title: 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: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Research, Division of General Thoracic Surgery,  University Hospital Bern, Bern,  Switzerland.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Cortes-Dericks
authors.forename: Domenico
authors.initials: D
authors.lastname: Galetta
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Spaggiari
authors.forename: Ralph Alexander
authors.initials: RA
authors.lastname: Schmid
authors.forename: Golnaz
authors.initials: G
authors.lastname: Karoubi
mesh_terms: D000071916:AC133 Antigen; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics; D010455:Peptides / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D050814:Octamer Transcription Factor-3; C000606023:PROM1 protein, human; D010455:Peptides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000444:Aldehyde Dehydrogenase