Abstract:Several key transcription factors regulate cell growth, survival, and differentiation during neural crest and melanoblast development in the embryo, and these same pathways may be reactivated in tumors arising from the progenitors of these cells. The transcription factors PAX3 and FOXD3 have essential roles in melanoblasts and melanoma. In this study, we define a regulatory pathway where FOXD3 promotes the expression of PAX3. Both factors are expressed in melanoma cells and there is a positive correlation betw… Show more
“…These observations were in accord with previous studies showing that a subset of Pax3 EGFP cells in the forelimb differentiate into vascular epithelial cells 39 . In limb formation, the vascular and nervous systems develop in parallel to the skeletal system 40 , 41 , and the Pax3 lineage is likely to give rise to cells that will populate different systems 42 , 43 . Figure 3 Myogenic and non-myogenic cells populate the Pax3 EGFP lineage in the forelimb.…”
Skeletal muscle in the forelimb develops during embryonic and fetal development and perinatally. While much is known regarding the molecules involved in forelimb myogenesis, little is known about the specific mechanisms and interactions. Migrating skeletal muscle precursor cells express Pax3 as they migrate into the forelimb from the dermomyotome. To compare gene expression profiles of the same cell population over time, we isolated lineage-traced Pax3+ cells (Pax3EGFP) from forelimbs at different embryonic days. We performed whole transcriptome profiling via RNA-Seq of Pax3+ cells to construct gene networks involved in different stages of embryonic and fetal development. With this, we identified genes involved in the skeletal, muscular, vascular, nervous and immune systems. Expression of genes related to the immune, skeletal and vascular systems showed prominent increases over time, suggesting a non-skeletal myogenic context of Pax3-derived cells. Using co-expression analysis, we observed an immune-related gene subnetwork active during fetal myogenesis, further implying that Pax3-derived cells are not a strictly myogenic lineage, and are involved in patterning and three-dimensional formation of the forelimb through multiple systems.
“…These observations were in accord with previous studies showing that a subset of Pax3 EGFP cells in the forelimb differentiate into vascular epithelial cells 39 . In limb formation, the vascular and nervous systems develop in parallel to the skeletal system 40 , 41 , and the Pax3 lineage is likely to give rise to cells that will populate different systems 42 , 43 . Figure 3 Myogenic and non-myogenic cells populate the Pax3 EGFP lineage in the forelimb.…”
Skeletal muscle in the forelimb develops during embryonic and fetal development and perinatally. While much is known regarding the molecules involved in forelimb myogenesis, little is known about the specific mechanisms and interactions. Migrating skeletal muscle precursor cells express Pax3 as they migrate into the forelimb from the dermomyotome. To compare gene expression profiles of the same cell population over time, we isolated lineage-traced Pax3+ cells (Pax3EGFP) from forelimbs at different embryonic days. We performed whole transcriptome profiling via RNA-Seq of Pax3+ cells to construct gene networks involved in different stages of embryonic and fetal development. With this, we identified genes involved in the skeletal, muscular, vascular, nervous and immune systems. Expression of genes related to the immune, skeletal and vascular systems showed prominent increases over time, suggesting a non-skeletal myogenic context of Pax3-derived cells. Using co-expression analysis, we observed an immune-related gene subnetwork active during fetal myogenesis, further implying that Pax3-derived cells are not a strictly myogenic lineage, and are involved in patterning and three-dimensional formation of the forelimb through multiple systems.
“…However, based on previous reports, there are some possible mechanisms to consider. First, FOXO1 and PAX3 might bind directly, as Kubic et al showed that overexpression of FOXD3, a member of the FOX protein family, upregulated PAX3 expression in melanoma cells by the direct binding of FOXD3 to PAX3 promoter [45]. Second, there might be other target genes that are activated or repressed by FOXO1 and PAX3.…”
BackgroundTranscription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers. However, their role in epithelial ovarian cancer (EOC) has not been elucidated yet. Therefore, we evaluated the expression and clinical significance of FOXO1 and PAX3 in EOC.MethodsImmunohistochemical analyses of FOXO1 and PAX3 in 212 EOCs, 57 borderline ovarian tumors, 153 benign epithelial ovarian tumors, and 79 nonadjacent normal epithelial tissues were performed using tissue microarray. Various clinicopathological variables, including the survival of EOC patients, were compared. In addition, the effect of FOXO1 on cell growth was assessed in EOC cell lines.ResultsFOXO1 and PAX3 protein expression levels were significantly higher in EOC tissues than in nonadjacent normal epithelial tissues, benign tissues, and borderline tumors (all p <â0.001). In EOC tissues, FOXO1 expression was positively correlated with PAX3 expression (Spearmanâs rho =â0.118, p =â0.149). Multivariate survival analysis revealed that high FOXO1 expression (hazard ratioâ=â2.77 [95% CI, 1.48â5.18], p =â0.001) could be an independent prognostic factor for overall survival. Most importantly, high expression of both FOXO1 and PAX3 showed a high hazard ratio (4.60 [95% CI, 2.00â10.55], p <â0.001) for overall survival. Also in vitro results demonstrated that knockdown of FOXO1 was associated with decreased cell viability, migration, and colony formation.ConclusionsThis study revealed that high expression of FOXO1/PAX3 is an indicator of poor prognosis in EOC. Our results suggest the promising potential of FOXO1 and PAX3 as prognostic and therapeutic markers. The possible link between biological functions of FOXO1 and PAX3 in EOC warrants further studies.
“…In melanoma, FOXD3 can directly upregulate PAX3 by binding to its promoter [124]. FOXD3 is suppressed by BRAF, and it acts as a cell cycle repressor by upregulating p21 Cip1 [125].…”
Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
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