Investigation of FOXM1 as a Potential New Target for Melanoma.
Investigation of FOXM1 as a Potential New Target for Melanoma.
复制标题
DOI：
10.1371/journal.pone.0144241
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ihn H
中科院分区：
文献类型：
--
作者：
Miyashita A;Fukushima S;Nakahara S;Yamashita J;Tokuzumi A;Aoi J;Ichihara A;Kanemaru H;Jinnin M;Ihn H
最近的研究表明，免疫治疗和分子靶向治疗对晚期黑色素瘤是有效的。非抗原特异性免疫疗法，如免疫检查点阻断，已被证明是有效的治疗晚期黑色素瘤。然而，答复率仍然很低。为了提高其疗效，应将其与抗原特异性免疫治疗相结合。转录因子叉头盒M1（FOXM 1）的表达升高已在各种人类癌症中报道，并且已显示其具有作为免疫治疗靶点的潜力。本研究的目的是研究FOXM 1在人类黑色素瘤样品和细胞系中的表达，以评估FOXM 1表达与黑色素瘤患者的临床特征之间的关系，并研究FOXM 1与黑色素瘤细胞系中MAPK和PI 3 K/AKT通路之间的关联。我们对黑色素瘤细胞系进行了定量逆转录PCR（qRT-PCR）和Western印迹分析，并通过qRT-PCR和免疫组织化学研究了黑色素瘤和痣组织样本。我们在黑色素瘤细胞系中进行了MEK siRNA和PI 3 K/AKT抑制剂研究以及FOXM 1 siRNA研究。我们发现FOXM 1在所有的黑色素瘤细胞系中表达，并且通过进行免疫组织化学染色，在49%的原发性黑色素瘤、67%的转移性黑色素瘤和10%的痣中表达。转移性黑色素瘤样品表现出显著更高的FOXM 1 mRNA水平（p = 0.004）。厚度大于2 mm的原发性黑色素瘤也更可能表达FOXM 1。原发性黑色素瘤表达FOXM 1的患者的总体生存率显著低于不表达FOXM 1的患者（p = 0.024）。通过siRNA下调FOXM 1显著抑制黑素瘤细胞的增殖，并且阻断MAPK和PI 3 K/AKT通路降低黑素瘤细胞系中FOXM 1的表达。总之，FOXM 1被认为是黑色素瘤的新的治疗靶点。
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.