Skip to main content

Advertisement

Log in

Differential expression of Oct4 in HPV-positive and HPV-negative cervical cancer cells is not regulated by DNA methyltransferase 3A

  • Research Article
  • Published:
Tumor Biology

Abstract

The colony-forming ability of cervical cancer is affected by many factors. Oct4, an important transcription factor, is highly expressed in several tumors and promotes the colony-forming ability of cancer cells. Thus, it is considered a potential target for the treatment of cancer. However, we know little about the expression level of Oct4 and its epigenetic regulatory mechanism in cervical cancer cells. In this study, we are the first to observe that human papillomavirus (HPV)-positive cervical cancer cell lines (HeLa, Caski) have a stronger colony-forming ability than HPV-negative cervical cancer cell lines (C-33A). Moreover, the expression level of Oct4 in both HeLa and Caski cells was also higher than that in C-33A cells. We then confirmed that there was a negative correlation between the expression of Oct4 and DNMT3A in these three types of cervical cancer cells, whereas DNA methyltransferase 1 and 3B had no differences among the cell lines. However, after DNA methylation in both key regulatory regions of the Oct4 gene and the genomic levels were analyzed, we found that DNA methyltransferase 3A could neither regulate the expression of Oct4 nor affect the whole level of genomic DNA methylation. These results suggest three points: (1) Oct4 might be treated as a new target for the treatment of cervical cancer, (2) we could not inhibit the expression of Oct4 by DNA demethylation, and (3) HPV virus might initiate cervical carcinogenesis by upregulation of Oct4 expression.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Boulet G, Horvath C, Vanden Broeck D, Sahebali S, Bogers J. Human papillomavirus: E6 and E7 oncogenes. Int J Biochem Cell Biol. 2007;39:2006–11.

    Article  PubMed  CAS  Google Scholar 

  2. Hamid NA, Brown C, Gaston K. The regulation of cell proliferation by the papillomavirus early proteins. Cell Mol Life Sci. 2009;66:1700–17.

    Article  PubMed  CAS  Google Scholar 

  3. Thomas M, Narayan N, Pim D, Tomaić V, Massimi P, Nagasaka K, et al. Human papillomaviruses, cervical cancer and cell polarity. Oncogene. 2008;27:7018–30.

    Article  PubMed  CAS  Google Scholar 

  4. Woodman Ciaran BJ, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7:11–22.

    Article  PubMed  CAS  Google Scholar 

  5. Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ, et al. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev. 2009;18:1093–108.

    Article  PubMed  CAS  Google Scholar 

  6. Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE. Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis. 2005;26:495–502.

    Article  PubMed  CAS  Google Scholar 

  7. Friedman S, Lu M, Schultz A, Thomas D, Lin RY. CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin. PLoS One. 2009;4:e5395.

    Article  PubMed  Google Scholar 

  8. Du Z, Jia D, Liu S, Wang F, Li G, Zhang Y, et al. Oct4 is expressed in human gliomas and promotes colony formation in glioma cells. Glia. 2009;57:724–33.

    Article  PubMed  Google Scholar 

  9. Hu T, Liu S, Breiter DR, Wang F, Tang Y, Sun S. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res. 2008;68:6533–40.

    Article  PubMed  CAS  Google Scholar 

  10. Feng D, Peng C, Li C, Zhou Y, Li M, Ling B, et al. Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri. Oncol Rep. 2009;22:1129–34.

    PubMed  CAS  Google Scholar 

  11. Yang HM, Do HJ, Kim DK, Park JK, Chang WK, Chung HM, et al. Transcriptional regulation of human Oct4 by steroidogenic factor-1. J Cell Biochem. 2007;101:1198–209.

    Article  PubMed  CAS  Google Scholar 

  12. Gu P, Goodwin B, Chung AC, Xu X, Wheeler DA, Price RR, et al. Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol Cell Biol. 2005;25:3492–505.

    Article  PubMed  CAS  Google Scholar 

  13. Miranda TB, Jones PA. DNA methylation: the nuts and bolts of repression. J Cell Physiol. 2007;213(2):384–90.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang HJ, Siu MK, Wong ES, Wong KY, Li AS, Chan KY, et al. Oct4 is epigenetically regulated by methylation in normal placenta and gestational trophoblastic disease. Placenta. 2008;29:549–54.

    Article  PubMed  CAS  Google Scholar 

  15. Liang J, Wan M, Zhang Y, Gu P, Xin H, Jung SY, et al. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat Cell Biol. 2008;10:731–9.

    Article  PubMed  CAS  Google Scholar 

  16. Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 2009;137:647–58.

    Article  PubMed  CAS  Google Scholar 

  17. Gunaratne PH. Embryonic stem cell microRNAs defining factors in induced pluripotent (iPS) and cancer (CSC) stem cells? Curr Stem Cell Res Ther. 2009;4:168–77.

    Article  PubMed  CAS  Google Scholar 

  18. Wei F, Schöler HR, Atchison ML. Sumoylation of Oct4 enhances its stability, DNA binding, and transactivation. J Biol Chem. 2007;282:21551–60.

    Article  PubMed  CAS  Google Scholar 

  19. Saxe JP, Tomilin A, Schöler HR, Plath K, Huang J. Post-translational regulation of Oct4 transcriptional activity. PLoS One. 2009;4:e4467.

    Article  PubMed  Google Scholar 

  20. Loh YH, Agarwal S, Park IH, Urbach A, Huo H, Heffner GC, et al. Generation of induced pluripotent stem cells from human blood. Blood. 2009;113:5476–9.

    Article  PubMed  CAS  Google Scholar 

  21. Dueñas-González A, Lizano M, Candelaria M, Cetina L, Arce C, Cervera E. Epigenetics of cervical cancer: an overview and therapeutic perspectives. Mol Cancer. 2005;4:38.

    Article  PubMed  Google Scholar 

  22. Kang S, Kim JW, Kang GH, Park NH, Song YS, Kang SB, et al. Polymorphism in folate- and methionine-metabolizing enzyme and aberrant CpG island hypermethylation in uterine cervical cancer. Gynecol Oncol. 2005;96:173–80.

    Article  PubMed  CAS  Google Scholar 

  23. Sonoda Y, Ozawa T, Hirose Y, Aldape KD, McMahon M, Berger MS, et al. Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res. 2001;61:4956–60.

    PubMed  CAS  Google Scholar 

  24. Mills KI, Ramsahoye BH. DNA methylation protocols. In: Ramsahoye BH, editor. Measurement of genome-wide DNA cytosine-5 methylation by reversed-phase high-pressure liquid chromatography. Totowa: Humana Press; 2001. p. 17–28.

    Google Scholar 

  25. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. PNAS. 2007;104:15805–10.

    Article  PubMed  CAS  Google Scholar 

  26. Sperança MA, Batista LM, Lourenço Rda S, Tavares WM, Bertolucci PH, Rigolin Vde O, et al. Can the rDNA methylation pattern be used as a marker for Alzheimer's disease? Alzheimers Dement. 2008;4(6):438–42.

    Article  PubMed  Google Scholar 

  27. Kumar D, Verma M. Methods in cancer epigenetics and epidemiology. Methods Mol Biol. 2009;471:273–88.

    Article  PubMed  CAS  Google Scholar 

  28. Cantz T, Key G, Bleidissel M, Gentile L, Han DW, Brenne A, et al. Absence of OCT4 expression in somatic tumor cell lines. Stem Cells. 2008;26:692–7.

    Article  PubMed  CAS  Google Scholar 

  29. Atlasi Y, Mowla SJ, Ziaee SA, Gokhale PJ, Andrews PW. OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells. 2008;26:3068–74.

    Article  PubMed  CAS  Google Scholar 

  30. Suo G, Han J, Wang X, Zhang J, Zhao Y, Zhao Y, et al. Oct4 pseudogenes are transcribed in cancers. BBRC. 2005;337:1047–51.

    PubMed  CAS  Google Scholar 

  31. Liedtke S, Enczmann J, Waclawczyk S, Wernet P, Kögler G. Oct4 and its pseudogenes confuse stem cell research. Cell Stem Cell. 2007;1:364–6.

    Article  PubMed  CAS  Google Scholar 

  32. Zhao S, Yuan QH, Hao HB, Guo YJ, Liu SM, Zhang YM, et al. Hao AJ expression of OCT4 pseudogenes in human tumours: lessons from glioma and breast carcinoma. J Pathol. 2011;223:672–82.

    Article  PubMed  CAS  Google Scholar 

  33. Cauffman G, Liebaers I, Van Steirteghem A, Van de Velde H. POU5F1 isoforms show different expression patterns in human embryonic stem cells and preimplantation embryos. Stem Cells. 2006;24(12):2685–91.

    Article  PubMed  CAS  Google Scholar 

  34. Lee J, Kim HK, Rho JY, Han YM, Kim J. The human OCT-4 isoforms differ in their ability to confer self-renewal. J Biol Chem. 2006;281(44):33554–65.

    Article  PubMed  CAS  Google Scholar 

  35. Altun G, Loring JF, Laurent LC. DNA methylation in embryonic stem cells. J Cell Biochem. 2010;109:1–6.

    PubMed  CAS  Google Scholar 

  36. Gu P, Le Menuet D, Chung AC, Cooney AJ. Differential recruitment of methylated CpG binding domains by the orphan receptor GCNF initiates the repression and silencing of Oct4 expression. Mol Cell Biol. 2006;26:9471–83.

    Article  PubMed  CAS  Google Scholar 

  37. Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, et al. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol. 2006;8:188–94.

    Article  PubMed  CAS  Google Scholar 

  38. Ishii T, Kohu K, Yamada S, Ishidoya S, Kanto S, Fuji H, et al. Up-regulation of DNA-methyltransferase 3A expression is associated with hypomethylation of intron 25 in human testicular germ cell tumors. Tohoku J Exp Med. 2007;212:177–90.

    Article  PubMed  CAS  Google Scholar 

  39. Nehls K, Vinokurova S, Schmidt D, Kommoss F, Reuschenbach M, Kisseljov F, et al. p16 methylation does not affect protein expression in cervical carcinogenesis. Eur J Cancer. 2008;44:2496–505.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Qian Zhang, Yan Zhang, Hongming Miao, and Chang Su for their technical assistance. We also want to thank Min Chen and Rong-Xia Liao (Medical English Department, Third Military Medical University, China) for a critical reading of the manuscript and kindly giving precious advice.

Disclosure statement

All authors have read and approved the manuscript for journal submission. The authors declare that they have no conflicts of interest. This paper has not been submitted elsewhere for consideration of publication.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yingru Zheng or Fengtian He.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, D., Zhou, P., Zhang, L. et al. Differential expression of Oct4 in HPV-positive and HPV-negative cervical cancer cells is not regulated by DNA methyltransferase 3A. Tumor Biol. 32, 941–950 (2011). https://doi.org/10.1007/s13277-011-0196-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-011-0196-z

Keywords

Navigation