High expression of octamer-binding transcription factor 4A, prominin-1 and aldehyde dehydrogenase strongly indicates involvement in the initiation of lung adenocarcinoma resulting in shorter disease-free intervals

Abstract

The increasing relevance of the cancer stem cell (CSC) hypothesis and the impact of CSC-associated markers in the carcinogenesis of solid tumours may provide potential prognostic implications in lung cancer. We propose that a collective genetic analysis of established CSC-related markers will generate data to better define the role of putative CSCs in lung adenocarcinoma (LAC). Sixty-four paired tumour and non-tumour biopsies from LAC patients were included in this study. Using the quantitative reverse transcriptase-polymerase chain reaction, we assessed the expression profiles of established CSC-related biomarkers: octamer-binding transcription factor 4 (OCT4A), CD133, aldehyde dehydrogenase (ALDH), BMI-1, ATP-binding cassette subfamily G, member 2 (ABCG2), SRY (sex-determining region Y)-box 2 (SOX2) and uPAR, and evaluated their relation to clinicopathological parameters and disease prognosis. All of the above-mentioned CSC-related markers were detectable in both tumour and corresponding normal tissues. Importantly, expression levels of OCT4A, CD133, BMI-1, SOX2 and uPAR were significantly higher (OCT4A, P = 0.0003; CD133, P = 0.002; BMI-1, P = 0.04; SOX2, P = 0.0003; uPAR, P = 0.03) in the tumour compared with those in the non-tumour tissues. By contrast, the quantities of ACBG2 and ALDH were markedly reduced (ACBG2, P = 0.0006; ALDH, P = 0.007) in the tumour relative to those in the normal biopsies. Using multivariate analysis, elevated ALDH and CD133 revealed significant associations in tumour stage (ALDH, P = 0.03; CD133, P = 0.007) and differentiation (ALDH, P = 0.03; CD133, P = 0.018). We observed that ALDH and OCT4A were associated with nodal status (ALDH, P = 0.05; OCT4A, P = 0.03) having lower mRNA levels in tumours with lymph node metastasis, N+, compared with that in N0. High OCT4A levels were significantly correlated with tumour size of <3 cm, decrease in tumours >3 cm (P = 0.03). Kaplan-Meier correlation analyses, showed that OCT4A and CD133 were correlated to short disease-free intervals (OCT4A, P = 0.047; CD133, P = 0.033) over a period of 29 months. Our study reveals that CSC-associated markers: OCT4A, CD133 and ALDH are involved in the initial phase of carcinogenesis of LAC, and can be used as predictors of early stage LAC and poor disease-free intervals. In addition, this work validates the relevance of the CSC hypothesis in LAC.