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Cited by 88Ovarian cancer diagnosis and treatmentFOXO transcription factor regulationReproductive Biology and Fertility

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

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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. +5 more·2014·PLoS ONE
DOI 10.1371/journal.pone.0113478PMC PMC4239070
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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.

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  • The FOXM1 signaling pathway is activated in 84% high-grade serous ovarian cancer and linked to platinum resistance.

    “Notably, the FOXM1 signaling pathway is activated in 84% high-grade serous ovarian cancer [61] and linked to platinum resistance [62, 63].”

    From Identification of a novel gene signature predicting response to first-line chemotherapy in BRCA wild-type high-grade serous ovarian cancer patients (2022) · cites this paper as [62]

    Citation [61] is attached to the claim that the FOXM1 pathway is activated in 84% of high-grade serous ovarian cancers; the platinum-resistance statement has separate citations. The Results section reports FOXM1 staining across ovarian tumour types and a nonsignificant trend for serous and high-grade cancers, but does not report pathway activation in 84% of high-grade serous cases. Searches for “84%” and high-grade serous pathway activation found no supporting passage in our copy. (LLM, conf=0.76)

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  1. [1]Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, et al (2003) Cancer statistics, 2003. CA Cancer J Clin 53(1): 5– 26. 12568441
  2. [2]Burger RA (2008) A new model of ovarian carcinogenesis may influence early detection strategies. Am J Obstet Gynecol 198(4): 349– 50. 18395029
  3. [3]Myatt SS, Lam EW (2007) The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 7(11): 847– 59. 17943136
  4. [4]Koo CY, Muir KW, Lam EW (2012) FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta 1819(1): 28– 37. 21978825
  5. [5]Katoh M (2004) Human FOX gene family (Review). Int J Oncol 25(5): 1495– 500. 15492844
  6. [6]Pilarsky C, Wenzig M, Specht T, Saeger HD, Grützmann R (2004) Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia 6(6): 744– 50. 15720800 PMC1531678
  7. [7]Francis RE, Myatt SS, Krol J, Hartman J, Peck B, et al (2009) FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer. Int J Oncol 35(1): 57– 68. 19513552 PMC3065068
  8. [8]Kwok JM, Peck B, Monteiro LJ, Schwenen HD, Millour J, et al (2010) FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol Cancer Res 8(1): 24– 34. 20068070 PMC2809047
  9. [9]Millour J, de Olano N, Horimoto Y, Monteiro LJ, Langer JK, et al (2011) ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Molecular cancer therapeutics 10(6): 1046– 58. 21518729 PMC4845881
  10. [10]Jiang L, Siu MK, Wong OG, Tam KF, Lu X, et al (2011) iASPP and chemoresistance in ovarian cancers: effects on paclitaxel-mediated mitotic catastrophe. Clin Cancer Res 17(21): 6924– 33. 21926165
  11. [11]Foster H, Coley HM, Goumenou A, Pados G, Harvey A, et al (2010) Differential expression of mTOR signalling components in drug resistance in ovarian cancer. Anticancer research 30(9): 3529– 34. 20944133
  12. [12]Siu MK, Wong ES, Chan HY, Kong DS, Woo NW, et al (2010) Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int J Cancer 127(1): 21– 31. 19876919
  13. [13]Zhao F, Siu MK, Jiang L, Tam KF, Ngan HY, et al (2011) Overexpression of dedicator of cytokinesis I (Dock180) in ovarian cancer correlated with aggressive phenotype and poor patient survival. Histopathology 59(6): 1163– 72. 22175896
  14. [14]Liao X, Siu MK, Au CW, Wong ES, Chan HY, et al (2009) Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis 30(1): 131– 40. 19028702 PMC7109814
  15. [15]Kwok JM, Myatt SS, Marson CM, Coombes RC, Constantinidou D, et al (2008) Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Molecular cancer therapeutics 7(7): 2022– 32. 18645012
  16. [16]Chan DW, Hui WW, Cai PC, Liu MX, Yung MM, et al (2012) Targeting GRB7/ERK/FOXM1 signaling pathway impairs aggressiveness of ovarian cancer cells. PLoS One 7(12): e52578. 23285101 PMC3527599
  17. [17]Hamroun D, Kato S, Ishioka C, Claustres M, Béroud C, et al (2006) The UMD TP53 database and website: update and revisions. Hum Mutat 27(1): 14– 20. 16278824
  18. [18]Wolf JK, Mills GB, Bazzet L, Bast RC Jr, Roth JA, et al (1999) Adenovirus-mediated p53 growth inhibition of ovarian cancer cells is independent of endogenous p53 status. Gynecol Oncol 75(2): 261– 6. 10525383
  19. [19]Yamakawa N, Takahashi A, Mori E, Imai Y, Furusawa Y, et al (2008) High LET radiation enhances apoptosis in mutated p53 cancer cells through Caspase-9 activation. Cancer science 99(7): 1455– 60. 18422753 PMC11158808
  20. [20]Wonsey DR, Follettie MT (2005) Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res 65(12): 5181– 9. 15958562
  21. [21]Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, et al (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23(16): 2825– 37. 15077146
  22. [22]Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, et al (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392(6673): 300– 3. 9521327
  23. [23]Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, et al (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282(5393): 1497– 501. 9822382
  24. [25]Sharp DJ, Rogers GC, Scholey JM (2000) Microtubule motors in mitosis. Nature 407(6800): 41– 7. 10993066
  25. [26]Maney T, Hunter AW, Wagenbach M, Wordeman L (1998) Mitotic centromere-associated kinesin is important for anaphase chromosome segregation. The Journal of cell biology 142(3): 787– 801. 9700166 PMC2148171
  26. [27]Shimo A, Tanikawa C, Nishidate T, Lin ML, Matsuda K, et al (2008) Involvement of kinesin family member 2C/mitotic centromere-associated kinesin overexpression in mammary carcinogenesis. Cancer science 99(1): 62– 70. 17944972 PMC11158784
  27. [28]Nakamura Y, Tanaka F, Haraguchi N, Mimori K, Matsumoto T, et al (2007) Clinicopathological and biological significance of mitotic centromere-associated kinesin overexpression in human gastric cancer. British journal of cancer 97(4): 543– 9. 17653072 PMC2360338
  28. [29]Ganguly A, Yang H, Cabral F (2011) Overexpression of mitotic centromere-associated Kinesin stimulates microtubule detachment and confers resistance to paclitaxel. Molecular cancer therapeutics 10(6): 929– 37. 21471284 PMC3112244

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Authors
Zhao, F., Siu, M. K. Y., Jiang, L., Tam, K. F., Ngan, H. Y. S., Le, X. F., Wong, O. G. W., Wong, E. S. Y., Gomes, A. R., Bella, L., Khongkow, P., Lam, E. W.-F., & Cheung, A. N. Y.
Affiliations
  • Imperial College London (GB)
  • University of Hong Kong (HK)
  • Sichuan University (CN)
Corresponding author
Lam, Eric W-F
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-11-20
Volume
9
Issue
11
Pages
e113478
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0113478
PMC
PMC4239070
OpenAlex
W1971577144
Cited by
88
References
2
Citations by year
2026: 3 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 11 · 2020: 4 · 2019: 9 · 2018: 11 · 2017: 13 · 2016: 8 · 2015: 8 · 2013: 1
FWCI
11.74
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion, cc-by-nc-nd)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
  • Cancer Research UK
  • Breast Cancer Campaign
  • Engineering and Physical Sciences Research Council (1234732)
  • Biotechnology and Biological Sciences Research Council (BBS/B/03785)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
FOXM1, ovarian cancer, paclitaxel resistance, chemoresistance, KIF2C, mitotic catastrophe, prognostic factors, cell migration and invasion, transcription factor target genes, p53-independent cell death, tumor stage
MeSH terms
Forkhead Box Protein M1, Antineoplastic Agents, Phytogenic, Cell Movement, Female, Follow-Up Studies, Humans, Immunohistochemistry, Neoplasm Staging, Ovarian Neoplasms, Prognosis, Down-Regulation, Kinesins, Apoptosis, Paclitaxel, Disease-Free Survival, Drug Resistance, Neoplasm, Cell Line, Tumor, Forkhead Transcription Factors, Kaplan-Meier Estimate, G2 Phase Cell Cycle Checkpoints, Real-Time Polymerase Chain Reaction

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