FOXM1c promotes pancreatic cancer epithelial-to-mesenchymal transition and metastasis via upregulation of expression of the urokinase plasminogen activator system.
FOXM1c promotes pancreatic cancer epithelial-to-mesenchymal transition and metastasis via upregulation of expression of the urokinase plasminogen activator system.
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DOI：
10.1158/1078-0432.ccr-13-2311
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Huang C;Xie D;Cui J;Li Q;Gao Y;Xie K
转录因子 Forkhead box M1 (FOXM1) 在包括胰腺癌在内的多种人类肿瘤的形成中发挥着重要作用。然而，FOXM1促进胰腺肿瘤上皮间质转化（EMT）和转移的分子机制尚不清楚。使用胰腺癌动物模型检查了 FOXM1 和尿激酶纤溶酶原激活剂受体 (uPAR) 表达改变对 EMT 和转移的影响。此外，还利用体外分子生物学测定分析了改变胰腺癌侵袭和转移的潜在机制。最后，使用胰腺肿瘤和正常胰腺组织样本研究了 FOXM1/uPAR 信号失调的临床相关性。胰腺肿瘤标本和细胞系主要过表达 FOXM1 同工型 FOXM1c。 FOXM1c 过表达促进胰腺癌细胞的 EMT 以及迁移、侵袭和转移，而 FOXM1 表达下调则抑制这些过程。 FOXM1 表达水平与胰腺癌细胞系和肿瘤标本中 uPAR 表达水平直接相关。此外，FOXM1c 过表达上调胰腺癌细胞中 uPAR 表达，而抑制 FOXM1 表达则抑制 uPAR 表达。此外，将FOXM1c转染到胰腺癌细胞中直接激活uPAR启动子，而FOXM1小干扰RNA对FOXM1表达的抑制抑制了其在这些细胞中的激活。最后，我们在 uPAR 启动子中鉴定了一个 FOXM1 结合位点，并证明 FOXM1 蛋白直接与其结合。该位点的缺失突变显着减弱了 uPAR 启动子活性。我们的研究结果表明，FOXM1c 通过增强 uPAR 基因转录，从而促进肿瘤 EMT 和转移，从而促进胰腺癌的发生和进展。
The transcription factor Forkhead box M1 (FOXM1) plays important roles in the formation of several human tumors, including pancreatic cancer. However, the molecular mechanisms by which FOXM1 promotes pancreatic tumor epithelial-to-mesenchymal transition (EMT) and metastasis are unknown. The effect of altered expression of FOXM1 and urokinase plasminogen activator receptor (uPAR) on EMT and metastasis was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer invasion and metastasis were analyzed using in vitro molecular biology assays. Finally, the clinical relevance of dysregulated FOXM1/uPAR signaling was investigated using pancreatic tumor and normal pancreatic tissue specimens. Pancreatic tumor specimens and cell lines predominantly overexpressed the FOXM1 isoform FOXM1c. FOXM1c overexpression promoted EMT in and migration, invasion, and metastasis of pancreatic cancer cells, whereas downregulation of FOXM1 expression inhibited these processes. The level of FOXM1 expression correlated directly with that of uPAR expression in pancreatic cancer cell lines and tumor specimens. Moreover, FOXM1c overexpression upregulated uPAR expression in pancreatic cancer cells, whereas inhibition of FOXM1 expression suppressed uPAR expression. Furthermore, transfection of FOXM1c into pancreatic cancer cells directly activated the uPAR promoter, whereas inhibition of FOXM1 expression by FOXM1 small interfering RNA suppressed its activation in these cells. Finally, we identified an FOXM1-binding site in the uPAR promoter and demonstrated that FOXM1 protein bound directly to it. Deletion mutation of this site significantly attenuated uPAR promoter activity. Our findings demonstrated that FOXM1c contributes to pancreatic cancer development and progression by enhancing uPAR gene transcription and, thus, tumor EMT and metastasis.