PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma
PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma
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DOI：
10.1074/jbc.m115.670976
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发表时间：
2015-09-04
影响因子：
4.8
通讯作者：
Lang, Deborah
中科院分区：
文献类型：
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作者：
Kubic, Jennifer D.;Lui, Jason W.;Lang, Deborah
转移性黑色素瘤是一种侵袭性且致命的疾病。趋化因子受体 CXCR4 在黑色素瘤转移中活跃，尽管在这些细胞中促进和维持 CXCR4 表达的机制大多未知。在这里，我们发现黑色素瘤细胞表达两种 CXCR4 同工型，即常见版本和通常仅限于发育过程中的细胞或成熟血细胞的变体。 CXCR4 表达由转录因子 PAX3 和 FOXD3 通过高度保守的内含子增强子元件驱动。抑制这些转录因子会减慢黑色素瘤细胞的生长、迁移和运动，并降低 CXCR4 的表达。这些转录因子的过度表达会导致 CXCR4 水平升高。 PAX3 和 FOXD3 转录因子活性的丧失会导致细胞运动、迁移和趋化性降低，所有这些都可以通过 CXCR4 过表达来挽救。在这里，我们发现了 PAX3 和 FOXD3 促进黑色素瘤中 CXCR4 基因表达的分子途径。
Metastatic melanoma is an aggressive and deadly disease. The chemokine receptor CXCR4 is active in melanoma metastasis, although the mechanism for the promotion and maintenance of CXCR4 expression in these cells is mostly unknown. Here, we find melanoma cells express two CXCR4 isoforms, the common version and a variant that is normally restricted to cells during development or to mature blood cells. CXCR4 expression is driven through a highly conserved intronic enhancer element by the transcription factors PAX3 and FOXD3. Inhibition of these transcription factors slows melanoma cell growth, migration, and motility, as well as reduces CXCR4 expression. Overexpression of these transcription factors drives the production of increased CXCR4 levels. Loss of PAX3 and FOXD3 transcription factor activity results in a reduction in cell motility, migration, and chemotaxis, all of which are rescued by CXCR4 overexpression. Here, we discover a molecular pathway wherein PAX3 and FOXD3 promote CXCR4 gene expression in melanoma.