Loss of neural crest-associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation
Huizi Wu1,2,3, Lionel Larribère1,2, Qian Sun1,2
1Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract:
Recent studies suggest that malignant melanoma heterogeneity includes subpopulations of cells with features of multipotent neural crest (NC) cells. Zebrafish and mouse models have shown that reactivation of neural crest-specific pathways during transformation determines the invasiveness of melanoma cells. In our study, we show that the neural crest-associated transcription factor FOXD1 plays a key role in the invasion and the migration capacities of metastatic melanomas both in vivo and in vitro. Gene expression profiling analysis identified both an upregulation of FOXD1 in NC and melanoma cells, as well as a downregulation of several genes related to cell invasion in FOXD1 knockdown cells, including MMP9 and RAC1B. Furthermore, we demonstrate that knockdown of RAC1B a tumor-specific isoform of RAC1, significantly impaired melanoma cell migration and invasion and could abrogate enhanced invasiveness induced by FOXD1 overexpression. We conclude that FOXD1 may influence invasion and migration via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells.
Insights
Neural crest-associated transcription factor FOXD1 promotes melanoma cell invasion and migration. Its overexpression upregulates FOXD1 and downregulates invasion genes like MMP9 and RAC1B, impacting metastatic melanoma progression.
Area of Science:
- Oncology
- Developmental Biology
- Molecular Biology
Background:
- Malignant melanoma exhibits heterogeneity, with subpopulations resembling multipotent neural crest (NC) cells.
- Reactivation of NC-specific pathways during melanoma transformation influences cellular invasiveness.
Purpose of the Study:
- To investigate the role of the neural crest-associated transcription factor FOXD1 in melanoma invasion and migration.
- To elucidate the molecular mechanisms by which FOXD1 influences metastatic melanoma progression.
Main Methods:
- In vivo and in vitro studies using melanoma models.
- Gene expression profiling to analyze FOXD1 and downstream gene regulation.
- Knockdown and overexpression experiments for FOXD1 and RAC1B.
Main Results:
- FOXD1 overexpression was identified in NC and melanoma cells.
- FOXD1 knockdown led to downregulation of invasion-related genes, including MMP9 and RAC1B.
- Knockdown of RAC1B significantly impaired melanoma cell migration and invasion, counteracting FOXD1-induced invasiveness.
Conclusions:
- FOXD1 plays a critical role in the invasion and migration of metastatic melanoma cells.
- FOXD1 may regulate melanoma cell invasion and migration through indirect modulation of MMP9 and RAC1B alternative splicing.
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