Skip to main content

Advertisement

SpringerLink
Log in

Predicting the Correlation of EZH2 and Cancer Stem Cell Markers in Esophageal Squamous Cell Carcinoma

  • Original Research
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Background

Enhancer of zeste homolog 2 (EZH2), a stemness factor, plays roles in regulation of cell differentiation and embryonic development as well as cancer progression. Deregulation of EZH2 in cancers is correlated with tumor cell invasiveness, metastasis, and the patients’ poor outcome. However, the mechanistic role of EZH2 in cancer is ambiguous. In this study, we aimed to inhibit the expression of EZH2 in a cancer cell line, and evaluate consequence changes in gene expression pattern.

Materials and methods

Using specific retroviral shRNA-EZH2, EZH2 gene was silenced in the KYSE30 cell line. Relative comparative real-time PCR was used to confirm silencing of EZH2 and evaluate expression pattern of selected markers.

Results

Inhibition of EZH2 expression in KYSE30 cells caused significant changes in different genes. Indeed, HIWI and HEY1 genes were over- and underexpressed in KYSE30 cells, respectively, following EZH2 silencing. Other selected cancer stem cell markers were not changed significantly.

Conclusion

To the best our knowledge, there are variety of small molecule inhibitors to target EZH2 in cancer cells as a treatment candidate; therefore, our data in this study helps the researchers to select EZH2 for cancer therapy based on its mechanism and correlation with other markers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

CSCs:

Cancer stem cells

PRC2:

Polycomb repressive complex 2

H3K27me3:

Trimethylation of histone H3 lysine 27

TFs:

Transcription factors

PIWIL1:

Piwi-like protein 1

NICD:

Notch intracellular domain

References

  1. Melling N, Thomsen E, Tsourlakis MC, Kluth M, Hube-Magg C, Minner S, et al. Overexpression of enhancer of zeste homolog 2 (EZH2) characterizes an aggressivesubset of prostate cancers and predicts patient prognosis independently from pre-and postoperatively assessed clinicopathological parameters. Carcinogenesis. 2015;36(11):1333–40. doi:10.1093/carcin/bgv137.

    Article  CAS  Google Scholar 

  2. Liu Y, Liu T, Bao X, He M, Li L, Yang X. Increased EZH2 expression is associated with proliferation and progression of cervical cancer and indicates a poor prognosis. Int J Gynecol Pathol. 2014;33(3):218–24.

    Article  CAS  Google Scholar 

  3. Ahani N, Shirkoohi R, Rokouei M, Eskandani MA, Nikravesh A. Overexpression of enhancer of zeste human homolog 2 (EZH2) gene in human cytomegalovirus positive glioblastoma multiforme tissues. Med Oncol. 2014;31(11):1–5.

    Article  Google Scholar 

  4. Song-Bing H, Hao Z, Jian Z, Guo-Qiang Z, Tuo H, Dai-Wei W, et al. Inhibition of EZH2 expression is associated with the proliferation, apoptosis and migration of SW620 colorectal cancer cells in vitro. Exp. Biol. Med. 2014. doi:10.1177/1535370214542215.

    Article  Google Scholar 

  5. Liu F, Gu L, Cao Y, Fan X, Zhang F, Sang M. Aberrant overexpression of EZH2 and H3K27me3 serves as poor prognostic biomarker for esophageal squamous cell carcinoma patients. Biomarkers. 2016;21(1):80–90. doi:10.3109/1354750X.2015.1118537.

    Article  CAS  Google Scholar 

  6. Kondo Y. Targeting histone methyltransferase EZH2 as cancer treatment. J Biochem. 2014;156(5):249–57. doi:10.1093/jb/mvu054.

    Article  CAS  Google Scholar 

  7. Chou R-H, Yu Y-L, Hung M-C. The roles of EZH2 in cell lineage commitment. Am J Transl Res. 2011;3(3):243.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cox DN, Chao A, Baker J, Chang L, Qiao D, Lin H. A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes Dev. 1998;12(23):3715–27.

    Article  CAS  Google Scholar 

  9. Raeisossadati R, Abbaszadegan MR, Moghbeli M, Tavassoli A, Kihara AH, Forghanifard MM. Aberrant expression of DPPA2 and HIWI genes in colorectal cancer and their impacts on poor prognosis. Tumor Biol. 2014;35(6):5299–305.

    Article  CAS  Google Scholar 

  10. Wang Y, Jiang Y, Bian C, Dong Y, Ma C, Hu X, et al. Overexpression of Hiwi inhibits the cell growth of chronic myeloid leukemia K562 cells and enhances their chemosensitivity to daunomycin. Cell Biochem Biophys. 2015;73(1):129–35. doi:10.1007/s12013-015-0668-7.

    Article  CAS  Google Scholar 

  11. Xie Y, Yang Y, Ji D, Zhang D, Yao X, Zhang X. Hiwi downregulation, mediated by shRNA, reduces the proliferation and migration of human hepatocellular carcinoma cells. Mol Med Rep. 2015;11(2):1455–61.

    Article  CAS  Google Scholar 

  12. Wang D-W, Wang Z-H, Wang L-L, Song Y, Zhang G-Z. Overexpression of hiwi promotes growth of human breast cancer cells. Asian Pac J cancer Prev APJCP. 2013;15(18):7553–8.

    Article  Google Scholar 

  13. Li S, Meng L, Zhu C, Wu L, Bai X, Wei J, et al. The universal overexpression of a cancer testis antigen hiwi is associated with cancer angiogenesis. Oncol Rep. 2010;23(4):1063–8.

    Article  CAS  Google Scholar 

  14. Yang L, Bi L, Liu Q, Zhao M, Cao B, Li D, et al. Hiwi promotes the proliferation of colorectal cancer cells via upregulating global DNA methylation. Dis Markers. 2015;2015:383056. doi:10.1155/2015/383056.

    CAS  Google Scholar 

  15. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12(8):445–64. doi:10.1038/nrclinonc.2015.61.

    Article  CAS  Google Scholar 

  16. Deng G, Ma L, Meng Q, Ju X, Jiang K, Jiang P, et al. (2015) Notch signaling in the prostate: critical roles during development and in the hallmarks of prostate cancer biology. J Cancer Res Clin Oncol. 2016;142(3):531-47. doi:10.1007/s00432-015-1946-x.

    Article  Google Scholar 

  17. Forghanifard MM, Taleb S, Abbaszadegan MR. Notch signaling target genes are directly correlated to esophageal squamous cell carcinoma tumorigenesis. Pathol Oncol Res. 2015;21(2):463–7.

    Article  CAS  Google Scholar 

  18. Barde I, Salmon P, Trono D (2010) Production and titration of lentiviral vectors. Curr Protoc Cell Biol. 2011;26:Unit 26.8. doi:10.1002/0471143030.cb2608s50.

  19. Wassef M, Rodilla V, Teissandier A, Zeitouni B, Gruel N, Sadacca B, et al. Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis. Genes Dev. 2015;29(24):2547–62. doi:10.1101/gad.269522.115.

  20. Islam F, Gopalan V, Wahab R, Smith RA, Lam AK-Y. Cancer stem cells in oesophageal squamous cell carcinoma: identification, prognostic and treatment perspectives. Crit Rev Oncol Hematol. 2015;96(1):9–19. doi:10.1016/j.critrevonc.2015.04.007.

    Article  Google Scholar 

  21. Zhao RC, Zhu Y-S, Shi Y. New hope for cancer treatment: exploring the distinction between normal adult stem cells and cancer stem cells. Pharmacol Ther. 2008;119(1):74–82.

    Article  CAS  Google Scholar 

  22. Rad A, Farshchian M, Forghanifard MM, Matin MM, Bahrami AR, Geerts D, et al. Predicting the molecular role of MEIS1 in esophageal squamous cell carcinoma. Tumor Biol. 2016;37(2):1715–25.

    Article  CAS  Google Scholar 

  23. Yamaguchi H, Hung M-C. Regulation and role of EZH2 in cancer. Cancer Res Treat Off J Korean Cancer Assoc. 2014;46(3):209.

    CAS  Google Scholar 

  24. Liu X, Sun Y, Guo J, Ma H, Li J, Dong B, et al. Expression of hiwi gene in human gastric cancer was associated with proliferation of cancer cells. Int J Cancer. 2006;118(8):1922–9.

    Article  CAS  Google Scholar 

  25. Liang D, Yang Y, Liu Y (2013) The role Hiwi gene in the maintenance of lung cancer stem cell populations. Neoplasma. 2013. doi:10.4149/neo_2014_022.

  26. Liu W, Gao Q, Chen K, Xue X, Li M, Chen Q, et al. Hiwi facilitates chemoresistance as a cancer stem cell marker in cervical cancer. Oncol Rep. 2014;32(5):1853–60.

    Article  CAS  Google Scholar 

  27. Liekens AM, De Knijf J, Daelemans W, Goethals B, De Rijk P, Del-Favero J. BioGraph: unsupervised biomedical knowledge discovery via automated hypothesis generation. Genome Biol. 2011;12(6):R57.

    Article  Google Scholar 

  28. Taleb S, Abbaszadegan MR, Moghbeli M, Roudbari NH, Forghanifard MM. HES1 as an independent prognostic marker in esophageal squamous cell carcinoma. J Gastrointest Cancer. 2014;45(4):466–71.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge colleagues at the Human Genetics Division of Avicenna Research Institute for their helps and technical supports.

Author information

Author notes

  1. GholamReza Karami Madani and Abolfazl Rad contributed equally in this study.

Authors and Affiliations

  1. Department of Biology, Damghan Branch, Islamic Azad University, Cheshmeh-Ali Boulevard, Sa’dei Square, P.O. Box: 3671639998, Damghan, Iran

    GholamReza Karami Madani & Mohammad Mahdi Forghanifard

  2. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran

    Abolfazl Rad

  3. Department of Internal Medicine, Faculty of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran

    Mehdi Molavi

  4. Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Sima Ardalan Khales & Mohammad Reza Abbaszadegan

Authors
  1. GholamReza Karami Madani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abolfazl Rad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehdi Molavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sima Ardalan Khales
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Reza Abbaszadegan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammad Mahdi Forghanifard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Mahdi Forghanifard.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karami Madani, G., Rad, A., Molavi, M. et al. Predicting the Correlation of EZH2 and Cancer Stem Cell Markers in Esophageal Squamous Cell Carcinoma. J Gastrointest Canc 49, 437–441 (2018). https://doi.org/10.1007/s12029-017-9985-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-017-9985-y

Keywords

Search

Navigation