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. 2010 Feb 9;5(2):e9112.
doi: 10.1371/journal.pone.0009112.

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

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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

Ping Yuan et al. PLoS One. .

Abstract

Background: Non-small cell lung cancer (NSCLC) represents the majority (85%) of lung cancers and is comprised mainly of adenocarcinomas and squamous cell carcinomas (SCCs). The sequential pathogenesis of lung adenocarcinomas and SCCs occurs through dissimilar phases as the former tumors typically arise in the lung periphery whereas the latter normally arise near the central airway.

Methodology/principal findings: We assessed the expression of SOX2, an embryonic stem cell transcriptional factor that also plays important roles in the proliferation of basal tracheal cells and whose expression is restricted to the main and central airways and bronchioles of the developing and adult mouse lung, in NSCLC by various methodologies. Here, we found that SOX2 mRNA levels, from various published datasets, were significantly elevated in lung SCCs compared to adenocarcinomas (all p<0.001). Moreover, a previously characterized OCT4/SOX2/NANOG signature effectively separated lung SCCs from adenocarcinomas in two independent publicly available datasets which correlated with increased SOX2 mRNA in SCCs. Immunohistochemical analysis of various histological lung tissue specimens demonstrated marked nuclear SOX2 protein expression in all normal bronchial epithelia, alveolar bronchiolization structures and premalignant lesions in SCC development (hyperplasia, dysplasia and carcinoma in situ) and absence of expression in all normal alveoli and atypical adenomatous hyperplasias. Moreover, SOX2 protein expression was greatly higher in lung SCCs compared to adenocarcinomas following analyses in two independent large TMA sets (TMA set I, n = 287; TMA set II, n = 511 both p<0.001). Furthermore, amplification of SOX2 DNA was detected in 20% of lung SCCs tested (n = 40) and in none of the adenocarcinomas (n = 17).

Conclusions/significance: Our findings highlight a cell-lineage gene expression pattern for the stem cell transcriptional factor SOX2 in the pathogenesis of lung SCCs and suggest a differential activation of stem cell-related pathways between squamous cell carcinomas and adenocarcinomas of the lung.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Increased expression of SOX2 mRNA in lung SCCs relative to adenocarcinomas.
A. Normalized centered SOX2 mRNA expression levels downloaded from four published microarray data sets as described in the Methods. The lead author of each published microarray cohort data is indicated in each panel. The number of analyzed samples is indicated below each column bar. p-values represent statistical significance assessed by independent two-sided t-tests. B. Hierarchical cluster analysis with average linkage of the expression of the previously characterized OCT4/SOX2/NANOG signature using present probe sets features in the array platforms of the datasets by Bhattacharjee et al. (B), and Bild et al. (C). Data are represented in a matrix format in which individual rows represent single gene features and columns represent experiments. High or low gene expression levels are indicated by red or green color, respectively as indicated by the log2 transformed scale bars. D. Principal component analysis of the signature in the Bild et al. dataset using metric centered correlation.
Figure 2
Figure 2. SOX2 protein is highly expressed in the pathogenesis of lung SCC but not of adenocarcinoma.
A. Representative photomicrographs displaying the immunohistochemical expression of SOX2 protein in histological tissue sections of normal bronchial epithelia, preneoplastic lesions representing SCC development (Hyperplasia, Dysplasia and carcinoma in situ), and in well (Well SCC) and poorly (Poor SCC) differentiated SCCs. B. Representative photomicrographs of SOX2 expression in lung parenchyma (LP), atypical adenomatous hyperplasia (AAH), alveolar bronchiolization structures (AB), and in acinar adenocarcinoma and bronchioalveolar carcinoma (BAC).
Figure 3
Figure 3. Increased SOX2 expression in lung SCCs compared to adenocarcinomas and its association with smoking patterns.
Box-plot depicting statistical analysis by the Wilcoxon-rank test of differences in nuclear SOX2 protein score in both TMA sets I and II between lung adenocarcinomas (ADC) and SCCs (A), ever and never NSCLC smokers (B) and between never, former and current smokers (C).

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