Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression
Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression
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DOI：
10.1158/0008-5472.can-06-1787
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发表时间：
2006-07-01
期刊：
影响因子：
11.2
通讯作者：
DuBois, Raymond N.
中科院分区：
文献类型：
--
作者：
Mann, Jason R.;Backlund, Michael G.;DuBois, Raymond N.
前列腺素E-2（PGE（2））是一种促炎性生物活性脂质，通过调节增殖、凋亡和血管生成促进癌症进展。PGE 2是环氧合酶（考克斯）的下游产物，并且被前列腺素脱氢酶（PGDH）生物化学灭活。在本研究中，我们研究了PGDH在癌症中下调的机制。我们发现，表皮生长因子（EGF）抑制PGDH在大肠癌细胞的表达。EGF受体（EGFR）信号传导诱导Snail，其结合PGDH启动子中的保守E-box元件以抑制转录。通过抑制EGFR信号传导诱导PGE 2催化剂阻断体内癌症生长。在人类结肠癌中，Snail表达升高与PGDH的下调密切相关。这些数据表明，PGDH可能在结直肠癌中发挥肿瘤抑制作用，并提供了一种可能的考克斯-2非依赖性靶向PGE 2的方式来抑制癌症进展。
Prostaglandin E-2 (PGE(2)), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE2 is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is down-regulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE2 catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE2 to inhibit cancer progression.