Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health And Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health And Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Breast and Thyroid Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
J Invest Dermatol. 2020 Nov;140(11):2268-2279.e11. doi: 10.1016/j.jid.2020.03.950. Epub 2020 Apr 8.
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 α-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-κB1 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.
癌症相关成纤维细胞（CAFs）是肿瘤微环境的重要组成部分，在多种癌症中介导肿瘤进展。先前的研究表明 TRAF6 促进黑色素瘤细胞的恶性表型。然而，TRAF6 在黑色素瘤 CAFs 中的作用尚不清楚。在本研究中，我们发现 TRAF6 在与黑色素瘤细胞相邻的 CAFs 中显著上调。功能测定表明 TRAF6 促进成纤维细胞增殖和迁移以及 MMP 和 α-SMA 表达。此外，成纤维细胞中 TRAF6 的表达促进了黑色素瘤细胞在体外和体内的恶性表型。同时，黑色素瘤细胞中 TRAF6 表达的干预影响了 CAFs 的激活。我们发现 FGF19 是通过 NF-κB1 通过黑色素瘤细胞中的荧光素酶测定和染色质免疫沉淀鉴定的 TRAF6 调节的关键细胞因子。由于黑色素瘤患者的血浆 FGF19 水平升高，它可能在体外和体内显著诱导成纤维细胞激活。总之，我们的研究结果表明 TRAF6 是介导黑色素瘤细胞与基质成纤维细胞相互作用的关键分子，提示 TRAF6 可能是黑色素瘤治疗的一个有前途的靶点。
