The deubiquitinase cylindromatosis (CYLD) is a well-known tumor suppressor, found to be down regulated in many cancer types including breast cancer, colon carcinoma and malignant melanoma. CYLD is suppressed in human melanoma cells by the transcriptional repressor SNAIL1 leading to an increase of their proliferative, invasive and migratory potential. To gain additional insights into the distinct function of this tumor suppressor gene a new mouse model Tg(Grm1)Cyld^−/− was generated. Herewith, we demonstrate that Cyld-deficiency leads to earlier melanoma onset and accelerated tumor growth and metastasis in the GRM1 melanoma mouse model. First, RNA sequencing data revealed a potential role of CYLD in the regulation of genes involved in proliferation, migration and angiogenesis. Experiments using cell lines generated from both primary and metastatic melanoma tissue of Tg(Grm1) Cyld^−/− and Tg(Grm1) Cyld^+/+ mice confirmed that loss of CYLD enhances the proliferative and migratory potential, as well as the clonogenicity in vitro. Moreover, we could show that Cyld-knockout leads to increased vasculogenic mimicry and enhanced (lymph-) angiogenesis shown by tube formation assays, immunohistochemistry and mRNA expression analyses. In summary, our findings reveal new functional aspects of CYLD in the process of (lymph-) angiogenesis and demonstrate its importance in the early process of melanoma progression.

去泛素化酶圆柱化病（CYLD）是一种众所周知的肿瘤抑制因子，在许多癌症类型（包括乳腺癌，结肠癌和恶性黑色素瘤）中均被下调。CYLD在人类黑素瘤细胞中受到转录阻抑物SNAIL1的抑制，导致其增殖，侵袭和迁移潜能的增加。为了获得对该肿瘤抑制基因的独特功能的进一步了解，生成了新的小鼠模型Tg（Grm1）Cyld ^-/-。借此，我们证明Cyld缺陷导致GRM1黑色素瘤小鼠模型中较早的黑色素瘤发作，并加速了肿瘤的生长和转移。首先，RNA测序数据揭示了CYLD在调节与增殖，迁移和血管生成有关的基因中的潜在作用。使用从Tg（Grm1）Cyld ^-/-和Tg（Grm1）Cyld ^{+ / +}小鼠的原发性和转移性黑素瘤组织产生的细胞系进行的实验证实，CYLD的丧失增强了增殖和迁移的潜力，并且在体外具有克隆形成性。而且，我们可以证明Cyld管形成试验，免疫组织化学和mRNA表达分析显示，基因敲除导致增加的血管生成模拟和增强的（淋巴）血管生成。总之，我们的发现揭示了CYLD在（淋巴）血管生成过程中的新功能方面，并证明了其在黑色素瘤进展的早期过程中的重要性。