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15-Hydroxyprostaglandin Dehydrogenase is a Target of Hepatocyte Nuclear Factor 3β and a Tumor Suppressor in Lung Cancer

¹ Division of Hematology/Oncology, Departments of ² Pathology and ³ Epidemiology and Biostatistics, University Hospitals of Cleveland/Case Western Reserve University, Cleveland, Ohio; ⁴ The Broad Institute of Harvard University/MIT, Cambridge, Massachusetts; ⁵ Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, Florida; ⁶ Beth Israel Deaconess Medical Center, Boston, Massachusetts; and ⁷ Howard Hughes Medical Institute, Chevy Chase, Maryland

Requests for reprints: Balazs Halmos, Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH 44106. Phone: 216-368-1175; Fax: 216-368-1166; E-mail: bxh60{at}case.edu.

Key Words: lung cancer • prostaglandin • tumor suppressor • 15-PGDH • angiogenesis

The forkhead transcription factor hepatocyte nuclear factor 3β (HNF3β) is essential in foregut development and the regulation of lung-specific genes. HNF3β expression leads to growth arrest and apoptosis in lung cancer cells and HNF3β 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 HNF3β 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 HNF3β in a number of systems and showed direct binding of HNF3β 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 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 HNF3β and show that 15-PGDH acts as a tumor suppressor in lung cancer. [Cancer Res 2008;68(13):5040–8]

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