Abstract
Melanoma is an aggressive cancer with highly metastatic ability. We propose cofilin-1, a key protein in the regulation of actin dynamics and migration, as a prognostic marker. We determined cofilin-1 levels in a retrospective cohort of patients with melanomas and benign lesions of melanocytes (nevi) by immunohistochemistry. Higher cofilin-1 levels were found in malignant melanoma (MM) with Breslow Index (BI)>2 vs MM with BI<2, melanoma in situ (MIS) and nevi and also in MM with metastasis vs MM without detected metastasis. Kaplan-Meier survival curves were performed, clustering patients according to either the type of melanocytic lesions or cofilin-1 level. Survival curves demonstrated worse prognosis of patients with high vs low cofilin-1 levels. TCGA database analysis of melanoma also showed low survival in patients with upregulated cofilin-1 mRNA vs patients without alteration in CFL1 mRNA expression. As cofilin-1 has a dual function depending on its intracellular localization, we evaluated nuclear and cytoplasmic levels of cofilin-1 in melanoma and nevi samples by immunofluorescence. MM with high Breslow index and metastatic cells not only presented cytoplasmic cofilin-1, but also showed this protein at the nucleus. An increase in nuclear/cytoplasmic cofilin-1 mean fluorescence ratio was observed in MM with BI>2 vs MM with BI<2, MIS and nevi.In conclusion, an association of cofilin-1 levels with malignant features and an inverse correlation with survival were demonstrated. Moreover, this study suggests that not only the higher levels of cofilin-1, but also its nuclear localization can be proposed as marker of worse outcome of patients with melanoma.
Highlights
Malignant melanoma (MM) is one of the most aggressive cancers, with high metastatic ability and increasing mortality rates
Results show a significant association between high levels of cofilin-1 and MM advanced stages (p
Www.oncotarget.com we focused on cofilin-1, which is a key mediator of actin cytoskeleton polymerization and migration [26]
Summary
Malignant melanoma (MM) is one of the most aggressive cancers, with high metastatic ability and increasing mortality rates. It is estimated that 91,270 new cases of invasive melanoma will be diagnosed in the U.S in 2018 [1]. Stage melanoma can be cured by surgery alone, but late stage metastatic disease has limited treatment options. There is a highly significant decline in survival rates as melanoma thickness ( called Breslow index, BI) increase. The chances of relapse do not differ much between stage T2 and stage T3 patients; in addition, for very early stage melanoma (≤1 mm, T1a or T1b) the risk of recurrence ranges between 1% and 12% [8]
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