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Suppression of cornified envelope formation and type 1 transglutaminase by epidermal growth factor in neoplastic
R I Monzon1, N McWilliams, L G Hudson
1Department of Molecular Pharmacology and Biological Chemistry, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
Abstract:
Epidermal growth factor (EGF) is a potent mitogen for keratinocytes. Although the role of the EGF receptor in cell proliferation has been extensively studied, the consequences of EGF receptor activation with respect to cell differentiation remain less well characterized. Our studies demonstrate that stimulation of the EGF receptor substantially suppresses cellular differentiation in squamous cell carcinoma lines that overexpress the EGF receptor, as assessed by an EGF-dependent reduction of cornified envelope formation. Only a modest ligand-dependent decrease in cornified envelope formation was observed in normal keratinocytes. The response is dependent on the concentration of EGF and is evident after 1-2 days of EGF treatment. With extended EGF treatment, the messenger RNA levels for involucrin, a major structural component of the cornified envelope, were unaltered by EGF. In contrast, membrane-associated transglutaminase enzyme activity, which predominantly represents type 1 (keratinocyte) transglutaminase, is markedly inhibited by EGF. The lost of type 1 transglutaminase activity is associated with reduced levels of the messenger RNA and protein. These studies suggest that the functional consequences of EGF receptor activation in squamous cell carcinomas involve not only aberrant growth regulation, but, additionally, reduction of terminal differentiation capacity.
Insights
Epidermal growth factor (EGF) significantly hinders keratinocyte differentiation in squamous cell carcinomas by suppressing transglutaminase activity. This impacts both cancer growth and the ability of cells to mature properly.
Area of Science:
- Cell Biology
- Dermatology
- Cancer Research
Background:
- Epidermal growth factor (EGF) is a known mitogen for keratinocytes.
- The role of the EGF receptor in cell proliferation is well-understood, but its effect on cell differentiation is less clear.
- Squamous cell carcinomas often overexpress the EGF receptor.
Purpose of the Study:
- To investigate the consequences of EGF receptor activation on keratinocyte differentiation.
- To compare the effects of EGF on differentiation in normal keratinocytes versus squamous cell carcinoma lines.
- To elucidate the molecular mechanisms underlying EGF-induced suppression of differentiation.
Main Methods:
- Stimulation of EGF receptor in keratinocyte cell lines with varying EGF receptor expression levels.
- Assessment of cellular differentiation via cornified envelope formation.
- Measurement of involucrin mRNA levels.
- Assay of membrane-associated transglutaminase activity and protein levels.
Main Results:
- EGF stimulation substantially suppressed cellular differentiation in squamous cell carcinoma lines overexpressing the EGF receptor, evidenced by reduced cornified envelope formation.
- Normal keratinocytes showed only a modest decrease in cornified envelope formation upon EGF treatment.
- EGF markedly inhibited type 1 transglutaminase activity, with associated reductions in its mRNA and protein levels, while involucrin mRNA remained unaltered with extended EGF treatment.
Conclusions:
- EGF receptor activation in squamous cell carcinomas leads to a significant reduction in terminal differentiation capacity.
- The functional consequences of EGF receptor activation extend beyond aberrant growth regulation to include impaired differentiation.
- Inhibition of type 1 transglutaminase is a key mechanism by which EGF suppresses keratinocyte differentiation in these cancers.