Tumor Biology

, Volume 36, Issue 7, pp 5551–5559 | Cite as

Dormancy activation mechanism of oral cavity cancer stem cells

  • Xiang Chen
  • Xin Li
  • Baohong Zhao
  • Dehao Shang
  • Ming Zhong
  • Chunfu Deng
  • Xinshan Jia
Research Article


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.


Oral cancer Cancer stem cells Dormancy Activation Mechanism 



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

Conflicts of interest



  1. 1.
    Winning TA, Townsend GC. Oral mucosal embryology and histology. Clin Dermatol. 2000;18:499–511.CrossRefPubMedGoogle Scholar
  2. 2.
    Mackenzie I. Stem cells in oral mucosal epithelia. Oral Biosci Med. 2005;2:1–9.Google Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 5.
    Hume WJ, Potten CS. Advances in epithelial kinetics—an oral view. J Oral Pathol Med. 1979;8:3–22.CrossRefGoogle Scholar
  6. 6.
    Barrett AW, Selvarajah S, Franey S, et al. Interspecies variations in oral epithelial cytokeratin expression. J Anat. 1998;193:185–93.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 18.
    Pittenger MF. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.Google Scholar
  27. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 30.
    Bickenbach JR. Identification and behavior of label-retaining cells in oral mucosa and skin. J Dent Res. 1981;60:1611–20.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.CrossRefPubMedGoogle Scholar
  35. 35.
    Mascré G, Dekoninck S, Drogat B, et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature. 2012;489:257–62.CrossRefPubMedGoogle Scholar
  36. 36.
    Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat Rev Cancer. 2006;6:425–36.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 38.
    Hajkovap, Anelin K, Waldmaa T, et al. Chromatin dynamice during epigenetic reproraning in the active DNA demethylation. J Cell. 2008;133:1145–8.CrossRefGoogle Scholar
  39. 39.
    Delerba P, ChoR W, Larke MF. Cancer Stem Cell:Morels and Concests. J Annu Rev Med. 2007;58:267–84.CrossRefGoogle Scholar
  40. 40.
    Squier CA, Kremer MJ. Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr. 2011;29:7–15.Google Scholar
  41. 41.
    Igarashi T, Shimmura S, Yoshida S, et al. Isolation of oral epithelial progenitors using collagen IV. Oral Dis. 2008;14:413–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Xiang Chen
    • 1
  • Xin Li
    • 2
  • Baohong Zhao
    • 1
  • Dehao Shang
    • 1
  • Ming Zhong
    • 3
  • Chunfu Deng
    • 1
  • Xinshan Jia
    • 4
    • 5
  1. 1.Center of Implant Dentistry, School of StomatologyChina Medical UniversityShenyangChina
  2. 2.Department of Pharmacology, College of Life Science and BiopharmaceuticsShenyang Pharmaceutical UniversityShenyangChina
  3. 3.Department of Pathology, School of StomatologyChina Medical UniversityShenyangChina
  4. 4.Department of Pathology, the First Affiliated HospitalChina Medical UniversityShenyangChina
  5. 5.Department of Pathology, College of Basic Medical SciencesChina Medical UniversityShenyangChina

Personalised recommendations