title: Overexpression of FoxM1 is associated with tumor progression in patients with clear cell renal cell carcinoma.
abstract: BACKGROUND
  Fork head box M1 (FoxM1) is a proliferation-associated transcription factor essential for cell cycle progression. Numerous studies have documented that FoxM1 has multiple functions in tumorigenesis and its elevated levels are frequently associated with cancer progression. The present study was conducted to investigate the expression of FoxM1 and its prognostic significance in clear cell renal cell carcinoma (ccRCC). Meanwhile, the function of FoxM1 in human ccRCC was further investigated in cell culture models.
  
  
  METHODS
  Real-time quantitative PCR, western blot and immunohistochemistry were used to explore FoxM1 expression in ccRCC cell lines and primary ccRCC clinical specimens. FoxM1 expression was knocked down by small interfering RNA (siRNA) in Caki-1 and 786-O cells; proliferation, colony formation, cell cycle, migration, invasion, and angiogenesis were assayed.
  
  
  RESULTS
  FoxM1 expression was up-regulated in the majority of the ccRCC clinical tissue specimens at both mRNA and protein levels. Clinic pathological analysis showed that FoxM1 expression was significantly correlated with primary tumor stage (P <0.001), lymph node metastasis (P = 0.01), distant metastasis (P = 0.01), TNM stage (P < 0.001) and histological grade (P = 0.003). The Kaplan-Meier survival curves revealed that high FoxM1 expression was associated with poor prognosis in ccRCC patients (P < 0.001). FoxM1 expression was an independent prognostic marker of overall ccRCC patient survival in a multivariate analysis (P = 0.008). Experimentally, we found that down-regulation of FoxM1 inhibited cell proliferation and induced cell cycle arrest with reduced expression of cyclin B1, cyclin D1, and Cdk2, and increased expression of p21 and p27. Also, down-regulation of FoxM1 reduced expression and activity of matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF), resulting in the inhibition of migration, invasion, and angiogenesis.
  
  
  CONCLUSIONS
  These results suggest that FoxM1 expression is likely to play important roles in ccRCC development and progression, and that FoxM1 is a prognostic biomarker and a promising therapeutic target for ccRCC.
authors.affiliation: Department of Urology, First Affiliated Hospital of Gannan Medical University, No 23, Qing Nian Road, Ganzhou 341000, People's Republic of China.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Xue
authors.forename: Ri-Hai
authors.initials: RH
authors.lastname: Xiao
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Long
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zou
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Wang
authors.forename: Guo-Xi
authors.initials: GX
authors.lastname: Zhang
authors.forename: Yuan-Hu
authors.initials: YH
authors.lastname: Yuan
authors.forename: Geng-Qing
authors.initials: GQ
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Fo-Lin
authors.initials: FL
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Liu
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007120:Immunochemistry; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger