Abstract
Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5–10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.
Highlights
Cutaneous melanoma (CM) is a tumor that originates from melanocytes of the skin, and continues to carry the potential to be a deadly disease worldwide [1]
The analysis of clinicopathological parameters of thick CM are depicted in Supplementary Materials Table S1 (a + b)
We found an upregulation of the TNF-like weak inducer of apoptosis (TWEAK) pathways in non-metastatic thick melanomas
Summary
Cutaneous melanoma (CM) is a tumor that originates from melanocytes of the skin, and continues to carry the potential to be a deadly disease worldwide [1]. CM is generally curable as a result of early detection and definitive surgery, diagnosis at a late stage and the consequential delay in treatment has an adverse effect on survival This is due to the propensity of CM to metastasize, and to the resistance of metastatic cells to classical chemotherapy. Targeted therapies and immunological approaches to treat metastatic disease have dramatically improved survival in patient with CM in recent years [2,3]. These therapies are not effective in all patients, and are burdened by adverse effects and the development of resistance. It has become crucial to identify biomarkers to assist in identifying patients at highest risk of disease progression to facilitate development of personalized therapy and follow-up care
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