Overexpression of forkhead box protein M1 (FOXM1) in ovarian cancer correlates with poor patient survival and contributes to paclitaxel resistance

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. Expression of FOXM1 was examined in 119 clinical samples by immunohistochemistry and correlated with clinicopathological pa...

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Published in:PloS one 2014-11, Vol.9 (11), p.e113478
Main Authors: Zhao, Fung, Siu, Michelle K Y, Jiang, LiLi, Tam, Kar Fai, Ngan, Hextan Y S, Le, Xiao Feng, Wong, Oscar G W, Wong, Esther S Y, Gomes, Ana R, Bella, Laura, Khongkow, Pasarat, Lam, Eric W-F, Cheung, Annie N Y
Format: Article
Language:English
Subjects:
Analysis
Antineoplastic Agents, Phytogenic - pharmacology
Antineoplastic Agents, Phytogenic - therapeutic use
Apoptosis
Apoptosis - drug effects
Bioinformatics
Biology and Life Sciences
Cancer
Cancer patients
Cell adhesion & migration
Cell cycle
Cell death
Cell Line, Tumor
Cell migration
Cell Movement
Chemoresistance
Chemotherapy
Deoxyribonucleic acid
Deregulation
Disease-Free Survival
DNA
DNA damage
Down-Regulation - drug effects
Drug Resistance, Neoplasm
Experimental design
Female
Follow-Up Studies
Forkhead Box Protein M1
Forkhead protein
Forkhead Transcription Factors - antagonists & inhibitors
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
G2 Phase Cell Cycle Checkpoints
Gene expression
Gynecology
Homeostasis
Humans
Immunohistochemistry
Kaplan-Meier Estimate
Kinesins - genetics
Medical prognosis
Medicine and Health Sciences
Multivariate analysis
Mutation
Neoplasm Staging
Obstetrics
Ovarian cancer
Ovarian carcinoma
Ovarian Neoplasms - diagnosis
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - mortality
Ovarian Neoplasms - pathology
p53 Protein
Paclitaxel
Paclitaxel - pharmacology
Paclitaxel - therapeutic use
Pathology
Patient outcomes
Patients
Penicillin
Prognosis
Real-Time Polymerase Chain Reaction
Surgery
Survival
Transcription
Tumor proteins
Tumorigenesis
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Summary: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. 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. 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0113478