TRAF6 Activates Fibroblasts to Cancer-Associated Fibroblasts through FGF19 in Tumor Microenvironment to Benefit the Malignant Phenotype of Melanoma Cells
TRAF6 Activates Fibroblasts to Cancer-Associated Fibroblasts through FGF19 in Tumor Microenvironment to Benefit the Malignant Phenotype of Melanoma Cells
复制标题
TRAF6通过肿瘤微环境中的FGF19激活成纤维细胞向癌相关成纤维细胞转化以利于黑色素瘤细胞的恶性表型
DOI：
10.1016/j.jid.2020.03.950
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发表时间：
2020-11-01
影响因子：
6.5
通讯作者：
Peng, Cong
中科院分区：
文献类型：
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作者：
Guo, Yeye;Zhang, Xu;Peng, Cong
癌症相关成纤维细胞（CAF）是肿瘤微环境的重要组成部分，并介导各种癌症的肿瘤进展。先前的研究表明，TRAF 6促进黑色素瘤细胞的恶性表型。然而，TRAF 6在黑色素瘤CAF中的作用仍不清楚。在这项研究中，我们发现TRAF 6在与黑色素瘤细胞相邻的CAFs中显著上调。功能分析显示TRAF 6促进成纤维细胞增殖和迁移以及MMP和α-SMA表达。此外，TRAF 6在成纤维细胞中的表达促进了体外和体内黑色素瘤细胞的恶性表型。同时，TRAF 6在黑色素瘤细胞中表达的干预影响CAFs的活化。我们发现，FGF 19是一个关键的细胞因子调节TRAF 6通过NF-κ B1在黑色素瘤细胞中使用荧光素酶测定和染色质免疫沉淀。由于血浆FGF 19水平在黑素瘤患者中升高，因此其可显著诱导体外和体内成纤维细胞活化。总之，我们的结果支持TRAF 6是介导黑色素瘤细胞和基质成纤维细胞之间相互作用的关键分子，表明TRAF 6是黑色素瘤治疗中潜在的有希望的靶点。
Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment and mediate tumor progression in various cancers. A previous study demonstrated that TRAF6 promotes the malignant phenotype of melanoma cells. However, the role of TRAF6 in melanoma CAFs remains unclear. In this study, we found that TRAF6 was significantly upregulated in CAFs adjacent to melanoma cells. Functional assays showed that TRAF6 promoted fibroblast proliferation and migration as well as MMP and alpha-SMA expression. Moreover, the expression of TRAF6 in fibroblasts promoted the malignant phenotype of melanoma cells in vitro and in vivo. Meanwhile, the intervention of TRAF6 expression in melanoma cells affected the activation of CAFs. We found that FGF19 was a key cytokine regulated by TRAF6 through NF-kappa B1 using luciferase assay and chromatin immunoprecipitation in melanoma cells. Because plasma FGF19 levels are elevated in patients with melanoma, it may significantly induce fibroblast activation in vitro and in vivo. Taken together, our results support that TRAF6 is a key molecule that mediates the interaction between melanoma cells and stromal fibroblasts, suggesting that TRAF6 is a potentially promising target in melanoma therapy.