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PMID: 19287496 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.

PloS one ·Vol. 4 ·No. 3 ·2009-00-00 ·Pages e4849

Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, Sugden D, Thurlow JK, Cheong SC, Teo SH, Wan H, Waseem A, Parkinson EK, Fortune F, Teh MT

Abstract

Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC). FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to 'trace' the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression. This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression.

MeSH Terms
Carcinoma, Squamous Cell/metabolism,pathology Cell Line, Tumor Cell Transformation, Neoplastic/drug effects Forkhead Box Protein M1 Forkhead Transcription Factors/genetics,metabolism Genomic Instability Head and Neck Neoplasms/metabolism,pathology Humans Immunohistochemistry Loss of Heterozygosity Nicotine/pharmacology Polymerase Chain Reaction RNA Interference RNA, Messenger/genetics Transcription, Genetic/drug effects Up-Regulation/drug effects
Chemicals
FOXM1 protein, human Forkhead Box Protein M1 Forkhead Transcription Factors RNA, Messenger Nicotine
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Gemenetzidis Emilios
Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Bose Amrita
Riaz Adeel M
Chaplin Tracy
Young Bryan D
Ali Muhammad
Sugden David
Thurlow Johanna K
Cheong Sok-Ching
Teo Soo-Hwang
Wan Hong
Waseem Ahmad
Parkinson Eric K
Fortune Farida
Teh Muy-Teck
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0004849
Published
2009-00-00
Epub
2009-00-16
Pages
e4849
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2654098
Subset
IM
Grants
Medical Research Council · United Kingdom
External Links
PubMed source DOI: 10.1371/journal.pone.0004849 PMC Full Text View journal details
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