title: Differentiation-promoting culture of competent and noncompetent keratinocytes identifies biomarkers for head and neck cancer.
abstract: Aberrant contact-inhibited proliferation and differentiation induction couple with tumor severity, albeit with an imprecise association with prognosis. Assessment of contact inhibition and differentiation-promoting culture in this study of normal and immortalized oral keratinocytes (NOK and SVpgC2a, respectively) demonstrated elevated cloning ability and saturation density in the immortalized versus normal state, including consistent absence of differentiated morphological features. Transcriptomic analysis implicated 48 gene ontology categories, 8 molecular networks, and 10 key regulator genes in confluency-induced differentiation of NOK, all of which remained nonregulated in SVpgC2a. The SVpgC2a versus NOK transcriptome enriched 52 gene ontology categories altogether, 18 molecular networks, and 39 key regulator genes, several of which were associated with epithelial-mesenchymal transition. Assessment of the previously described gene sets relative to training data sets of head and neck squamous cell carcinoma samples, one including data on tumor differentiation and patient outcome and one present in the Human Gene Expression Map, identified four genes with association to poor survival (COX7A1, MFAP5, MPDU1, and POLD1). This gene set predicted poor outcome in an independent data set of 71 head and neck squamous cell carcinomas. The present study defines, for the first time to our knowledge, the broad gene spectrum that couples to induction, and loss, of oral keratinocyte differentiation. Bioinformatics assessments of the results relative to clinical data generated novel differentiation-related tumor biomarkers relevant to patient outcome.
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ceder
authors.forename: Ylva
authors.initials: Y
authors.lastname: Haig
authors.forename: Marina
authors.initials: M
authors.lastname: Merne
authors.forename: Annette
authors.initials: A
authors.lastname: Hansson
authors.forename: Xi
authors.initials: X
authors.lastname: Zheng
authors.forename: Karin
authors.initials: K
authors.lastname: Roberg
authors.forename: Matthias
authors.initials: M
authors.lastname: Nees
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Balvinder K
authors.initials: BK
authors.lastname: Bloor
authors.forename: Peter R
authors.initials: PR
authors.lastname: Morgan
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Roland C
authors.initials: RC
authors.lastname: Grafström
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003285:Contractile Proteins / Q000235:genetics; D004258:DNA Polymerase III / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm / Q000235:genetics; D023281:Genomics / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D015603:Keratinocytes / Q000473:pathology*; D046228:Microarray Analysis; D011379:Prognosis; D011498:Protein Precursors; D000072260:RNA Splicing Factors; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D003285:Contractile Proteins; D016326:Extracellular Matrix Proteins; D011498:Protein Precursors; D000072260:RNA Splicing Factors; C016598:microfibrillar protein; C032253:involucrin; C513901:COX7A1 protein, human; D003576:Electron Transport Complex IV; C434055:POLD1 protein, human; D004258:DNA Polymerase III