FoxM1 expression is significantly associated with cisplatin-based chemotherapy resistance and poor prognosis in advanced non-small cell lung cancer patients
FoxM1 expression is significantly associated with cisplatin-based chemotherapy resistance and poor prognosis in advanced non-small cell lung cancer patients
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FoxM1表达与晚期非小细胞肺癌患者顺铂化疗耐药和不良预后显着相关
DOI：
10.1016/j.lungcan.2012.10.019
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发表时间：
2013-02-01
期刊：
影响因子：
5.3
通讯作者：
Liu, Wen-chao
中科院分区：
文献类型：
--
作者：
Wang, Yu;Wen, Li;Liu, Wen-chao
背景：已知转录因子 Forkhead box M1 (FoxM1) 在包括肺癌在内的许多恶性肿瘤的发生和进展中发挥重要作用。然而，FoxM1 表达与非小细胞肺癌 (NSCLC) 化疗临床反应和预后的关系仍不清楚。 方法：使用免疫组织化学方法评估治疗前有肿瘤标本的 162 例 NSCLC（IIIB 和 IV 期）患者的 FoxM1 表达。通过Kaplan-Meier曲线、对数秩检验和多元Cox回归分析来分析临床意义。采用MTT法检测DDP敏感性A549和相应的DDP耐药细胞亚系（A549/DDP）对顺铂的敏感性，并通过实时PCR和Western blot分析耐药相关基因。此外，将靶向FoxM1的小干扰RNA（siRNA）体外转染至A549和A549/DDP细胞系中，并通过Transwell小室实验分别检测迁移和侵袭。结果：与不表达FoxM1的患者相比，表达FoxM1的患者的缓解率（P = 0.009）显着较低，且无进展生存（PFS，P = 0.002）和总生存（OS，P = 0.007）较差。多变量分析表明，FoxM1 阳性分别是 PFS (P = 0.006) 和 OS (P = 0.021) 的独立预后因素。此外，A549/DDP细胞亚系中FoxM1的mRNA和蛋白水平表达均显着高于A549细胞。 FoxM1 抑制剂硫链丝菌肽还显示出通过下调 FoxM1 表达而导致顺铂耐药细胞死亡和增殖停滞的功效。通过 siRNA 敲除 FoxM1 可抑制 A549 和 A549/DDP 细胞中的细胞迁移和侵袭。通过siRNA介导的FoxM1抑制可以部分逆转A549/DDP细胞中的顺铂耐药性。结论：FoxM1的表达可能是晚期NSCLC患者的独立预后标志物，FoxM1抑制可能是NSCLC细胞化疗增敏的潜在策略。 (c) 2012 Elsevier Ireland Ltd. 保留所有权利。
Background: The transcription factor Forkhead box M1 (FoxM1) is known to play an important role in the development and progression of many malignancies including lung cancer. However, the relationship of FoxM1 expression and the clinical response to chemotherapy and prognosis in non-small cell lung cancer (NSCLC) remains unknown.Methods: Total 162 NSCLC (stages IIIB and IV) patients who had tumor specimens available before treatment were assessed for FoxM1 expression using immunohistochemistry. Clinical significance was analyzed by Kaplan-Meier curves, log-rank test and multivariate Cox regression analysis. Sensitivities to cisplatin were detected by the MTT assay and drug-resistance related genes were analyzed by real-time PCR and western blot between DDP-sensitive A549 and the corresponding DDP-resistant cell subline (A549/DDP). Furthermore, small interfering RNA (siRNA) targeting FoxM1 was transfected into A549 and A549/DDP cell lines in vitro and migration and invasion were examined separately by Transwell chamber assay.Results: Patients with FoxM1 expression had a significantly lower response rate (P = 0.009) and poor progression-free survival (PFS, P = 0.002) and overall survival (OS, P = 0.007) than those without FoxM1 expression. Multivariate analyses indicated that FoxM1 positivity was an independent prognostic factor for PFS (P = 0.006) and OS (P = 0.021), respectively. Moreover, the expression of FoxM1 was significantly higher in A549/DDP cell subline than in A549 cells at both mRNA and protein levels. The FoxM1 inhibitor thiostrepton also showed efficacy in causing cell death and proliferative arrest in the cisplatin-resistant cells through the downregulation of FoxM1 expression. Knockdown of FoxM1 by siRNA suppressed cell migration and invasion in A549 and A549/DDP cells. Cisplatin resistance in A549/DDP cells could be partially reversed through siRNA-mediated FoxM1 inhibition.Conclusions: The expression of FoxM1 might be an independent prognostic marker for advanced NSCLC patients and FoxM1 inhibition would be a potential strategy for chemosensitization of NSCLC cells. (c) 2012 Elsevier Ireland Ltd. All rights reserved.