|Publication Type||Journal Article|
|Year of Publication||2008|
|Authors||Huang, G, Eisenberg, R, Yan, M, Monti, S, Lawrence, E, Fu, P, Walbroehl, J, L,|
|Pages||5040 - 8|
|Keywords||Adenocarcinoma, Animals, Base Sequence, Binding Sites, Cancer, Down-Regulation, Enzymologic, Gene Expression Profiling, Gene Expression Regulation, Genes, Hepatocyte Nuclear Factor 3-beta, Humans, Hydroxyp, Neoplastic, Tumor Suppressor|
The forkhead transcription factor hepatocyte nuclear factor 3beta (HNF3beta) is essential in foregut development and the regulation of lung-specific genes. HNF3beta expression leads to growth arrest and apoptosis in lung cancer cells and HNF3beta is a candidate tumor suppressor in lung cancer. In a transcriptional profiling study using a conditional cell line system, we now identify 15-PGDH as one of the major genes induced by HNF3beta expression. 15-PGDH is a critical metabolic enzyme of proliferative prostaglandins, an antagonist to cyclooxygenase-2 and a tumor suppressor in colon cancer. We confirmed the regulation of 15-PGDH expression by HNF3beta in a number of systems and showed direct binding of HNF3beta to 15-PGDH promoter elements. Western blotting of lung cancer cell lines and immunohistochemical examination of human lung cancer tissues found loss of 15-PGDH expression in approximately 65% of lung cancers. Further studies using in vitro cell-based assays and in vivo xenograft tumorigenesis assays showed a lack of in vitro but significant in vivo tumor suppressor activity of 15-PGDH via an antiangiogenic mechanism analogous to its role in colon cancer. In summary, we identify 15-PGDH as a direct downstream effector of HNF3beta and show that 15-PGDH acts as a tumor suppressor in lung cancer.