FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.
FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.
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DOI：
10.1371/journal.pone.0004849
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Teh MT
中科院分区：
文献类型：
--
作者：
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
与吸烟和饮酒相关的癌症仍然是全球范围内的一个严重的健康问题。由于缺乏有效的早期生物标志物，患者的存活率很低。FOXM1的过度表达与大多数人类癌症有关，但其在头颈部鳞状细胞癌(HNSCC)中的作用机制尚不清楚。应用定量聚合酶链式反应(QPCR)、表达谱芯片、免疫组织化学和免疫组织化学方法，检测了4个独立队列(共75例)HNSCC组织和细胞中FOXM1mRNA和蛋白的表达。利用FOXM1特异的荧光素酶报告系统、qPCR、免疫印迹和短发夹状RNA干扰，对可能的口腔致癌物对FOXM1转录活性的影响进行了剂量依赖性的检测和确认。采用全基因组单核苷酸多态(SNP)技术对FOXM1诱导的8个口腔角质形成细胞克隆系的基因组不稳定性特征进行了研究。此外，FOXM1在原代口腔角质形成细胞中的急性上调直接导致了基因组的不稳定。我们首次证明FOXM1的过度表达先于HNSCC的恶性。对人类口腔角质形成细胞中可能致癌物质的筛选令人惊讶地表明，尼古丁(不被认为是人类致癌物质)在与烟草咀嚼相关的浓度下直接诱导FOXM1 mRNA、蛋白质稳定和转录活性。重要的是，尼古丁还增强了FOXM1诱导的人口腔角质形成细胞的转化。中心体蛋白CEP55和DNA解旋酶/干细胞标记Hells都位于一个共同的基因座(10q23)，被发现是FOXM1的新靶点，它们的表达与HNSCC的进展密切相关。这项研究警告了尼古丁在烟草替代疗法中潜在的共同致癌作用。我们假设FOXM1的异常上调可能通过涉及CEP55和Hells激活的恶性转化程序诱导基因组不稳定，这可能促进异常有丝分裂和表观遗传修饰。我们的发现是，FOXM1在口腔癌进展的早期就上调了，这使得FOXM1成为一个有吸引力的早期癌症检测的诊断生物标志物，以及它的候选机制靶点CEP55和Hells，作为恶性转化和进展的指标。
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.
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