Shanghai Key Laboratory of Pancreatic Diseases Research, Department of General Surgery, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, PR China.
Cancer Res. 2012 Feb 1;72(3):655-65. doi: 10.1158/0008-5472.CAN-11-3102. Epub 2011 Dec 22.
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-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 RNA interference (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.
窖蛋白-1（Cav-1）是质膜窖的主要结构成分，有助于癌症的发展，但它的确切功能作用和调节机制仍不清楚。在这项研究中，我们确定了 Cav-1 在胰腺癌的临床前模型和人类组织标本中的致癌功能。在小鼠和人胰腺癌细胞中，Cav-1 的表达水平与转移潜能和上皮间质转化（EMT）相关。细胞中 Cav-1 水平的升高促进了 EMT、迁移、侵袭和转移，而 RNA 干扰（RNAi）介导的敲低则抑制了这些过程。我们确定，在胰腺癌细胞和肿瘤组织中，Cav-1 和叉头转录因子 FoxM1 的水平直接相关。FoxM1 的强制表达增加了 Cav-1 的水平，而 FoxM1 的 RNAi 介导的敲低则产生了相反的效果。FoxM1 直接结合到 Cav-1 基因的启动子区域，并正向转录激活其活性。总的来说，我们的研究结果将 Cav-1 定义为 FoxM1 的一个重要下游致癌靶点，表明该新型 FoxM1-Cav-1 信号通路的失调信号促进了胰腺癌的发展和进展。
