Skip to main content

Peroxiredoxin 4 suppresses anoikis and augments growth and metastasis of hepatocellular carcinoma cells through the β-catenin/ID2 pathway

Cellular Oncology volume 42, pages 769–781 (2019)Cite this article

Abstract

Purpose

Peroxiredoxin 4 (PRDX4) has been reported to play a dual role in the progression of hepatocellular carcinoma (HCC). As yet, however, the underlying molecular mechanism has not been fully elucidated.

Methods

We examined the effects of PRDX4 on the growth and survival of HCC cells in an anchorage-independent microenvironment. The regulation of β-catenin stability and activity by PRDX4 was investigated.

Results

We found that PRDX4 depletion reduced, and PRDX4 overexpression increased, both anchorage-dependent and anchorage-independent growth of HCC cells. We also found that PRDX4 depletion caused an overproduction of reactive oxygen species (ROS) in HCC cells, especially under suspension conditions. PRDX4 knockdown predisposed HCC cells to anoikis, whereas PRDX4 overexpression induced resistance to anoikis. Subsequent in vivo studies confirmed that PRDX4 deficiency blocks HCC tumor growth and pulmonary metastasis. Mechanistically, we found that RDX4 reduced β-TrCP-mediated β-catenin ubiquitination and enhanced β-catenin protein stability, consequently leading to activation of β-catenin signaling. Silencing of β-catenin impaired PRDX4-mediated anchorage-independent growth and survival, whereas β-catenin overexpression increased the survival and growth of PRDX4-depleted cells under anchorage-independent conditions. Further investigation revealed that the β-catenin downstream gene ID2 is responsible for the oncogenic activity of PRDX4 in HCC cells, promoting anchorage-independent growth and anoikis resistance.

Conclusions

PRDX4 reduces anoikis and promotes tumorigenesis and metastasis of HCC cells through stabilization of the β-catenin protein and upregulation of ID2. Targeting of PRDX4 may represent a promising strategy to block HCC cell growth and metastasis.

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

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. E.B. Rankin, A.J. Giaccia, Hypoxic control of metastasis. Science 352, 175–180 (2016)

    CAS  Article  Google Scholar 

  2. M. Yousefi, T. Bahrami, A. Salmaninejad, R. Nosrati, P. Ghaffari, S.H. Ghaffari, Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options. Cell Oncol 40, 419–441 (2017)

    CAS  Article  Google Scholar 

  3. R. Sharma, R. Sharma, T.P. Khaket, C. Dutta, B. Chakraborty, T.K. Mukherjee, Breast cancer metastasis: Putative therapeutic role of vascular cell adhesion molecule-1. Cell Oncol 40, 199–208 (2017)

    CAS  Article  Google Scholar 

  4. M. Yousefi, R. Nosrati, A. Salmaninejad, S. Dehghani, A. Shahryari, A. Saberi, Organ-specific metastasis of breast cancer: Molecular and cellular mechanisms underlying lung metastasis. Cell Oncol 41, 123–140 (2018)

    CAS  Article  Google Scholar 

  5. S. Talukdar, A.K. Pradhan, P. Bhoopathi, X.N. Shen, L.A. August, J.J. Windle, D. Sarkar, F.B. Furnari, W.K. Cavenee, S.K. Das, L. Emdad, P.B. Fisher, MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells. Proc Natl Acad Sci U S A 115, 5768–5773 (2018)

    CAS  Article  Google Scholar 

  6. P. Mehlen, A. Puisieux, Metastasis: A question of life or death. Nat Rev Cancer 6, 449–458 (2006)

    CAS  Article  Google Scholar 

  7. L. Zhou, Y. Liu, Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease. Nat Rev Nephrol 11, 535–545 (2015)

    CAS  Article  Google Scholar 

  8. S. Banskota, S. Dahal, E. Kwon, D.Y. Kim, J.A. Kim, β-Catenin gene promoter hypermethylation by reactive oxygen species correlates with the migratory and invasive potentials of colon cancer cells. Cell Oncol 41, 569–580 (2018)

    CAS  Article  Google Scholar 

  9. D. Zingg, J. Debbache, R. Peña-Hernández, A.T. Antunes, S.M. Schaefer, P.F. Cheng, D. Zimmerli, J. Haeusel, R.R. Calçada, E. Tuncer, Y. Zhang, R. Bossart, K.K. Wong, K. Basler, R. Dummer, R. Santoro, M.P. Levesque, L. Sommer, EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation. Cancer Cell 34, 69–84 (2018)

    CAS  Article  Google Scholar 

  10. K. Peng, G. Su, J. Ji, X. Yang, M. Miao, P. Mo, M. Li, J. Xu, W. Li, C. Yu, Histone demethylase JMJD1A promotes colorectal cancer growth and metastasis by enhancing Wnt/β-catenin signaling. J Biol Chem 293, 10606–10619 (2018)

    CAS  Article  Google Scholar 

  11. D.C. Lin, Y. Zhang, Q.J. Pan, H. Yang, Z.Z. Shi, Z.H. Xie, B.S. Wang, J.J. Hao, T.T. Zhang, X. Xu, Q.M. Zhan, M.R. Wang, PLK1 is transcriptionally activated by NF-κB during cell detachment and enhances anoikis resistance through inhibiting β-catenin degradation in esophageal squamous cell carcinoma. Clin Cancer Res 17, 4285–4295 (2011)

    CAS  Article  Google Scholar 

  12. G. D'Uva, S. Bertoni, M. Lauriola, S. De Carolis, A. Pacilli, L. D'Anello, D. Santini, M. Taffurelli, C. Ceccarelli, Y. Yarden, L. Montanaro, M. Bonafé, G. Storci, Beta-catenin/HuR post-transcriptional machinery governs cancer stem cell features in response to hypoxia. PLoS One 8, e80742 (2013)

    Article  Google Scholar 

  13. J.A. Mason, K.R. Hagel, M.A. Hawk, Z.T. Schafer, Metabolism during ECM detachment: Achilles heel of Cancer cells? Trends Cancer 3, 475–481 (2017)

    CAS  Article  Google Scholar 

  14. E. Giannoni, F. Buricchi, G. Grimaldi, M. Parri, F. Cialdai, M.L. Taddei, G. Raugei, G. Ramponi, P. Chiarugi, Redox regulation of anoikis: Reactive oxygen species as essential mediators of cell survival. Cell Death Differ 15, 867–878 (2008)

    CAS  Article  Google Scholar 

  15. A.E. Li, H. Ito, I.I. Rovira, K.S. Kim, K. Takeda, Z.Y. Yu, V.J. Ferrans, T. Finkel, A role for reactive oxygen species in endothelial cell anoikis. Circ Res 85, 304–310 (1999)

    CAS  Article  Google Scholar 

  16. S. Stöcker, M. Maurer, T. Ruppert, T.P. Dick, A role for 2-Cys peroxiredoxins in facilitating cytosolic protein thiol oxidation. Nat Chem Biol 14, 148–155 (2018)

    Article  Google Scholar 

  17. M.B. Hampton, K.A. Vick, J.J. Skoko, C.A. Neumann, Peroxiredoxin involvement in the initiation and progression of human Cancer. Antioxid Redox Signal 28, 591–608 (2018)

    CAS  Article  Google Scholar 

  18. D.H. Kang, D.J. Lee, S. Lee, S.Y. Lee, Y. Jun, Y. Kim, Y. Kim, J.S. Lee, D.K. Lee, S. Lee, E.H. Jho, D.Y. Yu, S.W. Kang, Interaction of tankyrase and peroxiredoxin II is indispensable for the survival of colorectal cancer cells. Nat Commun 8, 40 (2017)

  19. H.M. Ahn, J.W. Yoo, S. Lee, H.J. Lee, H.S. Lee, D.S. Lee, Peroxiredoxin 5 promotes the epithelial-mesenchymal transition in colon cancer. Biochem Biophys Res Commun 487, 580–586 (2017)

    CAS  Article  Google Scholar 

  20. I.S. Song, Y.J. Jeong, S.H. Jeong, H.J. Heo, H.K. Kim, K.B. Bae, Y.H. Park, S.U. Kim, J.M. Kim, N. Kim, K.S. Ko, B.D. Rhee, J. Han, FOXM1-induced PRX3 regulates Stemness and survival of Colon Cancer cells via maintenance of mitochondrial function. Gastroenterology 149, 1006–1016 (2015)

    CAS  Article  Google Scholar 

  21. X. Guo, H. Noguchi, N. Ishii, T. Homma, T. Hamada, T. Hiraki, J. Zhang, K. Matsuo, S. Yokoyama, H. Ishibashi, T. Fukushige, T. Kanekura, J. Fujii, H. Uramoto, A. Tanimoto, S. Yamada, The Association of Peroxiredoxin 4 with the initiation and progression of hepatocellular carcinoma. Antioxid Redox Signal 30, 1271–1284 (2019)

    CAS  Article  Google Scholar 

  22. S.K. Lim, S.Y. Lu, S.A. Kang, H.J. Tan, Z. Li, Z.N. Adrian Wee, J.S. Guan, V.P. Reddy Chichili, J. Sivaraman, T. Putti, A.A. Thike, P.H. Tan, M. Sudol, D.M. Virshup, S.W. Chan, W. Hong, Y.P. Lim, Wnt signaling promotes breast Cancer by blocking ITCH-mediated degradation of YAP/TAZ transcriptional coactivator WBP2. Cancer Res 76, 6278–6289 (2016)

    CAS  Article  Google Scholar 

  23. C. Zhang, B. Xu, S. Lu, Y. Zhao, P. Liu, HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity. Mol Cancer 16, 90 (2017)

  24. K. Zhang, S.M. Myllymäki, P. Gao, R. Devarajan, V. Kytölä, G.H. Wei, A. Manninen, Oncogenic K-Ras upregulates ITGA6 expression via FOSL1 to induce anoikis resistance and synergizes with αV-class integrins to promote EMT. Oncogene 36, 5681–5694 (2017)

    CAS  Article  Google Scholar 

  25. K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25, 402–408 (2001)

    CAS  Article  Google Scholar 

  26. Q. Xiao, K. Qu, C. Wang, Y. Kong, C. Liu, D. Jiang, H. Saiyin, F. Jia, C. Ni, T. Chen, Y. Zhang, P. Zhang, W. Qin, Q. Sun, H. Wang, Q. Yi, J. Liu, H. Huang, L. Yu, HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas. Gut 62, 440–451 (2013)

    CAS  Article  Google Scholar 

  27. Q. Wei, H. Jiang, Z. Xiao, A. Baker, M.R. Young, T.D. Veenstra, N.H. Colburn, Sulfiredoxin-Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling. Proc Natl Acad Sci U S A 108, 7004–7009 (2011)

    CAS  Article  Google Scholar 

  28. T.H. Kim, J. Song, S.R. Alcantara Llaguno, E. Murnan, S. Liyanarachchi, K. Palanichamy, J.Y. Yi, M.S. Viapiano, I. Nakano, S.O. Yoon, H. Wu, L.F. Parada, C.H. Kwon, Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth. PLoS One 7, e42818 (2012)

    CAS  Article  Google Scholar 

  29. R. Wang, Y. Liu, L. Liu, M. Chen, X. Wang, J. Yang, Y. Gong, B.S. Ding, Y. Wei, X. Wei, Tumor cells induce LAMP2a expression in tumor-associated macrophage for cancer progression. EBioMedicine 40, 118–134 (2019)

    Article  Google Scholar 

  30. M.A. Hawk, C.L. Gorsuch, P. Fagan, C. Lee, S.E. Kim, J.C. Hamann, J.A. Mason, K.J. Weigel, M.A. Tsegaye, L. Shen, S. Shuff, J. Zuo, S. Hu, L. Jiang, S. Chapman, W.M. Leevy, R.J. DeBerardinis, M. Overholtzer, Z.T. Schafer, RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells. Nat Cell Biol 20, 272–284 (2018)

    CAS  Article  Google Scholar 

  31. H. Kim, J.Y. Sung, E.K. Park, S. Kho, K.H. Koo, S.Y. Park, S.H. Goh, Y.K. Jeon, S. Oh, B.K. Park, Y.K. Jung, Y.N. Kim, Regulation of anoikis resistance by NADPH oxidase 4 and epidermal growth factor receptor. Br J Cancer 116, 370–381 (2017)

    CAS  Article  Google Scholar 

  32. C.A. Davison, S.M. Durbin, M.R. Thau, V.R. Zellmer, S.E. Chapman, J. Diener, C. Wathen, W.M. Leevy, Z.T. Schafer, Antioxidant enzymes mediate survival of breast cancer cells deprived of extracellular matrix. Cancer Res 73, 3704–3715 (2013)

    CAS  Article  Google Scholar 

  33. J.Y. Baek, S. Park, J. Park, J.Y. Jang, S.B. Wang, S.R. Kim, H.A. Woo, K.M. Lim, T.S. Chang, Protective role of mitochondrial Peroxiredoxin III against UVB-induced apoptosis of epidermal keratinocytes. J Invest Dermatol 137, 1333–1342 (2017)

    CAS  Article  Google Scholar 

  34. H.C. Whitaker, D. Patel, W.J. Howat, A.Y. Warren, J.D. Kay, T. Sangan, J.C. Marioni, J. Mitchell, S. Aldridge, H.J. Luxton, C. Massie, A.G. Lynch, D.E. Neal, Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress. Br J Cancer 109, 983–993 (2013)

    CAS  Article  Google Scholar 

  35. W. Lu, F. Z u, H. Wang, J. Feng, J. Wei, J. Guo, Peroxiredoxin 2 knockdown by RNA interference inhibits the growth of colorectal cancer cells by downregulating Wnt/β-catenin signaling. Cancer Lett 343, 190–199 (2014)

    CAS  Article  Google Scholar 

  36. S.J. Mo, X. Liu, X.Y. Hao, W. Chen, K.S. Zhang, J.P. Cai, J.M. Lai, L.J. Liang, X.Y. Yin, EYA4 functions as tumor suppressor gene and prognostic marker in pancreatic ductal adenocarcinoma through β-catenin/ID2 pathway. Cancer Lett 380, 403–412 (2016)

    CAS  Article  Google Scholar 

  37. S.P. Rockman, S.A. Currie, M. Ciavarella, E. Vincan, C. Dow, R.J. Thomas, W.A. Phillips, Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. J Biol Chem 276, 45113–45119 (2001)

    CAS  Article  Google Scholar 

  38. J. Ma, S. Zeng, Y. Zhang, G. Deng, Y. Qu, C. Guo, L. Yin, Y. Han, H. Shen, BMP4 enhances hepatocellular carcinoma proliferation by promoting cell cycle progression via ID2/CDKN1B signaling. Mol Carcinog 56, 2279–2289 (2017)

    CAS  Article  Google Scholar 

  39. M.J. Gray, N.A. Dallas, G. Van Buren, L. Xia, A.D. Yang, R.J. Somcio, P. Gaur, L.S. Mangala, P.E. Vivas-Mejia, F. Fan, A.M. Sanguino, G.E. Gallick, G. Lopez-Berestein, A.K. Sood, L.M. Ellis, Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. Oncogene 27, 7192–7200 (2008)

    CAS  Article  Google Scholar 

Download references

Acknowledgments

This work was partly supported by the Natural Science Foundation of Anhui Province (Nos. 1708085QH177 and 1808085MH234), the National Natural Science Foundation of China (No. 81201906) and the Chinese foundation for hepatitis prevention and control-TianQing liver disease research fund subject (No.TQGB20170171).

Author information

Affiliations

  1. Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No.17 Lujiang Road, Luyang District, Hefei, 230001, Anhui, People’s Republic of China

    Wei Wang, Xia-Bo Shen, Da-Bing Huang, Wei Jia & Yi-Fu He

  2. Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No.17 Lujiang Road, Luyang District, Hefei, 230001, Anhui, People’s Republic of China

    Wen-Bin Liu

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xia-Bo Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Da-Bing Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Bin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-Fu He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wen-Bin Liu or Yi-Fu He.

Ethics declarations

Conflict of interest

None declared.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 292 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Shen, XB., Huang, DB. et al. Peroxiredoxin 4 suppresses anoikis and augments growth and metastasis of hepatocellular carcinoma cells through the β-catenin/ID2 pathway. Cell Oncol. 42, 769–781 (2019). https://doi.org/10.1007/s13402-019-00460-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-019-00460-0

Keywords

  • Hepatocellular carcinoma
  • Anoikis
  • Growth
  • Metastasis
  • PRDX4