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Expression of TGF-beta related Smad proteins in human epithelial skin tumors
D Lange1, U Persson, U Wollina
1Department of Dermatology, Friedrich-Schiller-University of Jena, Jena, Germany.
Abstract:
Members of the transforming growth factor (TGF)-beta family regulate cell growth and differentiation activating intracellular Smad proteins. Their role in skin and skin tumorigenesis is not well understood. Therefore we investigated the expression of TGF-beta type I receptor (TbetaR-I) and Smad-proteins involved in the TGF-beta-pathway, e.g. Smad2, Smad3, Smad4, Smad6 and Smad7. We examined the effects of TGF-beta1, -beta2, BMP2, BMP7 on five epithelial cell lines in vitro. TGF-beta1-mediated growth inhibition of HaCaT and HSC4 were observed with half maximal effects at approximately 7 pg ml-1 and 20 pg ml-1, respectively. However, malignant HSC2 and A431 cells were unresponsive to TGF-beta1. A differentiation was seen after 5 days in HaCaT and HSC4 cells only. We compared the reactivity with specific antisera against TbetaR-I and Smad proteins among the different skin tumors: seborrheic keratoses (SK), actinic keratoses (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). There were statistically significant differences of the ratio between the expression in tumor and that in non-tumorous epithelial cells in each tissue specimen. There was a tendency for the lower level of TbetaR-I expression of SCC compared with SK (p=0.08). This was accompanied by the decreased expression of the TbetaR-I. We found a markedly decreased expression of all antigens in BCC. conversion of normal keratinocytes to tumorigenic cells may in part be due to an acquisition of resistance to TGF-beta and loss of expression of intracellular signalling Smad proteins.
Insights
Transforming growth factor-beta (TGF-β) signaling regulates skin cell growth. Loss of TGF-β pathway components like TbetaR-I and Smad proteins is linked to skin tumor development.
Area of Science:
- Dermatology
- Molecular Biology
- Cancer Research
Background:
- The transforming growth factor-beta (TGF-β) family influences cell growth and differentiation via Smad proteins.
- The specific role of TGF-β signaling in skin biology and tumorigenesis remains unclear.
Purpose of the Study:
- To investigate the expression of TGF-β type I receptor (TbetaR-I) and key Smad proteins in skin cells and various skin tumors.
- To analyze the functional effects of TGF-β ligands on epithelial cell lines in vitro.
Main Methods:
- Examined the expression of TbetaR-I and Smad proteins (Smad2, Smad3, Smad4, Smad6, Smad7) in normal skin cells and tumor types (seborrheic keratoses, actinic keratoses, basal cell carcinoma, squamous cell carcinoma).
- Assessed the in vitro effects of TGF-β1, TGF-β2, BMP2, and BMP7 on five different epithelial cell lines.
- Utilized specific antisera for protein expression analysis.
Main Results:
- TGF-β1 inhibited growth and induced differentiation in normal keratinocyte cell lines (HaCaT, HSC4) but not in malignant cell lines (HSC2, A431).
- Statistically significant differences in TbetaR-I and Smad protein expression ratios were observed between tumors and non-tumorous tissues.
- Basal cell carcinoma (BCC) showed markedly decreased expression of all investigated antigens, while squamous cell carcinoma (SCC) tended towards lower TbetaR-I expression compared to seborrheic keratoses.
Conclusions:
- Acquisition of resistance to TGF-β signaling and reduced expression of intracellular Smad proteins may contribute to the conversion of normal keratinocytes into tumorigenic cells.
- Dysregulation of the TGF-β pathway is implicated in the pathogenesis of various skin cancers.