Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway

Oncogene volume 35, pages 3503–3513 (2016)Cite this article

Subjects

Abstract

The current study was carried out to define the involvement of Peroxiredoxin (Prx) II in progression of hepatocellular carcinoma (HCC) and the underlying molecular mechanism(s). Expression and function of Prx II in HCC was determined using H-rasG12V-transformed HCC cells (H-rasG12V–HCC cells) and the tumor livers from H-rasG12V-transgenic (Tg) mice and HCC patients. Prx II was upregulated in H-rasG12V–HCC cells and H-rasG12V–Tg mouse tumor livers, the expression pattern of which highly similar to that of forkhead Box M1 (FoxM1). Moreover, either knockdown of FoxM1 or site-directed mutagenesis of FoxM1-binding site of Prx II promoter significantly reduced Prx II levels in H-rasG12V–HCC cells, indicating FoxM1 as a direct transcription factor of Prx II in HCC. Interestingly, the null mutation of Prx II markedly decreased the number and size of tumors in H-rasG12V–Tg livers. Consistent with this, knockdown of Prx II in H-rasG12V–HCC cells reduced the expression of cyclin D1, cell proliferation, anchorage-independent growth and tumor formation in athymic nude mice, whereas overexpression of Prx II increased or aggravated the tumor phenotypes. Importantly, the expression of Prx II was correlated with that of FoxM1 in HCC patients. The activation of extracellular signal-related kinase (ERK) pathway and the expression of FoxM1 and cyclin D1 were highly dependent on Prx II in H-rasG12V–HCC cells and H-rasG12V–Tg livers. Prx II is FoxM1-dependently-expressed antioxidant in HCC and function as an enhancer of RasG12V oncogenic potential in hepatic tumorigenesis through activation of ERK/FoxM1/cyclin D1 cascade.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Jungst C, Cheng B, Gehrke R, Schmitz V, Nischalke HD, Ramakers J et al. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 2004; 39: 1663–1672.

    Article  PubMed  Google Scholar 

  2. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447: 864–868.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Adjei AA . Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001; 93: 1062–1074.

    Article  CAS  PubMed  Google Scholar 

  4. Kiaris H, Spandidos D . Mutations of ras genes in human tumors (review). Int J Oncol 1995; 7: 413–421.

    CAS  PubMed  Google Scholar 

  5. Tai P, Ascoli M . Reactive oxygen species (ROS) play a critical role in the cAMP-induced activation of Ras and the phosphorylation of ERK1/2 in Leydig cells. Mol Endocrinol 2011; 25: 885–893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 2010; 107: 8788–8793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang AG, Moon HB, Lee MR, Hwang CY, Kwon KS, Yu SL et al. Gender-dependent hepatic alterations in H-ras12V transgenic mice. J Hepatol 2005; 43: 836–844.

    Article  CAS  PubMed  Google Scholar 

  8. Wang AG, Moon HB, Chae JI, Kim JM, Kim YE, Yu DY et al. Steatosis induced by the accumulation of apolipoprotein A-I and elevated ROS levels in H-ras12V transgenic mice contributes to hepatic lesions. Biochem Biophys Res Commun 2011; 409: 532–538.

    Article  CAS  PubMed  Google Scholar 

  9. Saha B, Nandi D . Farnesyltransferase inhibitors reduce Ras activation and ameliorate acetaminophen-induced liver injury in mice. Hepatology 2009; 50: 1547–1557.

    Article  CAS  PubMed  Google Scholar 

  10. Wierstra I, Alves J . FOXM1, a typical proliferation-associated transcription factor. Biol Chem 2007; 388: 1257–1274.

    CAS  PubMed  Google Scholar 

  11. Park HJ, Carr JR, Wang Z, Nogueira V, Hay N, Tyner AL et al. FoxM1, a critical regulator of oxidative stress during oncogenesis. EMBO J 2009; 28: 2908–2918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun HC, Li M, Lu JL, Yan DW, Zhou CZ, Fan JW et al. Overexpression of Forkhead box M1 protein associates with aggressive tumor features and poor prognosis of hepatocellular carcinoma. Oncol Rep 2011; 25: 1533–1539.

    PubMed  Google Scholar 

  13. Xia L, Huang W, Tian D, Zhu H, Zhang Y, Hu H et al. Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma. J Hepatol 2012; 57: 600–612.

    Article  CAS  PubMed  Google Scholar 

  14. Calvisi DF, Pinna F, Ladu S, Pellegrino R, Simile MM, Frau M et al. Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC. Gut 2009; 58: 679–687.

    Article  CAS  PubMed  Google Scholar 

  15. Perkins A, Nelson KJ, Parsonage D, Poole LB, Karplus PA . Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling. Trends Biochem Sci 2015; 40: 435–445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee TH, Kim SU, Yu SL, Kim SH, Park DS, Moon HB et al. Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice. Blood 2003; 101: 5033–5038.

    Article  CAS  PubMed  Google Scholar 

  17. Han YH, Kim SU, Kwon TH, Lee DS, Ha HL, Park DS et al. Peroxiredoxin II is essential for preventing hemolytic anemia from oxidative stress through maintaining hemoglobin stability. Biochem Biophys Res Commun 2012; 426: 427–432.

    Article  CAS  PubMed  Google Scholar 

  18. Park JG, Yoo JY, Jeong SJ, Choi JH, Lee MR, Lee MN et al. Peroxiredoxin 2 deficiency exacerbates atherosclerosis in apolipoprotein E-deficient mice. Circ Res 2011; 109: 739–749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Han YH, Kim HS, Kim JM, Kim SK, Yu DY, Moon EY . Inhibitory role of peroxiredoxin II (Prx II) on cellular senescence. FEBS Lett 2005; 579: 4897–4902.

    Article  CAS  PubMed  Google Scholar 

  20. Kim SU, Jin MH, Kim YS, Lee SH, Cho YS, Cho KJ et al. Peroxiredoxin II preserves cognitive function against age-linked hippocampal oxidative damage. Neurobiol Aging 2011; 32: 1054–1068.

    Article  CAS  PubMed  Google Scholar 

  21. Li Y, Qin X, Cui J, Dai Z, Kang X, Yue H et al. Proteome analysis of aflatoxin B1-induced hepatocarcinogenesis in tree shrew (Tupaia belangeri chinensis) and functional identification of candidate protein peroxiredoxin II. Proteomics 2008; 8: 1490–1501.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang B, Wang Y, Su Y . Peroxiredoxins, a novel target in cancer radiotherapy. Cancer Lett 2009; 286: 154–160.

    Article  CAS  PubMed  Google Scholar 

  23. Diao S, Zhang JF, Wang H, He ML, Lin MC, Chen Y et al. Proteomic identification of microRNA-122a target proteins in hepatocellular carcinoma. Proteomics 2010; 10: 3723–3731.

    Article  CAS  PubMed  Google Scholar 

  24. Lee KW, Lee DJ, Lee JY, Kang DH, Kwon J, Kang SW . Peroxiredoxin II restrains DNA damage-induced death in cancer cells by positively regulating JNK-dependent DNA repair. J Biol Chem 2011; 286: 8394–8404.

    Article  CAS  PubMed  Google Scholar 

  25. Kang DH, Lee DJ, Lee KW, Park YS, Lee JY, Lee SH et al. Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells. Mol Cell 2011; 44: 545–558.

    Article  CAS  PubMed  Google Scholar 

  26. Lu Y, Liu J, Lin C, Wang H, Jiang Y, Wang J et al. Peroxiredoxin 2: a potential biomarker for early diagnosis of hepatitis B virus related liver fibrosis identified by proteomic analysis of the plasma. BMC Gastroenterol 2010; 10: 115.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Li W, Febbraio M, Reddy SP, Yu DY, Yamamoto M, Silverstein RL . CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs. J Clin Invest 2010; 120: 3996–4006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara et al. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology 1998; 27: 951–958.

    Article  CAS  PubMed  Google Scholar 

  29. Whittaker S, Marais R, Zhu AX . The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 2010; 29: 4989–5005.

    Article  CAS  PubMed  Google Scholar 

  30. Kwon J, Devadas S, Williams MS . T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. Free Radic Biol Med 2003; 35: 406–417.

    Article  CAS  PubMed  Google Scholar 

  31. Klein EA, Assoian RK . Transcriptional regulation of the cyclin D1 gene at a glance. J Cell Sci 2008; 121: 3853–3857.

    Article  CAS  PubMed  Google Scholar 

  32. Petrovic V, Costa RH, Lau LF, Raychaudhuri P, Tyner AL . FoxM1 regulates growth factor-induced expression of kinase-interacting stathmin (KIS) to promote cell cycle progression. J Biol Chem 2008; 283: 453–460.

    Article  CAS  PubMed  Google Scholar 

  33. Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P . Redox regulation of cell survival. Antioxid Redox Signal 2008; 10: 1343–1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shi X, Zhang Y, Zheng J, Pan J . Reactive oxygen species in cancer stem cells. Antioxid Redox Signal 2012; 16: 1215–1228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 2006; 10: 241–252.

    Article  CAS  PubMed  Google Scholar 

  36. Cho HJ, Jeong HG, Lee JS, Woo ER, Hyun JW, Chung MH et al. Oncogenic H-Ras enhances DNA repair through the Ras/phosphatidylinositol 3-kinase/Rac1 pathway in NIH3T3 cells. Evidence for association with reactive oxygen species. J Biol Chem 2002; 277: 19358–19366.

    Article  CAS  PubMed  Google Scholar 

  37. Trachootham D, Alexandre J, Huang P . Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009; 8: 579–591.

    Article  CAS  PubMed  Google Scholar 

  38. Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM et al. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev 2004; 18: 830–850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim H, Choi GH, Na DC, Ahn EY, Kim GI, Lee JE et al. Human hepatocellular carcinomas with "Stemness"-related marker expression: keratin 19 expression and a poor prognosis. Hepatology 2011; 54: 1707–1717.

    Article  CAS  PubMed  Google Scholar 

  40. Choi AR, Park JR, Kim RJ, Kim SR, Cho SD, Jung JY et al. Inhibition of Wnt1 expression reduces the enrichment of cancer stem cells in a mouse model of breast cancer. Biochem Biophys Res Commun 2012; 425: 436–442.

    Article  CAS  PubMed  Google Scholar 

  41. Wang IC, Chen YJ, Hughes DE, Ackerson T, Major ML, Kalinichenko VV et al. FoxM1 regulates transcription of JNK1 to promote the G1/S transition and tumor cell invasiveness. J Biol Chem 2008; 283: 20770–20778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Major ML, Lepe R, Costa RH . Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol Cell Biol 2004; 24: 2649–2661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sun HN, Kim SU, Huang SM, Kim JM, Park YH, Kim SH et al. Microglial peroxiredoxin V acts as an inducible anti-inflammatory antioxidant through cooperation with redox signaling cascades. J Neurochem 2010; 114: 39–50.

    CAS  PubMed  Google Scholar 

  44. Park YH, Kim SU, Lee BK, Kim HS, Song IS, Shin HJ et al. Prx I suppresses K-ras-driven lung tumorigenesis by opposing redox-sensitive ERK/cyclin D1 pathway. Antioxid Redox Signal 2013; 19: 482–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Mid-career Researcher Program through NFR grant funded by the MSIP (OGM0021312), by the World Class Institute (WCI) Program of the NRF, funded by the MSIP NRF (WCI 2009-002), by the National Research Foundation of Korea (2010-0020877), funded by Korean government, by the KRIBB Research Initiative Program (KGM3141312) of Korea, and by the Next-Generation BioGreen 21 Program (PJ0099592015), funded by Rural Development Administration of Korea. We thank Dr Pradip Raychaudhuri (University of Illinois at Chicago) who provided us with pCMV-T7-FoxM1 expression vectors.

Author information

Author notes

  1. Y-H Park and S-U Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology,, Daejeon,, Korea

    Y-H Park, S-U Kim, T-H Kwon, H-J Shin, B-K Lee & D-Y Yu

  2. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea

    Y-H Park, S-U Kim & K-T Chang

  3. Department of Functional Genomics, University of Science and Technology, Daejeon, Korea

    Y-H Park, S-U Kim & D-Y Yu

  4. School of Medicine, Chungnam National University, Daejeon, Korea

    J-M Kim

  5. Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea

    I-S Song

  6. School of Medicine, Wonkwang University, Iksan, Korea

    D-H Bang

  7. Research Institute for Natural Sciences, Hanyang University, Seoul, Korea

    S-J Lee

  8. College of Natural Sciences, Kyungpook National University, Daegu, Korea

    D-S Lee

  9. World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang, Korea

    B-Y Kim

Authors
  1. Y-H Park
    View author publications

    Search author on:PubMed Google Scholar

  2. S-U Kim
    View author publications

    Search author on:PubMed Google Scholar

  3. T-H Kwon
    View author publications

    Search author on:PubMed Google Scholar

  4. J-M Kim
    View author publications

    Search author on:PubMed Google Scholar

  5. I-S Song
    View author publications

    Search author on:PubMed Google Scholar

  6. H-J Shin
    View author publications

    Search author on:PubMed Google Scholar

  7. B-K Lee
    View author publications

    Search author on:PubMed Google Scholar

  8. D-H Bang
    View author publications

    Search author on:PubMed Google Scholar

  9. S-J Lee
    View author publications

    Search author on:PubMed Google Scholar

  10. D-S Lee
    View author publications

    Search author on:PubMed Google Scholar

  11. K-T Chang
    View author publications

    Search author on:PubMed Google Scholar

  12. B-Y Kim
    View author publications

    Search author on:PubMed Google Scholar

  13. D-Y Yu
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to D-Y Yu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, YH., Kim, SU., Kwon, TH. et al. Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway. Oncogene 35, 3503–3513 (2016). https://doi.org/10.1038/onc.2015.411

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/onc.2015.411

This article is cited by

Search

Advanced search

Quick links