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Alteration of Egr-1 mRNA during multistage carcinogenesis in mouse skin
P K Riggs1, O Rho, J DiGiovanni
1Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas, USA.
Abstract:
Immediate early genes, including fos, jun, and early growth response-1 (Egr-1), are induced during cellular response to changes in extracellular environment. These immediate early genes are believed to mediate processes of cell growth and differentiation. In particular, Egr-1 is induced during mitogenic stimulation of a variety of cell types, including fibroblasts, B cells, and epithelial cells. In the present study, we examined Egr-1 gene expression during multistage carcinogenesis in mouse skin. After a single topical treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) to SENCAR mouse skin, Egr-1 mRNA was induced, and maximal induction was observed at 2 h in both epidermis and dermis. Induction of Egr-1 mRNA by TPA was inhibited by fluocinolone acetonide, a potent inhibitor of tumor promotion by TPA. Egr-1 mRNA was present in primary keratinocytes derived from adult SENCAR mice. The keratinocyte cultures were maintained in low Ca(2+) medium, and Egr-1 mRNA levels became significantly elevated after the cultures were switched to high Ca(2+) medium. Additionally, a large proportion of primary papillomas and carcinomas generated from SENCAR mice by standard initiation-promotion regimens exhibited elevated Egr-1 mRNA compared with normal epidermis. Taken together, these data suggest a possible role of Egr-1 during multistage carcinogenesis in mouse skin.
Insights
Early Growth Response-1 (Egr-1) gene expression increases in mouse skin during tumor promotion and in skin cancer. These findings suggest Egr-1 may play a role in multistage skin carcinogenesis.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- Immediate early genes, such as fos, jun, and Early Growth Response-1 (Egr-1), are rapidly induced by extracellular environment changes.
- These genes are implicated in mediating cell growth and differentiation processes.
- Egr-1 is notably induced by mitogenic stimulation across various cell types, including epithelial cells.
Purpose of the Study:
- To investigate the expression of Egr-1 during multistage carcinogenesis in mouse skin.
- To determine the role of Egr-1 in skin tumor promotion and development.
Main Methods:
- Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to SENCAR mouse skin to induce Egr-1 mRNA.
- Treatment with fluocinolone acetonide to assess its inhibitory effect on TPA-induced Egr-1 expression.
- Culturing primary keratinocytes in varying calcium concentrations to observe Egr-1 mRNA levels.
- Analyzing Egr-1 mRNA levels in experimentally induced papillomas and carcinomas.
Main Results:
- Egr-1 mRNA was significantly induced in both epidermis and dermis of mouse skin within 2 hours after TPA treatment.
- Fluocinolone acetonide, a tumor promotion inhibitor, suppressed TPA-induced Egr-1 mRNA.
- Switching primary keratinocyte cultures from low to high calcium medium led to a significant elevation in Egr-1 mRNA levels.
- Elevated Egr-1 mRNA expression was observed in a majority of papillomas and carcinomas compared to normal epidermis.
Conclusions:
- Egr-1 gene expression is upregulated during TPA-induced skin responses and in skin tumors.
- Calcium levels influence Egr-1 expression in keratinocytes.
- The data strongly suggest a potential role for Egr-1 in the complex process of multistage skin carcinogenesis.