title: FoxM1 expression is significantly associated with cisplatin-based chemotherapy resistance and poor prognosis in advanced non-small cell lung cancer patients.
abstract: 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.
authors.affiliation: Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.forename: Shu-hua
authors.initials: SH
authors.lastname: Zhao
authors.forename: Zhen-hua
authors.initials: ZH
authors.lastname: Ai
authors.forename: Jun-zhao
authors.initials: JZ
authors.lastname: Guo
authors.forename: Wen-chao
authors.initials: WC
authors.lastname: Liu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D000093542:Gemcitabine
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D014747:Vinblastine; D002945:Cisplatin; D000077235:Vinorelbine; D000093542:Gemcitabine