Backlund Michael G, Mann Jason R, Holla Vijaykumar R, Buchanan F Gregory, Tai Hsin-Hsiung, Musiek Erik S, Milne Ginger L, Katkuri Sharada, DuBois Raymond N
Department of Medicine, Cell and Developmental Biology, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838, USA.
J Biol Chem. 2005 Feb 4;280(5):3217-23. doi: 10.1074/jbc.M411221200. Epub 2004 Nov 12.
Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/- mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.
前列腺素E2（PGE2）可通过调节多种促肿瘤途径来刺激肿瘤进展，这些途径包括增殖、血管生成、细胞迁移、侵袭和凋亡。尽管PGE2的稳态组织水平源于生物合成和分解的相对速率，但大多数研究PGE2的报告仅关注这种生物活性脂质的环氧化酶依赖性形成。PGE2的酶促降解涉及NAD+依赖性15-羟基前列腺素脱氢酶（15-PGDH）。本研究检测了一系列人和小鼠的正常组织，发现大肠中15-PGDH水平很高。相比之下，15-PGDH在几种结肠癌细胞系以及其他人类恶性肿瘤（如乳腺癌和肺癌）中的表达降低。与这些发现一致，我们观察到ApcMin+/-小鼠腺瘤中15-Pgdh表达减少。15-PGDH的酶活性与表达水平相关，15-Pgdh的基因破坏完全阻断了尿中PGE2代谢产物的产生。最后，相对于匹配的正常组织，人结肠癌中15-PGDH的表达和活性显著下调。总之，这些结果表明15-PGDH在结直肠肿瘤进展过程中由于表达缺失而具有一种新的肿瘤抑制作用。
