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Published on: November 11, 2014
Altered gene expression in a clonal epidermal cell model of carcinogenesis identified by RNA differential display
1Program of Biochemistry and Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Abstract:
We have developed a multistage model system in which a normal mouse keratinocyte clone has been initiated with 7,12-dimethylbenz[a]anthracene and variant clones derived with benign or malignant phenotypes. To identify specific genes altered during mouse skin carcinogenesis, the gene expression patterns of the normal parental epidermal cell, an initiated cell, a benign papilloma, and a poorly differentiated squamous cell carcinoma were compared using RNA differential display. Most alterations in gene expression were observed at malignant conversion, that is, in the poorly differentiated squamous cell carcinoma that is known to have deregulated expression of p53. The sequence of a cloned cDNA fragment lost in the poorly differentiated squamous cell carcinoma was nearly identical to the 3' region of an adhesion-related kinase which is involved in homophilic cell aggregation. It is found in normal epidermal progenitor cells as well as tumorigenic cells with differentiation potential, but not in tumorigenic cells with a poorly differentiated phenotype, suggesting that this adhesion-related kinase may be involved in epidermal cell differentiation. Differential display within the cloned epidermal cell model appears to be useful in detecting and identifying malignant conversion-associated genes which then can be tested directly for their potential role in epithelial carcinogenesis.
Insights
Researchers identified a key adhesion-related kinase gene lost during mouse skin cancer progression. This gene
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Mouse skin carcinogenesis involves genetic alterations leading to benign and malignant phenotypes.
- Understanding gene expression changes is crucial for identifying key drivers of cancer progression.
- The p53 tumor suppressor pathway is often deregulated in malignant skin tumors.
Purpose of the Study:
- To identify specific genes altered during multistage mouse skin carcinogenesis.
- To compare gene expression patterns between normal, initiated, benign, and malignant epidermal cells.
- To investigate the role of identified genes in epidermal cell differentiation and carcinogenesis.
Main Methods:
- Development of a multistage mouse skin carcinogenesis model using 7,12-dimethylbenz[a]anthracene.
- Comparison of gene expression profiles using RNA differential display.
- Sequencing of a cloned cDNA fragment to identify candidate genes.
Main Results:
- Significant gene expression alterations were observed during malignant conversion, particularly in poorly differentiated squamous cell carcinoma.
- A specific adhesion-related kinase gene, involved in homophilic cell aggregation, was found to be downregulated or lost in malignant cells.
- This kinase is present in normal and differentiating tumor cells but absent in poorly differentiated tumor cells, suggesting a role in differentiation.
Conclusions:
- The identified adhesion-related kinase may play a critical role in epidermal cell differentiation and suppressing malignant progression.
- RNA differential display is a valuable tool for detecting genes associated with malignant conversion in epithelial carcinogenesis.
- Further investigation of this kinase can elucidate its direct role in skin cancer development.
