It was reported that genetically-engineered RASAL2 knockout mice are prone to development of several sporadic tumor, including lung adenocarcinoma. However, a causative relationship between RASAL2 deficiency and lung adenocarcinoma development still remains unknown. In the present study, RASAL2 level was determined in patients with lung adenocarcinoma and control subjects in an attempt to explore its potential clinical diagnostic and prognostic value. Low RASAL2 expression levels were found in 71% (37 of 52) of lung adenocarcinoma, which were correlated with lymph node metastasis in lung adenocarcinoma. Moreover, Low RASAL2 expression levels were correlated with reduced overall survival (OS) in lung adenocarcinoma. We find that inactivation of RASAL2 promotes lung cancer cell migration through the induction of epithelial mesenchymal transition (EMT) and promoted lung metastasis in nude mice. Our results suggest that the down-regulation of RASAL2 promotes metastatic progression of lung adenocarcinoma, hence it could serve as a potential target for the development of lung cancer therapies. (C) 2014 Elsevier Inc. All rights reserved.