Loss of 15-Hydroxyprostaglandin Dehydrogenase Increases Prostaglandin E2 in Pancreatic Tumors
Loss of 15-Hydroxyprostaglandin Dehydrogenase Increases Prostaglandin E2 in Pancreatic Tumors
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DOI：
10.1097/mpa.0b013e3181baecbe
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发表时间：
2010-04-01
期刊：
影响因子：
2.9
通讯作者：
Eibl, Guido
中科院分区：
文献类型：
--
作者：
Pham, Hung;Chen, Monica;Eibl, Guido
目的：前列腺素E-2（PGE（2））是环氧合酶（考克斯）和前列腺素E合酶（PGES）的产物，被15-羟基前列腺素脱氢酶（PGDH）失活。PGDH的下调有助于肺癌和结肠癌中PGE（2）的积累，但尚未在胰腺癌中确定。评估正常人胰腺和肿瘤匹配组织以及MiaPaCa-2和BxPC-3细胞系的考克斯-2、微粒体PGES-1、PGDH、用实时荧光定量聚合酶链反应（PCR）和Western blotting检测SNAI 1和SNAI 2的表达，用酶联免疫吸附法检测PGE（2）的表达。正常组织显示低考克斯-2信使RNA（mRNA）和蛋白质表达，高PGDH mRNA和蛋白质表达和PGE（2）水平为13 pg/mg蛋白。相反，肿瘤组织显示高考克斯-2 mRNA和蛋白表达，低PGDH mRNA和蛋白表达以及32 pg/mg蛋白的PGE（2）水平。肿瘤组织中SNAI 2 mRNA和蛋白表达显著升高，但SNAI 1没有，因为据报道SNAI 1和SNAI 2下调PGDH表达。用100 nmol/L PGE（2）处理的考克斯-2阳性BxPC-3而不是考克斯-2阴性MiaPaCa-2诱导磷酸化的细胞外信号相关激酶，该激酶被丝裂原活化蛋白激酶激酶抑制剂U 0126阻断，证明PGE（2）激活ERK的能力。这些结果表明，胰腺肿瘤中PGE（2）的增加是通过考克斯-2和微粒体PGES-1的表达以及SNAI 2下调PGDH来实现的。
Objectives: Prostaglandin E-2 (PGE(2)) is a product of cyclooxygenase (COX) and PGE synthase (PGES) and deactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH). Down-regulation of PGDH contributes to PGE(2) accumulation in lung and colon cancers but has not been identified in pancreatic cancer.Methods: Normal human pancreatic and tumor-matched tissues, as well as MiaPaCa-2 and BxPC-3 cell lines, were assessed for COX-2, microsomal PGES-1, PGDH, and snail homolog 1 (SNAI1) and SNAI2 expressions by real-time polymerase chain reaction and Western blotting and PGE(2) by enzyme-linked immunosorbent assay.Results: Normal tissues exhibited low COX-2 messenger RNA (mRNA) and protein expressions and high PGDH mRNA and protein expressions and PGE(2) levels at 13 pg/mg of protein. In contrast, tumor tissues exhibited high COX-2 mRNA and protein expressions and low PGDH mRNA and protein expressions and PGE(2) levels at 32 pg/mg of protein. Tumor tissues exhibited significantly elevated expressions of SNAI2 mRNA and protein but not SNAI1 because SNAI1 and SNAI2 reportedly down-regulate PGDH expression. The COX-2-positive BxPC-3 but not the COX-2-negative MiaPaCa-2 treated with 100-nmol/L PGE(2) induced phosphorylated extracellular signal-related kinase that was blocked by the mitogen-activated protein kinase kinase inhibitor U0126, demonstrating the ability of PGE(2) to activate ERK.Conclusions: These results suggest that enhanced PGE(2) production proceeds through the expressions of COX-2 and microsomal PGES-1 and down-regulation of PGDH by SNAI2 in pancreatic tumors.