Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer.
Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer.
复制标题
DOI：
10.1158/0008-5472.can-12-3859
复制
发表时间：
2013-07-01
期刊：
影响因子：
11.2
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Kong X;Li L;Li Z;Le X;Huang C;Jia Z;Cui J;Huang S;Wang L;Xie K
转录因子叉头盒M1（FOXM1）在肿瘤发生中起重要作用。然而，FOXM1亚型的表达状态及其对肿瘤发生的影响和分子基础尚不清楚。我们试图确定FOXM1亚型的身份及其表达对胰腺癌的发展和进展的影响，使用人类组织，细胞系和动物模型。FOXM1 mRNA和蛋白在人胰腺肿瘤和癌细胞系中明显过表达。我们确定了胰腺癌中存在的五种FOXM1亚型：FOXM1a、FOXM1b和FOXM1c沿着两种暂时命名为FOXM1b 1和FOXM1b 2的亚型，因为它们与FOXM1b密切相关。有趣的是，FOXM1c主要在胰腺肿瘤和癌细胞系中表达，而FOXM1a的表达在它们中通常检测不到。功能分析显示FOXM1b、FOXM1b1、FOXM1b2和FOXM1c促进胰腺肿瘤的生长和转移，而FOXM1a则不促进。FOXM1b、FOXM1b1、FOXM1b2和FOXM1c激活其典型下游基因的转录。此外，Sp1机械地激活FOXM1启动子，而Krüppel样因子4（KLF4）抑制其活性。最后，我们在FOXM 1启动子中鉴定了Sp1和KLF 4结合位点，并证明Sp1和KLF 4蛋白都直接与其结合。该结合位点的缺失突变显着减弱了Sp1对FOXM 1启动子的转录调节，而KLF 4则显着减弱。我们证明了特异性FOXM1亚型的过表达通过增强肿瘤细胞的侵袭和转移来关键性地调节胰腺癌的发展和进展。我们的研究结果强烈表明，靶向特定的FOXM1亚型有效地减弱胰腺癌的发展和进展。
The transcription factor Forkhead box M1 (FOXM1) plays important roles in oncogenesis. However, the expression statuses of FOXM1 isoforms and their impact on and molecular basis in oncogenesis are unknown. We sought to determine the identities of FOXM1 isoforms in and the impact of their expression on pancreatic cancer development and progression using human tissues, cell lines and animal models. Overexpression of FOXM1 mRNA and protein was pronounced in human pancreatic tumors and cancer cell lines. We identified five FOXM1 isoforms present in pancreatic cancer: FOXM1a, FOXM1b, and FOXM1c along with two isoforms tentatively designated as FOXM1b1 and FOXM1b2 because they were closely related to FOXM1b. Interestingly, FOXM1c was predominantly expressed in pancreatic tumors and cancer cell lines, whereas FOXM1a expression was generally undetectable in them. Functional analysis revealed that FOXM1b, FOXM1b1, FOXM1b2, and FOXM1c but not FOXM1a promoted pancreatic tumor growth and metastasis. Consistently, FOXM1b, FOXM1b1, FOXM1b2, and FOXM1c activated transcription of their typical downstream genes. Also, Sp1 mechanistically activated the FOXM1 promoter, whereas Krüppel-like factor 4 (KLF4) repressed its activity. Finally, we identified an Sp1- and KLF4-binding site in the FOXM1 promoter and demonstrated that both Sp1 and KLF4 protein bound directly to it. Deletion mutation of this binding site significantly attenuated the transcriptional regulation of the FOXM1 promoter positively by Sp1 and negatively by KLF4. We demonstrated that overexpression of specific FOXM1 isoforms critically regulates pancreatic cancer development and progression by enhancing tumor cell invasion and metastasis. Our findings strongly suggest that targeting specific FOXM1 isoforms effectively attenuates pancreatic cancer development and progression.