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Clinical and Experimental Medicine

, Volume 19, Issue 2, pp 235–243 | Cite as

Microcystin-LR in peripheral circulation worsens the prognosis partly through oxidative stress in patients with hepatocellular carcinoma

  • Feifei Lei
  • Xu Lei
  • Rugui Li
  • Huabing TanEmail author
Original Article
  • 38 Downloads

Abstract

Prognostic significance of serum microcystin in hepatocellular carcinoma has not been well investigated. The aim of the study was to reveal the relationship between serum microcystin-LR and prognosis in these patients. There were 650 early-stage hepatitis B-induced hepatocellular carcinoma patients, who were not affected by hepatitis C, cirrhosis, heavy drinking or excessive aflatoxin exposure. All of them underwent hepatectomy and were followed up for 5 years. Tumor relapse and overall death were recorded. Blood specimens were collected on admission and at the time of relapse. Serum levels of microcystin-LR and fluorescent oxidation products (FlOP_360, FlOP_320 and FlOP_400) were measured separately using enzyme-linked immunosorbent assay and fluorescence spectrometry. Multifactorial COX regression analysis suggested that serum microcystin-LR ≥ 0.97 ng/ml was associated with the increased risk of the tumor relapse (HR: 1.53, 95% CI: 1.35–1.77) and serum microcystin-LR ≥ 1.09 ng/ml was related to the higher risk of the overall death (HR: 1.58, 95% CI: 1.35–1.84) in the follow-up period. Furthermore, there was a linear relationship between serum level of microcystin-LR and serum levels of FlOP_360, FlOP_320 and FlOP_400 (P = 0.001, P = 0.023, P = 0.047). Serum levels of these fluorescent oxidation products were also higher in the patients with tumor relapse (P < 0.001, P < 0.001, P = 0.001) or overall death (P < 0.001, P = 0.001, P = 0.002) compared with the remaining patients. Serum microcystin-LR independently worsens the prognosis partly through promoting oxidative stress in patients with hepatocellular carcinoma.

Keywords

Hepatocellular carcinoma Microcystin Oxidative stress Prognosis Recurrence 

Notes

Funding

The study was supported by the Innovation Team Project of Renmin Hospital Affiliated to Hubei Medical College (201404) and the Free Exploration Fund Project of Hubei Medical College (2017).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19:223–38.CrossRefGoogle Scholar
  2. 2.
    Ozakyol A. Global epidemiology of hepatocellular carcinoma (HCC epidemiology). J Gastrointest Cancer. 2017.  https://doi.org/10.1007/s12029-017-9959-0.Google Scholar
  3. 3.
    Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation. Am Fam Physician. 2006;74:756–62.Google Scholar
  4. 4.
    Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007;13:2436–41.CrossRefGoogle Scholar
  5. 5.
    Kucukcakan B, Hayrulai-Musliu Z. Challenging role of dietary aflatoxin B1 exposure and hepatitis B infection on risk of hepatocellular carcinoma. Open Access Maced J Med Sci. 2015;3:363–9.CrossRefGoogle Scholar
  6. 6.
    Chan SL, Wong VW, Qin S, Chan HL. Infection and cancer: the case of hepatitis B. J Clin Oncol. 2016;34:83–90.CrossRefGoogle Scholar
  7. 7.
    Liu Y, Chang CC, Marsh GM, Wu F. Population attributable risk of aflatoxin-related liver cancer: systematic review and meta-analysis. Eur J Cancer. 2012;48:2125–36.CrossRefGoogle Scholar
  8. 8.
    Ufelmann H, Krüger T, Luckas B, Schrenk D. Human and rat hepatocyte toxicity and protein phosphatase 1 and 2A inhibitory activity of naturally occurring desmethyl-microcystins and nodularins. Toxicology. 2012;293:59–67.CrossRefGoogle Scholar
  9. 9.
    Gupta N, Pant SC, Vijayaraghavan R, Rao PV. Comparative toxicity evaluation of cyanobacterial cyclic peptide toxin microcystin variants (LR, RR, YR) in mice. Toxicology. 2003;188:285–96.CrossRefGoogle Scholar
  10. 10.
    Schirrmeister BE, de Vos JM, Antonelli A, Bagheri HC. Evolution of multicellularity coincided with increased diversification of cyanobacteria and the Great Oxidation Event. Proc Natl Acad Sci USA. 2013;110:1791–6.CrossRefGoogle Scholar
  11. 11.
    Dittmann E, Wiegand C. Cyanobacterial toxins–occurrence, biosynthesis and impact on human affairs. Mol Nutr Food Res. 2006;50:7–17.CrossRefGoogle Scholar
  12. 12.
    Smith JL, Haney JF. Foodweb transfer, accumulation, and depuration of microcystins, a cyanobacterial toxin, in pumpkinseed sunfish (Lepomis gibbosus). Toxicon. 2006;48:580–9.CrossRefGoogle Scholar
  13. 13.
    Cheung MY, Liang S, Lee J. Toxin-producing cyanobacteria in freshwater: a review of the problems, impact on drinking water safety, and efforts for protecting public health. J Microbiol. 2013;51:1–10.CrossRefGoogle Scholar
  14. 14.
    Hejkal TW, Larock PA, Winchester JW. Water-to-air fractionation of bacteria. Appl Environ Microbiol. 1980;39:335–8.Google Scholar
  15. 15.
    O’Neil JM, Davis TW, Burford MA, Gobler CJ. The rise of harmful cyanobacteria blooms: the potential roles of eutrophication and climate change. Harmful Algae. 2012;14:313–34.CrossRefGoogle Scholar
  16. 16.
    Paerl HW, Huisman J. Climate. Blooms like it hot. Science. 2008;320:57–8.CrossRefGoogle Scholar
  17. 17.
    Svirčev Z, Drobac D, Tokodi N, et al. Epidemiology of cancers in Serbia and possible connection with cyanobacterial blooms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2014;32:319–37.CrossRefGoogle Scholar
  18. 18.
    Svirčev Z, Drobac D, Tokodi N, et al. Epidemiology of primary liver cancer in Serbia and possible connection with cyanobacterial blooms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2013;31:181–200.CrossRefGoogle Scholar
  19. 19.
    Zhang F, Lee J, Liang S, Shum CK. Cyanobacteria blooms and non-alcoholic liver disease: evidence from a county level ecological study in the United States. Environ Health. 2015;14:41.CrossRefGoogle Scholar
  20. 20.
    Li Y, Chen JA, Zhao Q, et al. A cross-sectional investigation of chronic exposure to microcystin in relationship to childhood liver damage in the Three Gorges Reservoir Region, China. Environ Health Perspect. 2011;119:1483–8.CrossRefGoogle Scholar
  21. 21.
    Chen J, Xie P, Li L, Xu J. First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage. Toxicol Sci. 2009;108:81–9.CrossRefGoogle Scholar
  22. 22.
    Zheng C, Zeng H, Lin H, et al. Serum microcystin levels positively linked with risk of hepatocellular carcinoma: a case-control study in southwest China. Hepatology. 2017;66:1519–28.CrossRefGoogle Scholar
  23. 23.
    Zegura B, Sedmak B, Filipic M. Microcystin-LR induces oxidative DNA damage in human hepatoma cell line HepG2. Toxicon. 2003;41:41–8.CrossRefGoogle Scholar
  24. 24.
    Svircev Z, Baltić V, Gantar M, Juković M, Stojanović D, Baltić M. Molecular aspects of microcystin-induced hepatotoxicity and hepatocarcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2010;28:39–59.CrossRefGoogle Scholar
  25. 25.
    Wu T, Willett WC, Rifai N, Rimm EB. Plasma fluorescent oxidation products as potential markers of oxidative stress for epidemiologic studies. Am J Epidemiol. 2007;166:552–60.CrossRefGoogle Scholar
  26. 26.
    Fortner RT, Tworoger SS, Wu T, Eliassen AH. Plasma florescent oxidation products and breast cancer risk: repeated measures in the Nurses’ Health Study. Breast Cancer Res Treat. 2013;141:307–16.CrossRefGoogle Scholar
  27. 27.
    Kurozawa Y, Ogimoto I, Shibata A, et al. Dietary habits and risk of death due to hepatocellular carcinoma in a large scale cohort study in Japan Univariate analysis of JACC study data. Kurume Med J. 2004;51:141–9.CrossRefGoogle Scholar
  28. 28.
    Pang Q, Qu K, Liu C. Central obesity early in adulthood may affect outcomes of hepatocellular carcinoma. Gastroenterology. 2015;149:1642–3.CrossRefGoogle Scholar
  29. 29.
    Funakoshi N, Chaze I, Alary AS, et al. The role of genetic factors in patients with hepatocellular carcinoma and iron overload—a prospective series of 234 patients. Liver Int. 2016;36:746–54.CrossRefGoogle Scholar
  30. 30.
    Nong Q, Komatsu M, Izumo K, et al. Involvement of reactive oxygen species in microcystin-LR-induced cytogenotoxicity. Free Radic Res. 2007;41:1326–37.CrossRefGoogle Scholar
  31. 31.
    Zegura B, Lah TT, Filipic M. Alteration of intracellular GSH levels and its role in microcystin-LR-induced DNA damage in human hepatoma HepG2 cells. Mutat Res. 2006;611:25–33.CrossRefGoogle Scholar
  32. 32.
    Wu T, Rifai N, Roberts LJ 2nd, Willett WC, Rimm EB. Stability of measurements of biomarkers of oxidative stress in blood over 36 hours. Cancer Epidemiol Prev Biomark. 2004;13:1399–402.CrossRefGoogle Scholar
  33. 33.
    Li X, Zhang X, Xie W, Zhou C, Li Y, Zhang X. Alterations in transcription and protein expressions of HCC-related genes in HepG2 cells caused by microcystin-LR. Toxicol In Vitro. 2017;40:115–23.CrossRefGoogle Scholar
  34. 34.
    Liu J, Wang B, Huang P, et al. Microcystin-LR promotes cell proliferation in the mice liver by activating Akt and p38/ERK/JNK cascades. Chemosphere. 2016;163:14–21.CrossRefGoogle Scholar
  35. 35.
    Liu J, Wang H, Wang B, et al. Microcystin-LR promotes proliferation by activating Akt/S6K1 pathway and disordering apoptosis and cell cycle associated proteins phosphorylation in HL7702 cells. Toxicol Lett. 2016;240:214–25.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Infectious Diseases and Lab. of Liver Disease, Renmin HospitalHubei University of MedicineShiyanChina

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