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: Guosheng Huang, Rosana Eisenberg, Min Yan, Stefano Monti, Earl Lawrence, Pingfu Fu, Jaclyn Walbroehl, Ester Löwenberg, Todd Golub, Jaime Merchan, Daniel G Tenen, Sanford D Markowitz, Balazs Halmos
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 13 Pg. 5040-8 (Jul 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18593902 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hepatocyte Nuclear Factor 3-beta
• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase

Topics

• Adenocarcinoma (genetics)
• Animals
• Base Sequence
• Binding Sites
• Down-Regulation
• Gene Expression Profiling
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Hepatocyte Nuclear Factor 3-beta (metabolism, physiology)
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics, physiology)
• Lung Neoplasms (genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic
• Protein Binding
• Transplantation, Heterologous
• Tumor Cells, Cultured