A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis.
A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis.
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DOI：
10.1158/0008-5472.can-11-3102
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发表时间：
2012-02-01
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：
Huang C;Qiu Z;Wang L;Peng Z;Jia Z;Logsdon CD;Le X;Wei D;Huang S;Xie K
小窝蛋白-1（Cav-1）是小窝膜结构域的主要结构组分，其参与癌症的发生，但其确切的功能作用和调控尚不清楚。在这项研究中，我们确定了Cav-1在胰腺癌临床前模型和人体组织标本中的致癌功能。Cav-1表达水平与小鼠和人胰腺癌细胞的转移潜能和上皮-间质转化（EMT）相关。在动物模型中，细胞中升高的水平促进了EMT、迁移、侵袭和转移，而RNAi介导的敲低抑制了这些过程。我们确定Cav-1和Forkhead转录因子FoxM 1的水平在胰腺癌细胞和肿瘤组织中直接相关。FoxM 1的增强表达增加了Cav-1水平，而RNAi介导的FoxM 1敲低则具有相反的效果。FoxM 1直接结合于Cav-1基因的启动子区并正反式激活其活性。总的来说，我们的研究结果将Cav-1定义为FoxM 1的重要下游致癌靶点，这表明这种新型FoxM 1-Cav-1通路的信号失调促进胰腺癌的发展和进展。
Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its precise functional roles and regulation remain unclear. In this study, we determined the oncogenic function of Cav-1 in preclinical models of pancreatic cancer and in human tissue specimens. Cav-1 expression levels correlated with metastatic potential and epithelial-to-mesenchymal transition (EMT) in both mouse and human pancreatic cancer cells. Elevated levels in cells promoted EMT, migration, invasion and metastasis in animal models, whereas RNAi-mediated knockdown inhibited these processes. We determined that levels of Cav-1 and the Forkhead transcription factor FoxM1 correlated directly in pancreatic cancer cells and tumor tissues. Enforced expression of FoxM1 increased Cav-1 levels, whereas RNAi-mediated knockdown of FoxM1 had the opposite effect. FoxM1 directly bound to the promoter region of Cav-1 gene and positively transactivated its activity. Collectively, our findings defined Cav-1 as an important downstream oncogenic target of FoxM1, suggesting that dysregulated signaling of this novel FoxM1-Cav-1 pathway promotes pancreatic cancer development and progression.