NANOG expression correlates with differentiation, metastasis and resistance to preoperative adjuvant therapy in oral squamous cell carcinoma

Watanabe,Masahiro; Ohnishi,Yuichi; Inoue,Hiroshi; Wato,Masahiro; Tanaka,Akio; Kakudo,Kenji; Nozaki,Masami

doi:10.3892/ol.2013.1690

NANOG expression correlates with differentiation, metastasis and resistance to preoperative adjuvant therapy in oral squamous cell carcinoma

Authors:
- Masahiro Watanabe
- Yuichi Ohnishi
- Hiroshi Inoue
- Masahiro Wato
- Akio Tanaka
- Kenji Kakudo
- Masami Nozaki
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Affiliations: Graduate School of Dentistry, Osaka Dental University, Hirakata, Osaka 573‑1121, Japan, Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565‑0871, Japan, Second Department of Oral and Maxillofacial Surgery, Osaka Dental University, Hirakata, Osaka 573‑1121, Japan, Oral Pathology, Osaka Dental University, Hirakata, Osaka 573‑1121, Japan
Published online on: November 19, 2013 https://doi.org/10.3892/ol.2013.1690
Pages: 35-40

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Abstract

NANOG protein, a transcription factor expressed in embryonic stem cells, is overexpressed in tumor development. Although studies investigating the function of NANOG in cancer have shown that it plays several roles, such as in cell proliferation, invasion and metastasis, the overall function of NANOG in cancer cells has remained elusive. In the present study, NANOG expression in oral squamous cell carcinoma (OSCC) was examined to determine its potential clinical significance. The expression of NANOG protein was assessed in 60 patients with OSCC by immunohistochemistry, and its correlation with clinicopathological factors and metastasis was evaluated. NANOG protein levels in human OSCC cell lines were determined by western blotting and immunofluorescence staining. NANOG protein expression was identified in 52 cases (86.7%) and expression levels were higher in primary foci of poorly differentiated OSCC than in those of well‑differentiated OSCC, indicating that NANOG expression is associated with OSCC differentiation. Regardless of the differentiation levels of primary foci, NANOG expression levels in metastatic foci were extremely high. In addition, NANOG expression in metastatic foci was maintained at high levels following preoperative adjuvant therapy. Furthermore, NANOG protein was detected at an identical level in human OSCC cell lines. These data indicate that NANOG‑expressing OSCC cells tend to metastasize and that metastatic tumors expressing NANOG may be resistant to preoperative adjuvant therapy, including chemoradiation. Thus, assessment of NANOG expression may assist the strategy for treatment of OSCC metastasis.

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1	Chen YJ, Lin SC, Kao T, et al: Genome-wide profiling of oral squamous cell carcinoma. J Pathol. 204:326–332. 2004. View Article : Google Scholar : PubMed/NCBI
2	Pentenero M, Gandolfo S and Carrozzo M: Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck. 27:1080–1091. 2005. View Article : Google Scholar
3	Myers JN, Elkins T, Roberts D and Byers RM: Squamous cell carcinoma of the tongue in young adults: increasing incidence and factors that predict treatment outcomes. Otolaryngol Head Neck Surg. 122:44–51. 2000. View Article : Google Scholar
4	Chambers I, Colby D, Robertson M, et al: Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 113:643–655. 2003. View Article : Google Scholar : PubMed/NCBI
5	Mitsui K, Tokuzawa Y, Itoh H, et al: The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 113:631–642. 2003. View Article : Google Scholar
6	Cavaleri F and Schöler HR: Nanog: a new recruit to the embryonic stem cell orchestra. Cell. 113:551–552. 2003. View Article : Google Scholar : PubMed/NCBI
7	Pan G and Thomson JA: Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 17:42–49. 2007. View Article : Google Scholar : PubMed/NCBI
8	Ezeh UI, Turek PJ, Reijo RA and Clark AT: Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer. 104:2255–2265. 2005. View Article : Google Scholar
9	Meng HM, Zheng P, Wang XY, et al: Overexpression of nanog predicts tumor progression and poor prognosis in colorectal cancer. Cancer Biol Ther. 9:295–302. 2010. View Article : Google Scholar : PubMed/NCBI
10	Xu F, Dai C, Zhang R, Zhao Y, Peng S and Jia C: Nanog: a potential biomarker for liver metastasis of colorectal cancer. Dig Dis Sci. 57:2340–2346. 2012. View Article : Google Scholar : PubMed/NCBI
11	Matsuoka J, Yashiro M, Sakurai K, et al: Role of the stemness factor sox2, oct3/4, and nanog in gastric carcinoma. J Surg Res. 174:130–135. 2012. View Article : Google Scholar
12	Tsai LL, Yu CC, Chang YC, Yu CH and Chou MY: Markedly increased Oct4 and Nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma. J Oral Pathol Med. 40:621–628. 2011. View Article : Google Scholar : PubMed/NCBI
13	Bourguignon LY, Earle C, Wong G, Spevak CC and Krueger K: Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 31:149–160. 2012. View Article : Google Scholar
14	Chiou SH, Yu CC, Huang CY, et al: Positive correlations of oct-4 and nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res. 14:4085–4095. 2008. View Article : Google Scholar : PubMed/NCBI
15	Zhang Q, Shi S, Yen Y, Brown J, Ta JQ and Le AD: A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett. 289:151–160. 2010.
16	Sobin LH and Wittekind C: International Union Against Cancer TNM classification of malignant tumors. 5th edition. Wiley-Liss Publications; Hoboken, NJ: 1997
17	Dalerba P, Cho RW and Clarke MF: Cancer Stem Cells: Models and Concepts. Annu Rev Med. 58:267–284. 2007. View Article : Google Scholar : PubMed/NCBI
18	Clarke MF, Dick JE, Dirks PB, et al: Cancer stem cells - perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar
19	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cell. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
20	Costea DE, Tsinkalovsky O, Vintermyr OK, Johannessen AC and Mackenzie IC: Cancer stem cells - new and potentially important targets for the therapy of oral squamous cell carcinoma. Oral Dis. 12:443–454. 2006. View Article : Google Scholar : PubMed/NCBI
21	Locke M, Heywood M, Fawell S and Mackenzie IC: Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res. 65:8944–8950. 2005. View Article : Google Scholar : PubMed/NCBI
22	Izumiya M, Kabashima A, Higuchi H, et al: Chemoresistance is associated with cancer stem cell-like properties and epithelial-to-mesenchymal transition in pancreatic cancer cells. Anticancer Res. 32:3847–3853. 2012.PubMed/NCBI
23	Moon JH, Kwon S, Jun EK, et al: Nanog-induced dedifferentiation of p53-deficient mouse astrocytes into brain cancer stem-like cells. Biochem Biophys Res Commun. 412:175–181. 2011.PubMed/NCBI
24	Chen SL, Iddings DM, Scheri RP and Bilchik AJ: Lymphatic mapping and sentinel node analysis: current concepts and applications. CA Cancer J Clin. 56:292–309. 2006. View Article : Google Scholar : PubMed/NCBI
25	Trivedi NP, Ravindran HK, Sundram S, et al: Pathologic evaluation of sentinel lymph nodes in oral squamous cell carcinoma. Head Neck. 32:1437–1443. 2010. View Article : Google Scholar : PubMed/NCBI
26	Kayahara H, Okuda M, Terakado N, Shintani S and Hamakawa H: Non-randomized clinical study comparing chemotherapy plus radiotherapy with radiotherapy alone in neoadjuvant therapy for oral cancer. Gan To Kagaku Ryoho. 29:911–916. 2002.(In Japanese).