The critical role of dysregulated FOXM1-PLAUR signaling in human colon cancer progression and metastasis.
The critical role of dysregulated FOXM1-PLAUR signaling in human colon cancer progression and metastasis.
复制标题
DOI：
10.1158/1078-0432.ccr-12-1588
复制
发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Li D;Wei P;Peng Z;Huang C;Tang H;Jia Z;Cui J;Le X;Huang S;Xie K
哺乳动物叉头盒（Fox）转录因子FOXM1与包括小鼠肠癌在内的肿瘤发生有关。然而，FOXM1信号在人类结直肠癌（CRC）发病机制中的临床意义尚不清楚。我们研究了203例原发性结肠癌和匹配的正常结肠组织标本中FOXM1的表达，并通过体外和动物结肠癌模型探讨了FOXM1表达改变的潜在机制及其对结肠癌生长和转移的影响。我们发现FOXM1蛋白在结肠粘膜中表达较弱，而在结肠癌和淋巴结转移的肿瘤细胞核中FOXM1表达较强。Cox比例风险模型显示FOXM1表达在多因素分析中是一个独立的预后因素。实验发现，在原位小鼠模型中，通过基因转移过表达FOXM1可显著促进结肠癌细胞的生长和转移，而通过小干扰RNA敲低FOXM1的表达则相反。FOXM1促进结肠肿瘤发生与尿激酶纤溶酶原激活物受体（PLAUR）表达的激活和侵袭转移的升高直接且显著相关。考虑到FOXM1在调节肿瘤生物学关键基因表达中的重要性，FOXM1的表达失调和激活可能在结肠癌的进展和转移中发挥重要作用。
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 (CRC) 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 small interfering RNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase 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.