The p75NTR carboxyl‐terminal fragment (p75NTR‐CTF) promotes melanoma cell proliferation and survival, as well as increasing sorafenib resistance in vivo and in vitro.,Moreover, p75NTR‐CTF activates the nuclear factor kappa B pathway and enhances the mRNA and protein levels of its downstream genes.,On the contrary, full‐length p75NTR inhibits these processes.,Overall, we found that p75NTR‐CTF and full‐length p75NTR have opposing functions in melanoma cells.,The p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor superfamily of receptors, is sensitive to proteolysis and has been observed to be expressed in various cancers.,However, the roles of p75NTR and its proteolytic fragments in tumorigenesis remain incompletely understood.,Here, we report that the proportion of the p75NTR carboxyl‐terminal fragment (p75NTR‐CTF) is much higher than that of the full‐length p75NTR (p75NTR‐FL) in melanoma cells.,Whereas p75NTR‐FL positively regulates apoptosis, p75NTR‐CTF promotes cell proliferation and survival, as well as increasing sorafenib resistance in vivo and in vitro.,Moreover, p75NTR‐CTF activates the nuclear factor kappa B pathway and enhances the mRNA and protein levels of its downstream genes c‐IAP1/2, FLIP, bFGF, IL8 and VEGF.,On the contrary, p75NTR‐FL inhibits these processes.,Taken together, these findings demonstrate that p75NTR‐CTF and p75NTR‐FL have opposing functions in melanoma cells, suggesting that the ratio of the two proteins affects the balance between cell death and survival.,The presence of distinct p75NTR proteolytic fragments may affect biological outcomes in tumor cells.
Skin cancer, which includes melanoma and squamous cell carcinoma, represents the most common type of cutaneous malignancy worldwide, and its incidence is expected to rise in the near future.,This condition derives from acquired genetic dysregulation of signaling pathways involved in the proliferation and apoptosis of skin cells.,The development of animal models has allowed a better understanding of these pathomechanisms, with the possibility of carrying out toxicological screening and drug development.,In particular, the zebrafish (Danio rerio) has been established as one of the most important model organisms for cancer research.,This model is particularly suitable for live cell imaging and high-throughput drug screening in a large-scale fashion.,Thanks to the recent advances in genome editing, such as the clustered regularly-interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) methodologies, the mechanisms associated with cancer development and progression, as well as drug resistance can be investigated and comprehended.,With these unique tools, the zebrafish represents a powerful platform for skin cancer research in the development of target therapies.,Here, we will review the advantages of using the zebrafish model for drug discovery and toxicological and phenotypical screening.,We will focus in detail on the most recent progress in the field of zebrafish model generation for the study of melanoma and squamous cell carcinoma (SCC), including cancer cell injection and transgenic animal development.,Moreover, we will report the latest compounds and small molecules under investigation in melanoma zebrafish models.