A Novel FoxM1-Caveolin Signaling Pathway Promotes Pancreatic Cancer Invasion and Metastasis

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 3; pp. 655 - 665
• Main Authors: CHEN HUANG, ZHENGJUN QIU, LIWEI WANG, ZHIHAI PENG, ZHILIANG JIA, LOGSDON, Craig D, XIANGDONG LE, DAOYAN WEI, SUYUN HUANG, KEPING XIE
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2012
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Caveolin 1 - genetics; Caveolin 1 - metabolism; Cell Line, Tumor; Chromatin Immunoprecipitation; Disease Progression; Epithelial-Mesenchymal Transition - genetics; Female; Forkhead Box Protein M1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmacology. Drug treatments; Promoter Regions, Genetic - genetics; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Tissue Array Analysis; Transplantation, Heterologous; Tumors; Signal transduction; Membrane protein; Signaling pathway; Pancreas cancer; Digestive diseases; Malignant tumor; Metastasis; Invasion; Cancer; Pancreatic disease
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-3102

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.