The FOXM1-induced resistance to oxaliplatin is partially mediated by its novel target gene Mcl-1 in gastric cancer cells
The FOXM1-induced resistance to oxaliplatin is partially mediated by its novel target gene Mcl-1 in gastric cancer cells
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DOI：
10.1016/j.bbagrm.2014.11.008
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发表时间：
2015-03-01
影响因子：
4.7
通讯作者：
Yang, Shi-Ming
中科院分区：
文献类型：
--
作者：
Hu, Chang-Jiang;Wang, Bin;Yang, Shi-Ming
髓样细胞白血病-1 (Mcl-1) 是一种属于 Bcl-2 家族的抗凋亡蛋白。 Mcl-1 的异常表达对于胃癌化疗药物的敏感性很重要。然而，Mcl-1在胃癌细胞中的调控机制仍不清楚。在这项研究中，我们首先发现人胃癌标本中Forkhead box M1（FOXM1）和Mcl-1的表达水平呈正相关，并且两者都与奥沙利铂治疗患者的不良预后相关。其次，我们证明胃癌细胞中 Mcl-1 的表达水平与 FOXM1 的表达相关。第三，报告基因检测显示 FOXM1 上调 Mcl-1 基因的启动子活性。电泳迁移率变动分析 (EMSA) 和染色质免疫沉淀 (ChIP) 分析进一步证明 FOXM1 可以结合到 Mcl-1 基因启动子区域的特定位点 (-635acaaacaa-628)。此外，CCK-8检测和细胞凋亡分析表明，抑制FOXM1/Mcl-1通路可诱导细胞凋亡，从而增加胃癌细胞对奥沙利铂的敏感性，而增强FOXM1/Mcl-1通路则抑制细胞凋亡并降低胃癌细胞对奥沙利铂的敏感性。总而言之，这项研究不仅首次表明 Mcl-1 是 FOXM1 的新靶基因，而且表明靶向 FOXM1/Mcl-1 可能是增强胃癌对奥沙利铂敏感性的新策略。 (C) 2014 Elsevier B.V. 保留所有权利。
Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that belongs to the Bcl-2 family. The aberrant expression of Mcl-1 is important for sensitivity to chemotherapy drugs in gastric cancer. However, the regulatory mechanism of Mcl-1 in gastric cancer cells remains unclear. In this study, we first found that Forkhead box M1 (FOXM1) and Mcl-1 expression levels were positively correlated in human gastric cancer specimens and that both are associated with poor prognosis of patients treated with oxaliplatin. Second, we demonstrated that the expression level of Mcl-1 was correlated with FOXM1 expression in gastric cancer cells. Third, reporter assays showed that FOXM1 upregulated the promoter activity of the Mcl-1 gene. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays further demonstrated that FOXM1 could bind to a particular site (-635acaaacaa-628) in the promoter region of the Mcl-1 gene. Moreover, CCK-8 assays and analyses of apoptosis revealed that the suppression of the FOXM1/Mcl-1 pathway induced apoptosis and thus increased sensitivity to oxaliplatin in gastric cancer cells, whereas the enhancement of the FOXMl/Mcl-1 pathway inhibited apoptosis and decreased sensitivity to oxaliplatin in gastric cancer cells. Taken together, this study is the first to not only show that Mcl-1 is a novel target gene of FOXM1 but also suggest that targeting FOXM1/Mcl-1 may be a novel strategy to enhance sensitivity to oxaliplatin in gastric cancer. (C) 2014 Elsevier B.V. All rights reserved.