Hu Chang-Jiang, Wang Bin, Tang Bo, Chen Bai-jun, Xiao Yu-Feng, Qin Yong, Yong Xin, Luo Gang, Zhang Jian-Wei, Zhang Dan, Li Song, He Fengtian, Yang Shi-Ming
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
Biochim Biophys Acta. 2015 Mar;1849(3):290-9. doi: 10.1016/j.bbagrm.2014.11.008. Epub 2014 Dec 4.
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 FOXM1/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.
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的异常表达对胃癌化疗药物敏感性至关重要。然而，Mcl-1在胃癌细胞中的调控机制仍不清楚。在本研究中，我们首先发现，在人胃癌标本中叉头框M1（FOXM1）与Mcl-1表达水平呈正相关，且二者均与接受奥沙利铂治疗患者的不良预后相关。其次，我们证明了在胃癌细胞中Mcl-1的表达水平与FOXM1表达相关。第三，报告基因检测表明FOXM1上调了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可与Mcl-1基因启动子区域的一个特定位点（-635acaaacaa-628）结合。此外，CCK-8检测和凋亡分析表明，抑制FOXM1/Mcl-1通路可诱导胃癌细胞凋亡，从而增加对奥沙利铂的敏感性，而增强FOXM1/Mcl-1通路则抑制胃癌细胞凋亡并降低对奥沙利铂的敏感性。综上所述，本研究首次不仅表明Mcl-1是FOXM1的一个新靶基因，还提示靶向FOXM1/Mcl-1可能是提高胃癌对奥沙利铂敏感性的一种新策略。
