Journal Article

Gene expression profiling of initiated epidermal cells with benign or malignant tumor fates

Zhiping Wang, Yuangang Liu, Motomi Mori and Molly Kulesz-Martin

in Carcinogenesis

Volume 23, issue 4, pages 635-643
Published in print April 2002 | ISSN: 0143-3334
Published online April 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.4.635
Gene expression profiling of initiated epidermal cells with benign or malignant tumor fates

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High-density oligonucleotide array technology was used to search for gene expression changes that may predict or cause sporadic tumorigenesis. To reduce variation among samples, a non-transformed mouse epidermal keratinocyte clone was compared with its carcinoma-producing or papilloma-producing 7,12-dimethylbenz[a]anthracene-initiated cell derivative. The majority of the ~12 325 genes or expressed sequence tags (ESTs) analyzed remained unaltered reflective of the clonal nature of the model. Consistent gene expression changes among biological replicates included 69 in malignancy-prone initiated cells, 46 in papilloma-precursor initiated cells and an additional 45 with changes in both initiated cell lineages. The changes covered a broad spectrum of cellular activities, implying that multiple pathways cooperate at the initiation of carcinogenesis. There was a tendency in the malignancy-prone cells for differences in proliferation and apoptosis-related genes. The benign lineage tended toward aberrant expression of genes involved in differentiation and epidermal barrier function. Several independently confirmed gene expression changes revealed plausible effectors to bypass an activated ras protein in proliferation pathways and to compromise the wild-type p53 and other apoptosis pathways at initiation of carcinogenesis. The differential expression patterns of the initiated cells are consistent with the hypothesis that changes in gene expression at initiation may cooperate with subsequent oncogenic changes to determine malignant fate. The cloned epidermal cell lineages allowed detection of putative early cancer genes in a model that is conducive to testing their direct role in epithelial multistep carcinogenesis in vitro and in vivo.

Keywords: DMBA, dimethylbenz[a]anthracene; HPRT, hypoxanthine-guanine phosphoribosyltransferase; RA, retinoic acid; SSC, squamous cell carcinoma; SCF, stem cell factor; TIMP-3, tissue inhibitor of metalloproteinases 3.

Journal Article.  7145 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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