Abstract
BackgroundNon-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 FindingsWe 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/SignificanceOur 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.
Highlights
Lung cancer continues to be the leading cause of cancer-related deaths in the United States and worldwide with over one million deaths each year [1]
Analysis of Sex Determining Region Y-Box 2 (SOX2) mRNA expression in Non-small cell lung cancer (NSCLC) samples of various publicly available datasets revealed the significant elevated expression of this stem cell-related transcriptional factor in lung squamous cell carcinomas (SCCs) compared to adenocarcinomas (Figure 1A)
Since SOX2 mRNA levels were largely higher in SCCs than adenocarcinomas of the lung, we questioned whether a SOX2
Summary
Lung cancer continues to be the leading cause of cancer-related deaths in the United States and worldwide with over one million deaths each year [1]. Few early changes that occur during NSCLC pathogenesis have been identified. Mutations in KRAS [3] and in the epidermal growth factor receptor (EGFR) [4] typically occur early in the development of lung adenocarcinomas, whereas amplification of EGFR and PI3KCA [2] and epigenetic inactivation of the p16 tumor suppressor [5] are more frequent in SCC pathogenesis relative to adenocarcinomas. 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
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