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Dormancy activation mechanism of oral cavity cancer stem cells

Tumor Biology volume 36, pages 5551–5559 (2015)Cite this article

Abstract

Radiotherapy and chemotherapy are targeted primarily at rapidly proliferating cancer cells and are unable to eliminate cancer stem cells in the G0 phase. Thus, these treatments cannot prevent the recurrence and metastasis of cancer. Understanding the mechanisms by which cancer stem cells are maintained in the dormant G0 phase, and how they become active is key to developing new cancer therapies. The current study found that the anti-cancer drug 5-fluorouracil, acting on the oral squamous cell carcinoma KB cell line, selectively killed proliferating cells while sparing cells in the G0 phase. Bisulfite sequencing PCR showed that demethylation of the Sox2 promoter led to the expression of Sox2. This then resulted in the transformation of cancer stem cells from the G0 phase to the division stage and suggested that the transformation of cancer stem cells from the G0 phase to the division stage is closely related to an epigenetic modification of the cell.

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References

  1. Winning TA, Townsend GC. Oral mucosal embryology and histology. Clin Dermatol. 2000;18:499–511.

    Article  CAS  PubMed  Google Scholar 

  2. Mackenzie I. Stem cells in oral mucosal epithelia. Oral Biosci Med. 2005;2:1–9.

    Google Scholar 

  3. Sen S, Sharma S, Gupta A, et al. Molecular characterization of explant cultured human oral mucosal epithelial cells. Invest Ophthalmol Vis Sci. 2011;52:9548–54.

    Article  CAS  PubMed  Google Scholar 

  4. Jones PH, Watt FM. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell. 1993;73:713–24.

    Article  CAS  PubMed  Google Scholar 

  5. Hume WJ, Potten CS. Advances in epithelial kinetics—an oral view. J Oral Pathol Med. 1979;8:3–22.

    Article  CAS  Google Scholar 

  6. Barrett AW, Selvarajah S, Franey S, et al. Interspecies variations in oral epithelial cytokeratin expression. J Anat. 1998;193:185–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen JS, Pardo FS, Wang-Rodriguez J, et al. EGFR regulates the side population in head and neck squamous cell carcinoma. Laryngoscope. 2006;116:401–6.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang QZ, Nguyen AL, Yu WH, et al. Human oral mucosa and gingiva: a unique reservoir for mesenchymal stem cells. J Dent Res. 2012;91:1011–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang Q, Shi S, Yen Y, et al. A subpopulation of CD133 + cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett. 2010;289:151–60.

    Article  CAS  PubMed  Google Scholar 

  10. Ravindran G, Devaraj H. Aberrant expression of CD133 and musashi-1 in preneoplastic and neoplastic human oral squamous epithelium and their correlation with clinicopathological factors. Head Neck. 2012;34:1129–35.

    Article  PubMed  Google Scholar 

  11. Chiou SH, Yu CC, Huang CY, et al. Positive correlations of Oct3/4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res. 2008;14:4085–95.

    Article  CAS  PubMed  Google Scholar 

  12. Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000;24:372–6.

    Article  CAS  PubMed  Google Scholar 

  13. Szotek PP, Pieretti-Vanmarcke R, et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proc Natl Acad Sci U S A. 2006;103:11154–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Häyry V, Makinen LK, Atula T, et al. Bmi-1 expression predicts prognosis in squamous cell carcinoma of the tongue. Br J Cancer. 2010;102:892–7.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Köse O, Lalli A, Kutulola AO, et al. Changes in the expression of stem cell markers in oral lichen planus and hyperkeratotic lesions. J Oral Sci. 2007;49:133–9.

    Article  PubMed  Google Scholar 

  16. Chen YC, Hsu HS, Chen YW, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One. 2008;3:e2637.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Haraguchi N, Utsunomiya T, Inoue H, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006;24:506–13.

    Article  CAS  PubMed  Google Scholar 

  18. Pittenger MF. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    Article  CAS  PubMed  Google Scholar 

  19. Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2007;26:101–6.

    Article  PubMed  Google Scholar 

  20. Kiyosue T, Collins CA, Nascimento E, et al. Immunohistochemical location of the p75 neurotrophin receptor (p75NTR) in oral leukoplakia and oral squamous cell carcinoma. Int J Clin Oncol. 2013;18:154–63.

    Article  CAS  PubMed  Google Scholar 

  21. Levina V, Marrangoni AM, DeMarco R, et al. Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS One. 2008;3:e3077.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ma XB, Jia XS, Liu YL, et al. Expression and role of notch signaling in the regeneration of rat tracheal epithelium. Cell Prolif. 2009;42:15–28.

    Article  CAS  PubMed  Google Scholar 

  23. Gidekel S, Pizov G, Bergman Y, et al. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell. 2003;4:361–70.

    Article  CAS  PubMed  Google Scholar 

  24. Tsai LL, Yu CC, Chang YC, et al. Markedly increased Oct4 and Nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma. J Oral Pathol Med. 2011;40:621–8.

    Article  CAS  PubMed  Google Scholar 

  25. Cutright DE, Bauer H. Cell renewal in the oral mucosa and skin of the rat. I. Turnover time. Oral Surg Oral Med Oral Pathol. 1967;23:249–59.

    Article  CAS  PubMed  Google Scholar 

  26. Ichimura T, Watanabe S, Sakamoto Y, et al. Transcriptional repression and heterochromatin formation by MBD1 and MCAF/AM family proteins. J Biol Chem. 2005;280:13928–35.

  27. Hussenet T, Dali S, Exinger J, Monga B, Jost B, et al. SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas. PLoS One. 2010;5:e8960.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yuan P, Kadara H, Behrens C, et al. Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. PLoS One. 2010;5:e9112.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2-cancer cells are similarly tumorigenic. Cancer Res. 2005;65:6207–19.

    Article  CAS  PubMed  Google Scholar 

  30. Bickenbach JR. Identification and behavior of label-retaining cells in oral mucosa and skin. J Dent Res. 1981;60:1611–20.

    Article  PubMed  Google Scholar 

  31. Takeda T, Sugihara K, Hirayama Y, et al. Immunohistological evaluation of Ki-67, p63, CK19 and p53 expression in oral epithelial dysplasias. J Oral Pathol Med. 2006;35:369–75.

    Article  CAS  PubMed  Google Scholar 

  32. Tani H, Morris RJ, Kaur P. Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci U S A. 2000;97:10960–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Clay MR, Tabor M, Owen JH, et al. Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck. 2010;32:1195–201.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    Article  CAS  PubMed  Google Scholar 

  35. Mascré G, Dekoninck S, Drogat B, et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature. 2012;489:257–62.

    Article  PubMed  Google Scholar 

  36. Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat Rev Cancer. 2006;6:425–36.

    Article  CAS  PubMed  Google Scholar 

  37. Song N, Jia X-S, Jia L-L, et al. Expression and role of Oct3/4, Nanog and Sox2 in regeneration of rat tracheal epithelium. Cell Prolif. 2010;43:49–55.

    Article  CAS  PubMed  Google Scholar 

  38. Hajkovap, Anelin K, Waldmaa T, et al. Chromatin dynamice during epigenetic reproraning in the active DNA demethylation. J Cell. 2008;133:1145–8.

    Article  Google Scholar 

  39. Delerba P, ChoR W, Larke MF. Cancer Stem Cell:Morels and Concests. J Annu Rev Med. 2007;58:267–84.

    Article  Google Scholar 

  40. Squier CA, Kremer MJ. Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr. 2011;29:7–15.

    Google Scholar 

  41. Igarashi T, Shimmura S, Yoshida S, et al. Isolation of oral epithelial progenitors using collagen IV. Oral Dis. 2008;14:413–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant no. 81370100 to Xinshan Jia).

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Authors and Affiliations

  1. Center of Implant Dentistry, School of Stomatology, China Medical University, Shenyang, China

    Xiang Chen, Baohong Zhao, Dehao Shang & Chunfu Deng

  2. Department of Pharmacology, College of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China

    Xin Li

  3. Department of Pathology, School of Stomatology, China Medical University, Shenyang, China

    Ming Zhong

  4. Department of Pathology, the First Affiliated Hospital, China Medical University, Shenyang, China

    Xinshan Jia

  5. Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China

    Xinshan Jia

Authors
  1. Xiang Chen
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  2. Xin Li
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  3. Baohong Zhao
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  4. Dehao Shang
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  5. Ming Zhong
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  6. Chunfu Deng
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  7. Xinshan Jia
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Correspondence to Chunfu Deng.

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Cite this article

Chen, X., Li, X., Zhao, B. et al. Dormancy activation mechanism of oral cavity cancer stem cells. Tumor Biol. 36, 5551–5559 (2015). https://doi.org/10.1007/s13277-015-3225-5

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  • DOI: https://doi.org/10.1007/s13277-015-3225-5

Keywords

  • Oral cancer
  • Cancer stem cells
  • Dormancy
  • Activation
  • Mechanism