title: Overexpression of forkhead box protein M1 (FOXM1) in ovarian cancer correlates with poor patient survival and contributes to paclitaxel resistance.
abstract: OBJECTIVE
  Deregulation of FOXM1 has been documented in various cancers. The aim of this study was to evaluate the role of FOXM1 in ovarian cancer tumorigenesis and paclitaxel resistance.
  
  
  METHODS
  Expression of FOXM1 was examined in 119 clinical samples by immunohistochemistry and correlated with clinicopathological parameters. Effects of FOXM1 knockdown on ovarian cancer cell migration, invasion and mitotic catastrophe were also studied. qPCR and ChIP-qPCR were used to establish KIF2C as a novel FOXM1 target gene implicated in chemoresistance.
  
  
  RESULTS
  High nuclear FOXM1 expression in ovarian cancer patient samples was significantly associated with advanced stages (P = 0.035), shorter overall (P = 0.019) and disease-free (P = 0.014) survival. Multivariate analysis confirmed FOXM1 expression as an independent prognostic factor for ovarian cancer. FOXM1 knockdown significantly inhibited migration and invasion of ovarian cancer cells and enhanced paclitaxel-mediated cell death and mitotic catastrophe in a p53-independent manner. Bioinformatics analysis suggested a number of potential transcription targets of FOXM1. One of the potential targets, KIF2C, exhibited similar expression pattern to FOXM1 in chemosensitive and chemoresistant cells in response to paclitaxel treatment. FOXM1 could be detected at the promoter of KIF2C and FOXM1 silencing significantly down-regulated KIF2C.
  
  
  CONCLUSIONS
  Our findings suggest that FOXM1 is associated with poor patient outcome and contributes to paclitaxel resistance by blocking mitotic catastrophe. KIF2C is identified as a novel FOXM1 transcriptional target that may be implicated in the acquisition of chemoresistance. FOXM1 should be further investigated as a potential prognostic marker and therapeutic target for ovarian cancer.
authors.affiliation: Department of Pathology, The University of Hong Kong, HKSAR, China; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Fung
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Obstetrics and Gynaecology, The University of Hong Kong, HKSAR, China.
authors.forename: Michelle K Y
authors.initials: MK
authors.lastname: Siu
authors.affiliation: Department of Pathology, West China Hospital, Sichuang University, Chengdu, China.
authors.forename: LiLi
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pathology, The University of Hong Kong, HKSAR, China.
authors.forename: Kar Fai
authors.initials: KF
authors.lastname: Tam
authors.affiliation: Obstetrics and Gynaecology, The University of Hong Kong, HKSAR, China.
authors.forename: Hextan Y S
authors.initials: HY
authors.lastname: Ngan
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Texas, United States of America.
authors.forename: Xiao Feng
authors.initials: XF
authors.lastname: Le
authors.affiliation: Department of Pathology, The University of Hong Kong, HKSAR, China.
authors.forename: Oscar G W
authors.initials: OG
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, HKSAR, China.
authors.forename: Esther S Y
authors.initials: ES
authors.lastname: Wong
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Gomes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Bella
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Pasarat
authors.initials: P
authors.lastname: Khongkow
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Department of Pathology, The University of Hong Kong, HKSAR, China; Department of Pathology, The University of Hong Kong -Shenzhen Hospital, Shenzhen, China.
authors.forename: Annie N Y
authors.initials: AN
authors.lastname: Cheung
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016547:Kinesins / Q000235:genetics; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C091489:KIF2C protein, human; D016547:Kinesins; D017239:Paclitaxel