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Modulation of epidermal tumor development caused by targeted overexpression of epidermis-type 12S-lipoxygenase
Karsten Müller1, Malte Siebert, Markus Heidt
1Deutsches Krebsforschungszentrum, Research Program on Tumor Cell Regulation, 69120 Heidelberg, Germany.
Abstract:
In contrast to other 12S-lipoxygenase (LOX) isoforms expressed in the skin of mice, epidermis-type (e) 12S-LOX was found to be transcriptionally down-regulated in the course of epidermal tumor development in NMRI mice. This may indicate that this enzyme is related to antitumorigenic rather than protumorigenic effects. To test this hypothesis, two transgenic mouse lines were generated that differentially expressed e12S-LOX under the control of the bovine keratin 6 promoter known to be constitutively up-regulated in mouse skin tumors. As compared with the wild-type, low transgene expression correlated with a decreased skin tumor response paralleled by an up-regulation of leukocyte-type 12S-LOX and an accumulation of the linoleic acid derivative 13S-hydroxyoctadecadienoic acid. In contrast, high transgene expression coincided with an increased tumor response paralleled by a strong keratin 6 promoter-driven up-regulation of the transgenic e12S-LOX and an accumulation of the arachidonic acid derivative 12S-hydroxyeicosatetraenoic acid as the predominant LOX product. These results indicate a complex interaction between different LOX isoforms and an opposite role of arachidonic acid and linoleic acid products in the modulation of skin carcinogenesis.
Insights
Epidermis-type 12S-lipoxygenase (LOX) may have antitumorigenic effects. Its expression level influences skin tumor development, with different LOX products playing opposing roles in carcinogenesis.
Area of Science:
- Biochemistry
- Dermatology
- Oncology
Background:
- Epidermis-type 12S-lipoxygenase (e12S-LOX) is downregulated during mouse skin tumor development.
- This suggests a potential antitumorigenic role for e12S-LOX.
- Understanding LOX isoform roles is crucial for skin cancer research.
Purpose of the Study:
- To investigate the role of e12S-LOX in skin carcinogenesis.
- To determine the impact of differential e12S-LOX expression on tumor development.
- To explore the influence of LOX-derived metabolites on skin cancer progression.
Main Methods:
- Generation of transgenic mouse lines with varying e12S-LOX expression under keratin 6 promoter control.
- Comparison of skin tumor response in transgenic mice versus wild-type controls.
- Analysis of LOX isoform expression and metabolite accumulation (e.g., 13S-hydroxyoctadecadienoic acid, 12S-hydroxyeicosatetraenoic acid).
Main Results:
- Low e12S-LOX expression correlated with decreased tumor response, increased leukocyte-type 12S-LOX, and accumulation of linoleic acid derivatives.
- High e12S-LOX expression correlated with increased tumor response, keratin 6 promoter-driven upregulation, and accumulation of arachidonic acid derivatives.
- Demonstrated complex interactions between LOX isoforms and opposing roles of their products in skin carcinogenesis.
Conclusions:
- e12S-LOX exhibits a complex role in skin carcinogenesis, potentially influenced by expression levels.
- Linoleic acid and arachidonic acid metabolites derived from LOX activity have opposing effects on skin tumor development.
- Findings highlight the intricate interplay of LOX pathways in modulating skin cancer progression.