Clinical Oral Investigations

, Volume 22, Issue 3, pp 1131–1138 | Cite as

Prognostic implication of NOTCH1 in early stage oral squamous cell cancer with occult metastases

  • Shan Wang
  • Haixia Fan
  • Jiankai Xu
  • Eryang Zhao
Original Article



The objective of this study was to explore the prognostic value of cancer stem cell markers, namely CD133, NANOG, and NOTCH1, in early stage oral squamous cell carcinoma (OSCC).

Materials and methods

One hundred forty-four patients with early stage (cT1T2N0) OSCC were identified from a pre-existing database of patients with oral cancer. We examined the impact of the immunohistochemical expression of CD133, NANOG, and NOTCH1 in OSCC. Overall survival (OS) curves were calculated using the Kaplan–Meier method. Predictors of outcome were identified using multivariate analysis.


We found that CD133, NANOG, and NOTCH1 were significantly associated with lymph node metastasis, and NOTCH1 was also significantly associated with depth of invasion and locoregional recurrence.


NOTCH1 was identified as an independent prognostic factor for OS.

Clinical relevance

NOTCH1 might prove to be a useful indicator for high-risk patients with occult metastases from early stage OSCC.


CD133 NANOG NOTCH1 Oral squamous cell carcinoma Early stage 



This work was supported by grants from the Doctoral Program Foundation of First Affiliated Hospital of Harbin Medical University in China (no. 2016B015).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the First Affiliated Hospitals of Harbin Medical University Institutional Research Board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

784_2017_2197_MOESM1_ESM.pdf (110 kb)
ESM 1 (PDF 110 kb)
784_2017_2197_MOESM2_ESM.pdf (117 kb)
ESM 2 (PDF 117 kb)
784_2017_2197_MOESM3_ESM.pdf (111 kb)
ESM 3 (PDF 111 kb)


  1. 1.
    National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) web site. Accessed January 2011.
  2. 2.
    The 2012 Chinese Cancer Registry Annual Report. Military Science and Technology Press, Beijing, China 2012Google Scholar
  3. 3.
    Shim SJ, Cha J, Koom WS et al (2010) Clinical outcomes for T1–2N0–1 oral tongue cancer patients underwent surgery with and without postoperative radiotherapy. Radiat Oncol 27(5):43CrossRefGoogle Scholar
  4. 4.
    Yuen AP, Ho CM, Chow TL et al (2009) Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma. Head Neck. 31:765–772CrossRefPubMedGoogle Scholar
  5. 5.
    Mücke T, Mitchell DA, Wagenpfeil S et al (2014) Incidence and outcome for patients with occult lymph node involvement in T1and T2 oral squamous cell carcinoma: a prospective study. BMC Cancer 14:346CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ganly I, Patel S, Shah J (2012) Early stage squamous cell cancer of the oral tongue—clinicopathologic features affecting outcome. Cancer 118(1):101–111CrossRefPubMedGoogle Scholar
  7. 7.
    Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21(3):283–296CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Clarke MF, Dick JE, Dirks PB et al (2006) Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66(19):9339–9344CrossRefPubMedGoogle Scholar
  9. 9.
    Ghuwalewala S, Ghatak D, Das P et al (2016) CD44(high)CD24(low) molecular signature determines the cancer stem cell and EMT phenotype in oral squamous cell carcinoma. Stem Cell Res 16(2):405–417CrossRefPubMedGoogle Scholar
  10. 10.
    Shrivastava S, Steele R, Sowadski M et al (2015) Identification of molecular signature of head and neck cancer stem-like cells. Sci Rep 5:7819CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Barns L, Everson JW, Reichart P et al. Pathology and genetics of head and neck tumors[M]. Lyon: IARC Press 168–175Google Scholar
  12. 12.
    Elsir T, Edqvist P-H, Carlson J et al (2014) A study of embryonic stem cell-related proteins in human astrocytomas: identification of Nanog as a predictor of survival. Int J Cancer 134:1123–1131CrossRefPubMedGoogle Scholar
  13. 13.
    Hashimoto K, Aoyagi K, Isobe T et al (2014) Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer 17(1):97–106CrossRefPubMedGoogle Scholar
  14. 14.
    Sharma BK, Manglik V, O'Connell M et al (2012) Clonal dominance of CD133(+) subset population as risk factor in tumor progression and disease recurrence of human cutaneous melanoma. Int J Oncol 41(5):1570–1576CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lee HJ, Kang YH, Lee JS et al (2015) Positive expression of NANOG, mutant p53, and CD44 is directly associated with clinicopathological features and poor prognosis of oral squamous cell carcinoma. BMC Oral Health 15(1):153CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Shibahara I, Sonoda Y, Saito R et al (2013) The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence. Neuro-Oncology 15(9):1151–1159CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Raso A, Mascelli S, Biassoni R et al (2011) High levels of PROM1 (CD133) transcript are a potential predictor of poor prognosis in medulloblastoma. Neuro-Oncology 13:500–508CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Arne G, Kristiansson E, Nerman O et al (2011) Expression profiling of GIST:CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis. Int J Cancer 129:1149–1161CrossRefPubMedGoogle Scholar
  19. 19.
    Irollov E, Pirozzi G (2013) CD133: to be or not to be, is this the real question? Am J Transl Res 5(6):563–581Google Scholar
  20. 20.
    Collins AT, Berry PA, Hyde C et al (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951CrossRefPubMedGoogle Scholar
  21. 21.
    O’Brien CA, Pollett A, Gallinger S et al (2007) A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature 445:106–110CrossRefPubMedGoogle Scholar
  22. 22.
    Ravindran G, Sawant SS, Hague A et al (2015) Association of differential β-catenin expression with Oct-4 and Nanog in oral squamous cell carcinoma and their correlation with clinicopathological factors and prognosis. Head Neck 37:982–993CrossRefPubMedGoogle Scholar
  23. 23.
    Chiou SH, Yu CC, Huang CY et al (2008) Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res 14:4085–4095CrossRefPubMedGoogle Scholar
  24. 24.
    Watanabe M, Ohnishi Y, Inoue H et al (2014) NANOG expression correlates with differentiation, metastasis and resistance to preoperative adjuvant therapy in oral squamous cell carcinoma. Oncol Lett 7:35–40CrossRefPubMedGoogle Scholar
  25. 25.
    Li YM, Ma J, Qian XJ et al (2013) Regulation of EMT by Notch signaling pathway in tumor progression. Curr Cancer Drug Targets 13(9):957–962CrossRefPubMedGoogle Scholar
  26. 26.
    Zoni E, van der Pluijm G, Gray PC et al (2015) Epithelial plasticity in cancer: unmasking a MicroRNA network for TGF-β, Notch-, and Wnt-mediated EMT. J Oncol 2015:198967CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Espinoza I, Pochampally R, Xing F et al (2013) Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther 6:1249–1259PubMedPubMedCentralGoogle Scholar
  28. 28.
    Lee SH, Do SI, Lee HJ et al (2016) Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma. Lab Investig 96(5):508–516CrossRefPubMedGoogle Scholar
  29. 29.
    Fakih AR, Rao RS, Borges AM et al (1989) Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg 158:309–313CrossRefPubMedGoogle Scholar
  30. 30.
    Nakagawa T, Shibuya H, Yoshimura R et al (2003) Neck node metastasis after successful brachytherapy for early stage tongue carcinoma. Radiother Oncol 68:129–135CrossRefPubMedGoogle Scholar
  31. 31.
    Sparano A, Weinstein G, Chalian A et al (2000) Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 122:139–142CrossRefGoogle Scholar
  32. 32.
    Keski-Santti H, Atula T, Tikka J et al (2007) Predictive value of histopathologic parameters in early squamous cell carcinoma of oral tongue. Oral Oncol 43:1007–1013CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Shan Wang
    • 1
  • Haixia Fan
    • 2
  • Jiankai Xu
    • 3
  • Eryang Zhao
    • 1
  1. 1.Department of Oral Pathology, Hospital of Stomatology, The First Affiliated HospitalHarbin Medical UniversityHarbinPeople’s Republic of China
  2. 2.Department of Anatomy, Basic Medical Science CollegeHarbin Medical UniversityHarbinPeople’s Republic of China
  3. 3.College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinPeople’s Republic of China

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