Abstract
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.
Highlights
The tumor suppressor function of cylindromatosis (CYLD) was first described in the disease of familiar cylindromatosis, a rare benign tumor of skin appendages[1]
Loss of CYLD accelerates melanoma onset and increases tumor growth in vivo To study the role of CYLD in melanoma tumorigenesis in vivo, Tg(Grm1) mice[11] were crossbred with C57BL/6 Cyld-knockout mice[19]
The generated Tg(Grm1) Cyld+/+ and Tg(Grm1) Cyld−/− mice were analyzed for melanoma onset (Fig. 1a)
Summary
The tumor suppressor function of cylindromatosis (CYLD) was first described in the disease of familiar cylindromatosis, a rare benign tumor of skin appendages[1]. Since both depletion and mutation of CYLD have been associated with development and progression of a variety of tumors such as cancer of the breast, colon and lung[2,3,4]. We analyzed the role of CYLD for the first time in a murine model for spontaneous melanoma development. Tg(Grm1) mice display pigmented lesions after a short latency and with complete penetrance[11]. GRM1 is a seven transmembrane domain comprising G-
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