15-Hydroxyprostaglandin dehydrogenase is a target of hepatocyte nuclear factor 3β and a tumor suppressor in lung cancer

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

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5040-5048
Number of pages9
JournalCancer Research
Volume68
Issue number13
DOIs
StatePublished - Jul 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Huang, G., Eisenberg, R., Yan, M., Monti, S., Lawrence, E., Fu, P., Walbroehl, J., Löwenberg, E., Golub, T., Merchan, J., Tenen, D. G., Markowitz, S. D., & Halmos, B. (2008). 15-Hydroxyprostaglandin dehydrogenase is a target of hepatocyte nuclear factor 3β and a tumor suppressor in lung cancer. Cancer Research, 68(13), 5040-5048. https://doi.org/10.1158/0008-5472.CAN-07-6575