Abstract
This study aimed to investigate the prognostic value and molecular mechanism of DDX39 and its effector SNAIL in melanoma. First, overexpression of DDX39 in melanoma, which was identified by database analysis, was further validated in patient tissues. Cell growth, cell cycle, cell migration, and cell invasion assays were then performed to evaluate the effects of downregulated DDX39 on the melanoma cell proliferation and aggressiveness. The same approaches were also used to reveal the cooperation of the transcription factor SNAIL with DDX39 to promote the aggressiveness of melanoma cells. We found that the expression of DDX39 was significantly upregulated in melanoma tissue compared to pigmented nevus tissue, and it was positively correlated with the clinical stage defined by the American Joint Committee on Cancer (AJCC) and the prognosis. Downregulation of DDX39 in melanoma cells was found to significantly inhibit cell proliferation, increase G2/M cell cycle arrest, enhance caspase-mediated cell apoptosis, and suppress cell invasion and migration. In addition, we demonstrated that the overexpression of SNAIL could restore the cell growth and aggressiveness impaired by DDX39 RNA interference. Immunohistochemical staining also showed a positive correlation between DDX39 overexpression and SNAIL overexpression in melanoma tissues, suggesting that SNAIL is one of the effectors activated by DDX39. In summary, the overexpression of DDX39 and SNAIL was positively related to the poor prognosis of melanoma patients and the increased aggressiveness of melanoma cells. Our study provides valuable evidence regarding the prognostic value of DDX39 and SNAIL as well as their potential as novel therapeutic targets for treating melanoma patients.
Highlights
Melanoma is a malignant tumor originating from the skin or mucosal pigmented cells and is the leading cause of death from malignant skin tumors; the worldwide morbidity of melanoma is increasing by 3–8% per year [1]
By analyzing the Affymetrix expression profile in the Gene Expression Omnibus (GEO) database GSE 46517, we identified DDX39, a member of the DEAD box RNA helicase family, as an overexpressed gene in melanoma but not in pigmented nevi tissues (Figure 1A; P < 0.001)
The overexpression of DDX39 protein was positively correlated with the American Joint Committee on Cancer (AJCC) clinical stage (P = 0.014), Breslow thickness (P = 0.014), and Clark grade (P = 0.009) (Table 3)
Summary
Melanoma is a malignant tumor originating from the skin or mucosal pigmented cells and is the leading cause of death from malignant skin tumors; the worldwide morbidity of melanoma is increasing by 3–8% per year [1]. Cutaneous melanoma is mostly associated with sunlight exposure; while in China, most cases occur at the extremities. Melanoma, characterized by occult onset, rapid progression, and low survival rates in advanced patients, is insensitive to radiotherapy, and chemotherapy, making surgery the most effective treatment [2]. Since 2011, Vemurafenib (BRAF inhibitor), Trametinib (MEK inhibitor), Ipilimumab (cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody), as well as Nivolumab and Pembrolizumab (programmed cell death protein 1 monoclonal antibodies) have been successively approved by the US Federal Drug Administration for melanoma treatment. The mutation rate of the BRAF V600 gene of melanoma patients in China is only 25%, which is lower than the rate of 50–60% found in western countries [4]. Studying the gene expression discrepancy between pigmented nevi and melanoma would be helpful to identify genes involved in melanoma progressiveness
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