title: 15-Hydroxyprostaglandin dehydrogenase is a target of hepatocyte nuclear factor 3beta and a tumor suppressor in lung cancer.
abstract: 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.
authors.affiliation: Department of Pathology, Division of Hematology/Oncology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Huang
authors.forename: Rosana
authors.initials: R
authors.lastname: Eisenberg
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Earl
authors.initials: E
authors.lastname: Lawrence
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Walbroehl
authors.forename: Ester
authors.initials: E
authors.lastname: Löwenberg
authors.forename: Todd
authors.initials: T
authors.lastname: Golub
authors.forename: Jaime
authors.initials: J
authors.lastname: Merchan
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D051542:Hepatocyte Nuclear Factor 3-beta; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase