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PMID: 23136192 Published · ppublish English Journal Article

The critical role of dysregulated FOXM1-PLAUR signaling in human colon cancer progression and metastasis.

Clinical cancer research : an official journal of the American Association for Cancer Research ·Vol. 19 ·No. 1 ·2013-01-01 ·Pages 62-72

Li D, Wei P, Peng Z, Huang C, Tang H, Jia Z, Cui J, Le X, Huang S, Xie K

Abstract

The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer pathogenesis remains unknown. We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer. We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by siRNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase-type plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis. Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis.

MeSH Terms
Animals Cell Line, Tumor Cell Movement/genetics Colonic Neoplasms/genetics,metabolism,mortality,pathology Disease Progression Female Forkhead Box Protein M1 Forkhead Transcription Factors/genetics,metabolism Gene Expression Gene Expression Regulation, Neoplastic Humans Mice Neoplasm Invasiveness Neoplasm Metastasis Prognosis Promoter Regions, Genetic Receptors, Urokinase Plasminogen Activator/genetics,metabolism Signal Transduction Transcriptional Activation
Chemicals
FOXM1 protein, human Forkhead Box Protein M1 Forkhead Transcription Factors PLAUR protein, human Receptors, Urokinase Plasminogen Activator
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Li Dawei
Department of General Surgery, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
Wei Ping
Peng Zhihai
Huang Chen
Tang Huamei
Jia Zhiliang
Cui Jiujie
Le Xiangdong
Huang Suyun
Xie Keping
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Article Info
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
Abbr.
Clin Cancer Res
ISSN
1557-3265
DOI
10.1158/1078-0432.CCR-12-1588
Published
2013-01-01
Epub
2012-00-07
Pages
62-72
Language
English
Region
United States
NLM ID
9502500
PMCID
PMC3537853
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · P01 CA130821 · United States
NCI NIH HHS · R01 CA129956 · United States
NCI NIH HHS · R01 CA148954 · United States
NCI NIH HHS · R01 CA157933 · United States
NCI NIH HHS · R01 CA152309 · United States
NCI NIH HHS · R01 CA116528 · United States
NCI NIH HHS · R21 CA140999 · United States
External Links
PubMed source DOI: 10.1158/1078-0432.CCR-12-1588 PMC Full Text View journal details
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