Abstract
Recent studies have shown that immunotherapies and molecular targeted therapies are effective for advanced melanoma. Non-antigen-specific immunotherapies such as immunocheckpoint blockades have been shown to be effective in the treatment of advanced melanoma. However, the response rates remain low. To improve their efficacy, they should be combined with antigen-specific immunotherapy. Elevated expression of the transcription factor, Forkhead box M1 (FOXM1), has been reported in various human cancers, and it has been shown to have potential as a target for immunotherapy. The purpose of this study was to investigate the FOXM1 expression in human melanoma samples and cell lines, to evaluate the relationship between the FOXM1 expression and the clinical features of melanoma patients and to investigate the association between the FOXM1 and MAPK and PI3K/AKT pathways in melanoma cell lines. We conducted the quantitative reverse transcription PCR (qRT-PCR) and Western blotting analyses of melanoma cell lines, and investigated melanoma and nevus tissue samples by qRT-PCR and immunohistochemistry. We performed MEK siRNA and PI3K/AKT inhibitor studies and FOXM1 siRNA studies in melanoma cell lines. We found that FOXM1 was expressed in all of the melanoma cell lines, and was expressed in 49% of primary melanomas, 67% of metastatic melanomas and 10% of nevi by performing immunohistochemical staining. Metastatic melanoma samples exhibited significantly higher mRNA levels of FOXM1 (p = 0.004). Primary melanomas thicker than 2 mm were also more likely to express FOXM1. Patients whose primary melanoma expressed FOXM1 had a significantly poorer overall survival compared to patients without FOXM1 expression (p = 0.024). Downregulation of FOXM1 by siRNA significantly inhibited the proliferation of melanoma cells, and blockade of the MAPK and PI3K/AKT pathways decreased the FOXM1 expression in melanoma cell lines. In conclusion, FOXM1 is considered to be a new therapeutic target for melanoma.
Highlights
Malignant melanoma is one of the most aggressive skin cancers, and its incidence has been gradually increasing [1]
We found that MEK1 small interfering RNA (siRNA) downregulated the expression of Forkhead box M1 (FOXM1), together with p-MEK, in three melanoma cells (MeWo cells, MM-LH cells and VM115 cells). (Fig 6) These data suggest the possibility that FOXM1 is activated by the MAPK pathway in these melanoma cell lines
We found that LY294002 and the AKT inhibitor reduced the expression of FOXM1 (Fig 7B), suggesting that FOXM1 is regulated by the PI3K/AKT pathway in melanoma cells
Summary
Malignant melanoma is one of the most aggressive skin cancers, and its incidence has been gradually increasing [1]. Malignant melanoma is responsible for most skin cancer-related deaths. Recent studies have shown that immunotherapies and molecular targeted therapies are effective for advanced melanoma. Ipilimumab (a fully human monoclonal antibody against cytotoxic T-lymphocyte antigen 4) has demonstrated consistent activity against advanced melanoma [2]. Nivolumab (anti–programmed death 1 antibodies) was associated with objective responses in 30–40% of patients with metastatic melanoma [4]. The median progressionfree survival that was observed with the combination of BRAF and MEK inhibition is similar to that recently reported with combined nivolumab and ipilimumab (11.7 months in patients with a BRAF mutation) [4]. It can be said that the therapies for advanced melanoma have improved greatly. We have focused our attention on Forkhead box M1 (FOXM1) as a target for anti-cancer immunotherapy in melanoma
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