Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling
Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling
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DOI：
10.1073/pnas.1813802116
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发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Boiko, Alexander D.
中科院分区：
文献类型：
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作者：
Li, Chen;Nguyen, Vincent;Boiko, Alexander D.
卷曲3受体(FZD3)在神经脊及其衍生物的动态平衡中起重要作用，产生色素合成细胞，即黑素细胞。虽然FZD3在确定神经沟黑素细胞谱系中的作用已经得到了很好的证实，但它在黑色素瘤及其相关恶性肿瘤形成中的意义却知之甚少。在这项研究中，我们确定FZD3是人类黑色素瘤发生的关键调节因子。FZD3的下调抑制了患者来源的黑色素瘤细胞的生长、克隆形成能力和侵袭能力。携带BRAF(V600)突变的黑色素瘤来源的FZD3水平下调的肿瘤细胞异种移植，均可抑制它们的肿瘤和转移形成能力。在具有高活性BRAF癌基因的黑色素瘤中，FZD3基因敲除导致核心细胞周期蛋白成分(细胞周期蛋白D1、E2、B1和CDKs1、2和4)的下调，表明该受体在黑色素瘤的发病机制中起主导作用。富集途径分析表明，FZD3抑制由CREB5、FOXD1和ATF3控制的转录网络，从而抑制MAPK介导的信号转导活性。因此，FZD3建立了一种正反馈机制，激活了对黑色素瘤发生至关重要的MAPK信号转导网络。重要的是，高水平的FZD3mRNA被发现与黑色素瘤进展到转移阶段和限制患者生存有关。FZD3活性介导的基因表达模式的改变发生在缺乏核β-连环蛋白功能的情况下，因此对于黑色素瘤患者来说，这是一个重要的治疗靶点，他们的疾病进展不依赖于规范的WNT信号。
Frizzled 3 receptor (FZD3) plays an important role in the homeo-stasis of the neural crest and its derivatives, which give rise to pigment-synthesizing cells, melanocytes. While the role for FZD3 in specification of the melanocytic lineage from neural crest is well established, its significance in the formation of melanoma, its associated malignancy, is less understood. In this study we identified FZD3 as a critical regulator of human melanoma tumorigenesis. Down-regulation of FZD3 abrogated growth, colony-forming potential, and invasive capacity of patient-derived melanoma cells. Xenotransplantation of tumor cells with down-regulated FZD3 levels originating from melanomas carrying the BRAF(V600) mutation uniformly suppressed their capacity for tumor and metastasis formation. FZD3 knockdown leads to the down-regulation of the core cell cycle protein components (cyclins D1, E2, B1, and CDKs 1, 2, and 4) in melanomas with a hyperactive BRAF oncogene, indicating a dominant role of this receptor during melanoma pathogenesis. Enriched pathway analysis revealed that FZD3 inhibits transcriptional networks controlled by CREB5, FOXD1, and ATF3, which suppress the activity of MAPK-mediated signaling. Thus, FZD3 establishes a positive-feedback mechanism that activates MAPK signal transduction network, critical to melanoma carcinogenesis. Importantly, high levels of FZD3 mRNA were found to be correlated with melanoma advancement to metastatic stages and limited patient survival. Changes in gene-expression patterns mediated by FZD3 activity occur in the absence of nuclear beta-catenin function, thus representing an important therapeutic target for the melanoma patients whose disease progresses independent of canonical WNT signaling.