Abstract:Background: CXCR4 promotes melanoma metastasis. Results: FOXD3 and PAX3 drive CXCR4 expression. Blocking these factors inhibits cell migration, but this is rescued by ectopic CXCR4 expression. Conclusion: PAX3-and FOXD3-mediated melanoma cell migration is dependent on promoting the expression of CXCR4. Significance: This study identifies a new pathway and targets for therapeutic strategies to treat invasive melanoma.
“…De novo assembly and analysis of the foxd3 -mutant transcriptomes revealed the presence of truncated foxd3 fluorescent fusion transcripts (Figure S3A), encoding only 93 N-terminal amino acids, as shown previously (Hochgreb-Hägele and Bronner, 2013). The truncated N-terminal foxd3 variants are non-functional (Yaklichkin et al., 2007), whereas dominant negative activity is associated with the C terminus regions (Kubic et al., 2015, Zhu et al., 2014). Utilizing these lines, we investigated transcriptional changes in the absence of the functional foxd3 protein at three key stages of neural crest ontogeny (75% epiboly, 5–6ss, and 14–16ss) (Figure 2A).Figure 2Transcriptional Profiling of foxd3 Mutant NC(A) Experimental strategy for obtaining foxd3 -mutant (yellow) and foxd3 -control (green) NC cells.…”
SummaryThe neural crest (NC) is a transient embryonic stem cell-like population characterized by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that, during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, foxd3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses differential partners for each role. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from “permissive” to “repressive” nucleosome and chromatin organization to maintain multipotency and define cell fates.
“…De novo assembly and analysis of the foxd3 -mutant transcriptomes revealed the presence of truncated foxd3 fluorescent fusion transcripts (Figure S3A), encoding only 93 N-terminal amino acids, as shown previously (Hochgreb-Hägele and Bronner, 2013). The truncated N-terminal foxd3 variants are non-functional (Yaklichkin et al., 2007), whereas dominant negative activity is associated with the C terminus regions (Kubic et al., 2015, Zhu et al., 2014). Utilizing these lines, we investigated transcriptional changes in the absence of the functional foxd3 protein at three key stages of neural crest ontogeny (75% epiboly, 5–6ss, and 14–16ss) (Figure 2A).Figure 2Transcriptional Profiling of foxd3 Mutant NC(A) Experimental strategy for obtaining foxd3 -mutant (yellow) and foxd3 -control (green) NC cells.…”
SummaryThe neural crest (NC) is a transient embryonic stem cell-like population characterized by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that, during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, foxd3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses differential partners for each role. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from “permissive” to “repressive” nucleosome and chromatin organization to maintain multipotency and define cell fates.
“…Liu et al 6 showed that the metastasis of melanoma can be inhibited by microRNA (miR)-425, which represses the PI3K-Akt pathway by targeting insulin-like growth factor-1. Kubic et al 7 found that PAX3 (paired box 3) and FOXD3 (forkhead box D3) upregulate CXCR4 (C-X-C motif chemokine receptor 4) expression in melanoma. However, the discovery of these biomarkers still fails to fully explain the mechanisms underlying the growth and metastasis of melanoma.…”
Objective: Malignant melanoma is a highly invasive cancer whose pathogenesis remains unclear. We analyzed the microarray dataset GDS1375 in the Gene Expression Omnibus database to search for key genes involved in the occurrence and development of melanoma. Methods: The dataset included 52 samples (7 normal skin and 45 melanoma samples). We identified differentially expressed genes (DEGs) between the two groups and used integrated discovery databases for Gene Ontology (GO) and Kyoto Gene and Genome Encyclopedia (KEGG) pathway analyses. In addition, we used the STRING and MCODE plugins of Cytoscape to visualize the protein-protein interactions (PPI) for these DEGs. Results: A total of 509 upregulated and 618 downregulated DEGs were identified, which were enriched in GO terms including integrin binding, protein binding, and structural constituent of cytoskeleton, and in KEGG pathways such as melanogenesis, prostate cancer, focal adhesion, and renin secretion. Three major modules from the PPI networks and 10 hub genes were identified, including CDC20, GNB2, PPP2R1A, AURKB, POLR2E, and AGTR1. Overall survival was low when these six hub genes were highly expressed. Conclusion: This bioinformatics analysis identified hub genes that may promote the development of melanoma and represent potential new biomarkers for diagnosis and treatment of melanoma.
“…Previous studies have demonstrated that PAX3 can drive and activate C-X-C motif chemokine receptor 4 (CXCR4)/MET proto-oncogene receptor tyrosine kinase expression, and may promote melanoma metastasis and rapid tumor growth (15,16). E3 ligase APC/C (Cadherin 1) promotes ubiquitination-mediated PAX3 proteolysis and inhibits the proliferation of melanoma cells and melanoma growth (17).…”
Paired box 3 (PAX3) is a transcription factor and critical regulator of pigment cell development during embryonic development. However, while there have been several studies on PAX3, its expression patterns and precise role remain to be clarified. The present study is an in-depth computational study of tumor-associated gene information, with specific emphasis on the expression of PAX3 in melanoma, using Oncomine along with an investigation of corresponding expression profiles in an array of cancer cell lines through Cancer Cell Line Encyclopedia analysis. Based on Kaplan-Meier analysis, the prognostic value of high PAX3 expression in tissues from patients with melanoma compared with normal tissues was assessed. PAX3 was more highly expressed in male patients with melanoma compared with female patients with melanoma. Using Oncomine and Coexpedia analysis, it was demonstrated that PAX3 expression was clearly associated with SRY-box 10 expression. The survival analysis results revealed that high PAX3 mRNA expression was associated with worse survival rates in patients with melanoma. These results suggested that PAX3 may be a biomarker and essential prognostic factor for melanoma, and provided an important theoretical basis for the development of melanoma treatments.
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