Overexpression of Forkhead Box Protein M1 (FOXM1) in Ovarian Cancer Correlates with Poor Patient Survival and Contributes to Paclitaxel Resistance

Title: Overexpression of Forkhead Box Protein M1 (FOXM1) in Ovarian Cancer Correlates with Poor Patient Survival and Contributes to Paclitaxel Resistance
Authors: Zhao, F
Siu, MK
Jiang, L
Tam, KF
Ngan, HY
Le, XF
Wong, OG
Wong, ES
Gomes, AR
Bella, L
Khongkow, P
Lam, EW
Cheung, AN
Item Type: Journal Article
Abstract: AIM: 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. EXPERIMENTAL DESIGN: 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. CONCLUSION: 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.
Issue Date: 20-Nov-2014
Date of Acceptance: 28-Oct-2014
URI: http://hdl.handle.net/10044/1/39203
DOI: http://dx.doi.org/10.1371/journal.pone.0113478
ISSN: 1932-6203
Publisher: Public Library of Science
Journal / Book Title: PLOS One
Volume: 9
Issue: 11
Copyright Statement: © 2014 Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Antineoplastic Agents, Phytogenic
Cell Line, Tumor
Cell Movement
Disease-Free Survival
Drug Resistance, Neoplasm
Follow-Up Studies
Forkhead Transcription Factors
G2 Phase Cell Cycle Checkpoints
Kaplan-Meier Estimate
Neoplasm Staging
Ovarian Neoplasms
Real-Time Polymerase Chain Reaction
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Article Number: e113478
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine

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