Differentiation-Promoting Culture of Competent and Noncompetent Keratinocytes Identifies Biomarkers for Head and Neck Cancer

被引:25
作者
Ceder, Rebecca [1 ]
Haig, Ylva [1 ]
Merne, Marina [1 ]
Hansson, Annette [1 ]
Zheng, Xi [1 ]
Roberg, Karin [2 ]
Nees, Matthias [3 ]
Iljin, Kristiina [3 ]
Bloor, Balvinder K. [4 ]
Morgan, Peter R. [4 ]
Fadeel, Bengt [1 ]
Grafstrom, Roland C. [1 ,3 ]
机构
[1] Karolinska Inst, Div Mol Toxicol, Inst Environm Med, SE-17177 Stockholm, Sweden
[2] Linkoping Univ, Div Otorhinolaryngol, Dept Clin & Expt Med, Linkoping, Sweden
[3] VTT Tech Res Ctr Finland, Turku, Finland
[4] Kings Coll London, Inst Dent, Guys Hosp, Dept Oral Pathol, London WC2R 2LS, England
基金
瑞典研究理事会;
关键词
SQUAMOUS-CELL CARCINOMA; ORAL KERATINOCYTES; GROWTH; EXPRESSION; GENES; METASTASIS; TRANSCRIPTOME; PROLIFERATION; PROGRESSION; PROFILES;
D O I
10.1016/j.ajpath.2011.10.016
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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. (Am J Pathol 2012. 180:457-472; DOI: 10.1016/j.ajpath.2011.10.016)
引用
收藏
页码:457 / 472
页数:16
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