa G, Takada K, Takimoto R, Sato Y, Fujikawa K, Takahashi M, Takayama T, Ikeda T, Niitsu Y (2001) Normalization of elevated hepatic 8-hydroxy-2′-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. Cancer Res 61(24):8697–8702PubMedGoogle Scholar
  19. Koike Y, Shiratori Y, Sato S, Obi S, Teratani T, Imamura M, Hamamura K, Imai Y, Yoshida H, Shiina S, Omata M (2000) Risk factors for recurring hepatocellular carcinoma differ according to infected hepatitis virus-an analysis of 236 consecutive patients with a single lesion. Hepatology 32(6):1216–1223. doi: 10.1053/jhep.2000.20237 PubMedCrossRefGoogle Scholar
  20. Kudo M, Kubo S, Takayasu K, Sakamoto M, Tanaka M, Ikai I, Furuse J, Nakamura K, Makuuchi M (2010) Response evaluation criteria in cancer of the liver (RECICL) proposed by the Liver Cancer Study Group of Japan (2009 revised version). Hepatol Res Off J Jpn Soc Hepatol 40(7):686–692. doi: 10.1111/j.1872-034X.2010.00674.x CrossRefGoogle Scholar
  21. Liver Cancer Study Group of Japan (2010) General rules for the clinical and pathological study of primary liver cancer, 3rd English edn. Kanehara & Co., Ltd., TokyoGoogle Scholar
  22. Loguercio C, Federico A (2003) Oxidative stress in viral and alcoholic hepatitis. Free Radic Biol Med 34(1):1–10PubMedCrossRefGoogle Scholar
  23. Mahmood S, Kawanaka M, Kamei A, Izumi A, Nakata K, Niiyama G, Ikeda H, Hanano S, Suehiro M, Togawa K, Yamada G (2004) Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C. Antioxid Redox Signal 6(1):19–24. doi: 10.1089/152308604771978318 PubMedCrossRefGoogle Scholar
  24. Maki A, Kono H, Gupta M, Asakawa M, Suzuki T, Matsuda M, Fujii H, Rusyn I (2007) Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma. Ann Surg Oncol 14(3):1182–1190. doi: 10.1245/s10434-006-9049-1 PubMedCrossRefGoogle Scholar
  25. Morisco F, Verde V, Fogliano V, Ritieni A, Marmo R, De Luise G, Tuccillo C, Caporaso N (2004) Oxidative status in chronic hepatitis C: the influence of antiviral therapy and prognostic value of serum hydroperoxide assay. Free Radic Res 38(6):573–580PubMedCrossRefGoogle Scholar
  26. Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Miyazawa T, Ishibashi K, Horie T, Imai K, Todoroki T, Kimura S, Koike K (2001) Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 61(11):4365–4370PubMedGoogle Scholar
  27. Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G, Karin M (2008) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14(2):156–165. doi: 10.1016/j.ccr.2008.06.016 PubMedCrossRefGoogle Scholar
  28. Sasaki Y (2006) Does oxidative stress participate in the development of hepatocellular carcinoma? J Gastroenterol 41(12):1135–1148. doi: 10.1007/s00535-006-1982-z PubMedCrossRefGoogle Scholar
  29. Seronello S, Sheikh MY, Choi J (2007) Redox regulation of hepatitis C in nonalcoholic and alcoholic liver. Free Radic Biol Med 43(6):869–882. doi: 10.1016/j.freeradbiomed.2007.05.036 PubMedCrossRefGoogle Scholar
  30. Siegel AB, Zhu AX (2009) Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 115(24):5651–5661. doi: 10.1002/cncr.24687 PubMedCrossRefGoogle Scholar
  31. Sugiura T, Dohi Y, Takase H, Yamashita S, Tanaka S, Kimura G (2011) Increased reactive oxygen metabolites is associated with cardiovascular risk factors and vascular endothelial damage in middle-aged Japanese subjects. Vasc Health Risk Manag 7:475–482. doi: 10.2147/VHRM.S23097 PubMedCrossRefGoogle Scholar
  32. Sumida Y, Nakashima T, Yoh T, Nakajima Y, Ishikawa H, Mitsuyoshi H, Sakamoto Y, Okanoue T, Kashima K, Nakamura H, Yodoi J (2000) Serum thioredoxin levels as an indicator of oxidative stress in patients with hepatitis C virus infection. J Hepatol 33(4):616–622Google Scholar
  33. Tanaka S, Mogushi K, Yasen M, Ban D, Noguchi N, Irie T, Kudo A, Nakamura N, Tanaka H, Yamamoto M, Kokudo N, Takayama T, Kawasaki S, Sakamoto M, Arii S (2011) Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: a prospective, multicenter study. Hepatology 54(4):1273–1281. doi: 10.1002/hep.24536 PubMedCrossRefGoogle Scholar
  34. Toyama T, Hiramatsu N, Yakushijin T, Oze T, Nakanishi F, Yasumaru M, Mochizuki K, Kanto T, Takehara T, Kasahara A, Hayashi N (2008) A new prognostic system for hepatocellular carcinoma including recurrent cases: a study of 861 patients in a single institution. J Clin Gastroenterol 42(3):317–322. doi: 10.1097/MCG.0b013e3180ebe790 PubMedGoogle Scholar
  35. Trotti R, Carratelli M, Barbieri M (2002) Performance and clinical application of a new, fast method for the detection of hydroperoxides in serum. Panminerva Med 44(1):37–40PubMedGoogle Scholar
  36. Tsai SM, Lin SK, Lee KT, Hsiao JK, Huang JC, Wu SH, Ma H, Wu SH, Tsai LY (2009) Evaluation of redox statuses in patients with hepatitis B virus-associated hepatocellular carcinoma. Ann Clin Biochem 46(Pt 5):394–400. doi: 10.1258/acb.2009.009029 PubMedCrossRefGoogle Scholar
  37. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84. doi: 10.1016/j.biocel.2006.07.001 PubMedCrossRefGoogle Scholar
  38. Vassalle C, Pratali L, Boni C, Mercuri A, Ndreu R (2008) An oxidative stress score as a combined measure of the pro-oxidant and anti-oxidant counterparts in patients with coronary artery disease. Clin Biochem 41(14–15):1162–1167. doi: 10.1016/j.clinbiochem.2008.07.005 PubMedCrossRefGoogle Scholar
  39. Watanabe N, Takai K, Imai K, Shimizu M, Naiki T, Nagaki M, Moriwaki H (2011) Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment. J Clin Biochem Nutr 49(3):153–158. doi: 10.3164/jcbn.10-149 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Yusuke Suzuki
    • 1
  • Kenji Imai
    • 2
  • Koji Takai
    • 2
  • Tatsunori Hanai
    • 2
  • Hideki Hayashi
    • 1
  • Takafumi Naiki
    • 2
  • Yoichi Nishigaki
    • 1
  • Eiichi Tomita
    • 1
  • Masahito Shimizu
    • 2
    Email author
  • Hisataka Moriwaki
    • 2
  1. 1.Department of GastroenterologyGifu Municipal HospitalGifuJapan
  2. 2.Department of MedicineGifu University Graduate School of MedicineGifuJapan

Personalised recommendations