Skip to main content

Advertisement

SpringerLink
Log in

Expression of cancer stem cell marker during 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

One of the theories regarding oral carcinogenesis is that the tumor growth is initiated from cancer stem cells (CSCs) that self-renew and give rise to differentiated tumor cells, like stem cells do in normal tissues. The most common methods of CSC identification are based on CSC marker expression in carcinogenesis. This study examined the expression of CD133 and CD44, the most commonly used CSC biomarkers in oral squamous cell sarcoma (SCC), with the goal of identifying molecular biomarkers whose expression is associated with the multistep oral carcinogenesis. The expression of CD133, CD44, proliferating cell nuclear antigen (PCNA), and Cytokeratin (CK) was examined by Western blot analysis and confirmed by immunohistochemistry in a 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis model. Also, the expression of aldehyde dehydrogenase 1 (ALDH1), OCT-4 and Nanog were investigated for alteration of cancer cell stemness by Western blot. Along with the progress of multistep carcinogenesis, there were slight increases of CD133 and CD44 expression in the dysplasia group compared with normal rats. However, CD133 protein level was significantly overexpressed in SCC. The expression of PCNA and CK were low in normal group, but sequentially increased in SCC. ALDH1, Nanog and OCT-4 expression were significantly increased according to SCC grade during carcinogenesis. The findings indicate that CD133 is useful in identifying oral CSCs, which suggests that CD133 may serve as a predictor to identify CSCs with a high risk of oral cancer development.

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
Fig. 4

Similar content being viewed by others

References

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Carvalho JG, Noguti J, da Silva VH, Dedivitis RA, Franco M, Ribeiro DA (2012) Alkylation-induced genotoxicity as a predictor of DNA repair deficiency following experimental oral carcinogenesis. J Mol Histol 43:145–150

    Article  CAS  PubMed  Google Scholar 

  • Celis JE, Celis A (1985) Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. Proc Natl Acad Sci USA 82:3262–3266

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, Chang HT, Chen YS, Lin TW, Hsu HS, Wu CW (2010) Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial–mesenchymal transdifferentiation. Cancer Res 70:10433–10444

    Article  CAS  PubMed  Google Scholar 

  • Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, Wolf GT, Wicha MS, Prince ME (2010) Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck 32:1195–1201

    Article  PubMed Central  PubMed  Google Scholar 

  • Dalley AJ, AbdulMajeed AA, Upton Z, Farah CS (2013) Organotypic culture of normal, dysplastic and squamous cell carcinoma-derived oral cell lines reveals loss of spatial regulation of CD44 and p75 NTR in malignancy. J Oral Pathol Med 42:37–46

    Article  CAS  PubMed  Google Scholar 

  • Fracalossi AC, Miranda SR, Oshima CT, Franco M, Ribeiro DA (2010) The role of matrix metalloproteinases 2 and 9 during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. J Mol Histol 41:19–25

    Article  CAS  PubMed  Google Scholar 

  • Grosse-Gehling P, Fargeas CA, Dittfeld C, Garbe Y, Alison MR, Corbeil D, Kunz-Schughart LA (2013) CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. J Pathol 229:355–378

    Article  CAS  PubMed  Google Scholar 

  • Hsu HS, Huang PI, Chang YL, Tzao C, Chen YW, Shih HC, Hung SC, Chen YC, Tseng LM, Chiou SH (2011) Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells. Cancer 117:2970–2985

    Article  CAS  PubMed  Google Scholar 

  • Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL (2004) Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351:657–667

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  • Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, Wang H, Liu Z, Su Y, Stass SA, Katz RL (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7:330–338

    Article  CAS  PubMed  Google Scholar 

  • Liu W, Wu L, Shen XM, Shi LJ, Zhang CP, Xu LQ, Zhou ZT (2013a) Expression patterns of cancer stem cell markers ALDH1 and CD133 correlate with a high risk of malignant transformation of oral leukoplakia. Int J Cancer 132:868–874

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Chen L, Jiang Z, Wang J, Su Z, Li G, Yu S, Liu Z (2013b) Malignant behaviorial characteristics of CD133(±) glioblastoma cells from a Northern Chinese population. Exp Ther Med 5:65–72

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lumerman H, Freedman P, Kerpel S (1995) Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79:321–329

    Article  CAS  PubMed  Google Scholar 

  • Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, Guan XY (2008) Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 6:1146–1153

    Article  CAS  PubMed  Google Scholar 

  • Margaritescu C, Pirici D, Simionescu C, Stepan A (2011) The utility of CD44, CD117 and CD133 in identification of cancer stem cells (CSC) in oral squamous cell carcinomas (OSCC). Rom J Morphol Embryol 52:985–993

    PubMed  Google Scholar 

  • Mine H, Sakurai T, Kashida H, Matsui S, Nishida N, Nagai T, Hagiwara S, Watanabe T, Kudo M (2013) Association of gankyrin and stemness factor expression in human colorectal cancer. Dig Dis Sci 58:2337–2344

    Article  CAS  PubMed  Google Scholar 

  • Miranda SR, Noguti J, Carvalho JG, Oshima CT, Ribeiro DA (2011) Oxidative DNA damage is a preliminary step during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. J Mol Histol 42:181–186

    Article  CAS  PubMed  Google Scholar 

  • Noguti J, De Moura CF, De Jesus GP, Da Silva VH, Hossaka TA, Oshima CT, Ribeiro DA (2012) Metastasis from oral cancer: an overview. Cancer Genomic Proteomics 9:329–335

    CAS  Google Scholar 

  • Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902

    Article  CAS  PubMed  Google Scholar 

  • Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146

    Article  CAS  PubMed  Google Scholar 

  • Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reid BC, Rozier RG (2006) Continuity of care and early diagnosis of head and neck cancer. Oral Oncol 42:510–516

    Article  PubMed  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro DA, Favero Salvadori DM, da Silva RN, Ribeiro Darros B, Alencar Marques ME (2004) Genomic instability in non-neoplastic oral mucosa cells can predict risk during 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Oral Oncol 40:910–915

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro DA, Kitakawa D, Domingues MA, Cabral LA, Marques ME, Salvadori DM (2007) Survivin and inducible nitric oxide synthase production during 4NQO-induced rat tongue carcinogenesis: a possible relationship. Exp Mol Pathol 83:131–137

    Article  CAS  PubMed  Google Scholar 

  • Romanach MJ, Azevedo RS, Carlos R, de Almeida OP, Pires FR (2010) Clinicopathological and immunohistochemical features of oral spindle cell carcinoma. J Oral Pathol Med 39:335–341

    Article  PubMed  Google Scholar 

  • Sathi GA, Tamamura R, Tsujigiwa H, Katase N, Lefeuvre M, Siar CH, Matsuda H, Nagatsuka H (2012) Analysis of immunoexpression of common cancer stem cell markers in ameloblastoma. Exp Ther Med 3:397–402

    PubMed Central  PubMed  Google Scholar 

  • Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D’Angelica M, Kemeny N, Lyden D, Rafii S (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133− metastatic colon cancer cells initiate tumors. J Clin Invest 118:2111–2120

    CAS  PubMed Central  PubMed  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  CAS  PubMed  Google Scholar 

  • van Diest PJ, Brugal G, Baak JP (1998) Proliferation markers in tumours: interpretation and clinical value. J Clin Pathol 51:716–724

    Article  PubMed Central  PubMed  Google Scholar 

  • Wu G, Sun X, Yuan H, Hu M (2013) Ezrin gene expression and protein production in the CD44(+) subpopulation of SCC-9 cells in a malignant oral cancer cell line in vitro. J Oral Maxillofac Surg 71:e151–e157

    Article  PubMed  Google Scholar 

  • Yu GY, Gao Y, Peng X, Chen Y, Zhao FY, Wu MJ (2008) A clinicopathologic study on basaloid squamous cell carcinoma in the oral and maxillofacial region. Int J Oral Maxillofac Surg 37:1003–1008

    Article  PubMed  Google Scholar 

  • Zhang J, Wang X, Chen B, Xiao Z, Li W, Lu Y, Dai J (2010a) The human pluripotency gene NANOG/NANOGP8 is expressed in gastric cancer and associated with tumor development. Oncol Lett 1:457–463

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Q, Shi S, Yen Y, Brown J, Ta JQ, Le AD (2010b) A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett 289:151–160

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (NRF-201310008107) and the National Research Foundation of Korea (NRF) Grant funded by the Korea Government (MSIP) (No. 2011-0030759).

Author information

Authors and Affiliations

  1. The Division of Natural Medical Sciences, College of Health Science, Chosun University, Dong-Gu, Gwangju, Korea

    Wonbong Lim

  2. Department of Oral Pathology, Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Bug-Gu, Gwangju, 500-757, Korea

    Hongran Choi, Jisun Kim, Sangwoo Kim, Sangmi Jeon, Kou Ni & Okjoon Kim

  3. Department of Oral Maxillofacial and Surgery, Dental Science Research Institute, School of Dentistry, Chonnam National University, Bug-Gu, Gwangju, Korea

    Sung-yong Song & Hee-kyun Oh

  4. Department of Oral Medicine, Dental Science Research Institute, School of Dentistry, Chonnam National University, Bug-Gu, Gwangju, Korea

    Yeonggwan Im

  5. Department of Orthopaedic Surgery, Chosun University Hospital, Dong-Gu, Gwangju, Korea

    Gwangchul Lee, Jun Young Lee, Young Lae Moon & Jae Won You

Authors
  1. Wonbong Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongran Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jisun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sangwoo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sangmi Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kou Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sung-yong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hee-kyun Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yeonggwan Im
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gwangchul Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jun Young Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Young Lae Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jae Won You
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Okjoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Okjoon Kim.

Additional information

Wonbong Lim and Hongran Choi have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lim, W., Choi, H., Kim, J. et al. Expression of cancer stem cell marker during 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. J Mol Hist 45, 653–663 (2014). https://doi.org/10.1007/s10735-014-9584-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-014-9584-1

Keywords

Search

Navigation