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. 2019 Sep 3;8(9):1376.
doi: 10.3390/jcm8091376.

The Emerging Role of NANOG as an Early Cancer Risk Biomarker in Patients with Oral Potentially Malignant Disorders

Juan C de Vicente  1   2   3   4 , Tania Rodríguez-Santamarta  5   6   7   8 , Juan P Rodrigo  9   10   11   12   13 , Eva Allonca  14   15   16 , Aitana Vallina  17   18   19 , Anusha Singhania  20 , Paula Donate-Pérez Del Molino  21   22 , Juana M García-Pedrero  23   24   25   26   27
Affiliations

The Emerging Role of NANOG as an Early Cancer Risk Biomarker in Patients with Oral Potentially Malignant Disorders

Juan C de Vicente et al. J Clin Med. .

Abstract

NANOG, a key regulator of pluripotency and self-renewal in embryonic and adult stem cells, is frequently overexpressed in multiple cancers, including oral squamous cell carcinoma (OSCC). It has been frequently associated with poor outcomes in epithelial cancers, and recently implicated in laryngeal tumorigenesis. On this basis, we investigated the role of NANOG protein expression as an early cancer risk biomarker in oral potentially malignant disorders (OPMD), and the impact on prognosis and disease outcomes in OSCC patients. NANOG expression was evaluated by immunohistochemistry in 55 patients with oral epithelial dysplasia, and 125 OSCC patients. Correlations with clinical and follow-up data were assessed. Nuclear NANOG expression was detected in 2 (3.6%) and cytoplasmic NANOG expression in 9 (16.4%) oral dysplasias. NANOG expression increased with the grade of dysplasia. Cytoplasmic NANOG expression and the histopathological grading were significantly correlated with oral cancer risk, although dysplasia grading was the only significant independent predictor of oral cancer development in multivariate analyses. Cytoplasmic NANOG expression was also detected in 39 (31%) OSCC samples. Positive NANOG expression was significantly associated with tobacco and alcohol consumption, and was more frequent in pN0 tumors, early I-II stages. These data unveil the clinical relevance of NANOG in early stages of OSCC tumorigenesis rather than in advanced neoplastic disease. NANOG expression emerges as an early predictor of oral cancer risk in patients with OPMD.

Keywords: NANOG; immunohistochemistry; oral cancer risk; oral epithelial dysplasia; oral squamous cell carcinoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immunohistochemical analysis of NANOG expression in oral epithelial dysplasias and oral squamous cell carcinoma (OSCC). The normal adjacent epithelium exhibited negative staining (A). Representative examples of oral dysplasias showing negative (B), and positive NANOG staining (C), human seminoma as a positive control (D). Examples of oral squamous cell carcinomas with positive (E), and negative NANOG staining (F). Magnification 200×. Scale bar 200 µm.
Figure 2
Figure 2
Kaplan–Meier cancer-free survival curves in the cohort of 55 patients with oral epithelial dysplasia categorized by histological grading (low-grade vs. high-grade) (A), cytoplasmic NANOG (Staining scores 0, 1 and 2) (B) and nuclear NANOG expression (positive vs. negative) (C). Disease-specific survival curves in the cohort of 125 OSCC patients dichotomized according to NANOG expression (positive vs. negative) (D).
Figure 3
Figure 3
Analysis of NANOG and OCT4 mRNA expression using RNAseq data from the The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinomas (HNSCC) cohorts. (A) Box plots comparing the mRNA expression levels of NANOG and OCT4 in primary tumors (in red) VS. normal tissue (in blue) in the TCGA cohort of 530 HNSCC patients using the UALCAN online resources (http://ualcan.path.uab.edu/). (B) Oncoprint and heatmap representations showing the percentage of cases with mRNA upregulation of each CSC-related gene assessed in the subset of 172 OSCC patients from the TCGA HNSCC cohort [19]. (C) Kaplan–Meier survival curves categorized by NANOG mRNA expression (RNA seq V2 RSEM, z-score threshold ±2) dichotomized as normal vs. upregulation, P value estimated using the Log-rank test.
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