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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Expression of Dickkopf genes is strongly reduced in malignant melanoma
S Kuphal1, S Lodermeyer, F Bataille
1Institute of Pathology, University Regensburg, Regensburg, Germany.
Abstract:
The Dickkopf (DKK) genes were originally identified as factors inducing head formation in Xenopus. The genes code for inhibitors that are involved in Wnt signaling. We speculate that loss of DKK expression plays a role in development or progression of malignant melanoma. Thus, we evaluated melanoma cell lines and tissue samples of malignant melanoma for loss of DKK, especially DKK-3 transcription. We found that DKK-1, -2 and -3 were downregulated or lost in all cell lines and in most of the tumor samples analysed. Reduced DKK-3 expression occurred as early as in primary tumors detected by both immunohistochemical and reverse transcription-polymerase chain reaction RT-PCR analysis. Functional assays with stable DKK-3 transfected cell lines revealed that DKK-3 expression increased cell-cell adhesion and decreased cell migration. Further, downregulation of fibronectin, snail-1 and re-expression of E-cadherin was found in the DKK-3 expressing cell clones supporting a role of DKK-3 in tumor progression. Our studies thus indicate that loss of DKK-3 expression may contribute to melanoma progression.
Insights
Loss of Dickkopf (DKK) gene expression, particularly DKK-3, is linked to melanoma progression. Restoring DKK-3 expression enhances cell adhesion and reduces migration, suggesting a role in inhibiting cancer spread.
Area of Science:
- Molecular Biology
- Oncology
- Developmental Biology
Background:
- Dickkopf (DKK) genes are known inhibitors in Wnt signaling pathways.
- Wnt signaling plays a crucial role in embryonic development and cancer progression.
- Alterations in DKK gene expression are implicated in various malignancies.
Purpose of the Study:
- To investigate the role of Dickkopf (DKK) gene expression, specifically DKK-3, in the development and progression of malignant melanoma.
- To evaluate DKK gene expression levels in melanoma cell lines and patient tumor samples.
- To determine the functional impact of DKK-3 restoration on melanoma cell behavior.
Main Methods:
- Analysis of DKK-1, -2, and -3 gene expression in melanoma cell lines and tumor tissues.
- Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to detect DKK-3 expression.
- Functional assays using melanoma cell lines stably transfected with DKK-3.
Main Results:
- DKK-1, -2, and -3 were downregulated or lost in all evaluated melanoma cell lines and most tumor samples.
- Reduced DKK-3 expression was observed in early-stage primary melanomas.
- DKK-3 re-expression increased cell-cell adhesion and decreased cell migration.
- DKK-3 expression led to downregulation of fibronectin and snail-1, and re-expression of E-cadherin.
Conclusions:
- Loss of DKK gene expression, especially DKK-3, is a frequent event in malignant melanoma.
- Reduced DKK-3 expression occurs early in melanoma development and correlates with tumor progression.
- DKK-3 functions as a suppressor of melanoma cell migration and invasion, potentially by modulating epithelial-mesenchymal transition markers.
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