Huang Guosheng, Eisenberg Rosana, Yan Min, Monti Stefano, Lawrence Earl, Fu Pingfu, Walbroehl Jaclyn, Löwenberg Ester, Golub Todd, Merchan Jaime, Tenen Daniel G, Markowitz Sanford D, Halmos Balazs
Department of Pathology, Division of Hematology/Oncology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Cancer Res. 2008 Jul 1;68(13):5040-8. doi: 10.1158/0008-5472.CAN-07-6575.
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.
叉头转录因子肝细胞核因子3β（HNF3β）在前肠发育和肺特异性基因的调控中至关重要。HNF3β的表达导致肺癌细胞生长停滞和凋亡，HNF3β是肺癌中的候选肿瘤抑制因子。在一项使用条件细胞系系统的转录谱研究中，我们现在确定15-前列腺素脱氢酶（15-PGDH）是HNF3β表达诱导的主要基因之一。15-PGDH是增殖性前列腺素的关键代谢酶，是环氧化酶-2的拮抗剂，也是结肠癌中的肿瘤抑制因子。我们在多个系统中证实了HNF3β对15-PGDH表达的调控，并显示HNF3β与15-PGDH启动子元件直接结合。对肺癌细胞系的蛋白质免疫印迹分析和对人肺癌组织的免疫组化检查发现，约65%的肺癌中15-PGDH表达缺失。使用基于体外细胞的试验和体内异种移植肿瘤发生试验的进一步研究表明，15-PGDH在体外缺乏但在体内具有显著的肿瘤抑制活性，其作用机制是通过类似于其在结肠癌中的作用的抗血管生成机制。总之，我们确定15-PGDH是HNF3β的直接下游效应物，并表明15-PGDH在肺癌中起肿瘤抑制作用。
