VEGF expression is augmented by hypoxia‑induced PGIS in human fibroblasts.
VEGF expression is augmented by hypoxia‑induced PGIS in human fibroblasts.
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DOI：
10.3892/ijo.2013.1994
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发表时间：
2013-09
影响因子：
5.2
通讯作者：
J. Wang;R. Ikeda;Xiao-Fang Che;A. Ooyama;Masatatsu Yamamoto;T. Furukawa;K. Hasui;Chun-lei Zheng
中科院分区：
文献类型：
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作者：
J. Wang;R. Ikeda;Xiao-Fang Che;A. Ooyama;Masatatsu Yamamoto;T. Furukawa;K. Hasui;Chun-lei Zheng
前列环素合酶（PGIS或PTGIS）是一种催化前列腺素H2（PGH 2）转化为前列腺素I2（PGI 2）的酶。PGI 2通过激活过氧化物酶体增殖物激活受体δ（PPARδ）促进癌症生长，并增加促血管生成因子血管内皮生长因子（VEGF）的表达水平。我们发现PGIS基因在WI-38、TIG-3-20和HEL人肺成纤维细胞以及两种癌细胞系（NB-1和G361）中的表达在低氧条件下增强。缺氧后WI-38细胞中PGIS的主要定位由胞浆向胞核转移。诱导的PGIS具有酶活性，因为随着PGIS水平的增加，细胞内6-酮-前列腺素（体内PGI 2生物合成的有用标记物）的水平增加。在低氧条件下，VEGF的表达与PGIS诱导平行增加。PGIS基因敲低导致VEGF mRNA表达降低。由于VEGF是已知的PPARδ靶基因，我们检测了靶向PPARδ的siRNA在缺氧条件下对VEGF表达的影响。在缺氧条件下，抑制PPARδ表达可抑制WI-38细胞VEGF的表达。这些结果表明，PGIS是由缺氧诱导的，并调节成纤维细胞VEGF的表达。肿瘤乏氧区的成纤维细胞在肿瘤生长和血管生成中起重要作用。
Prostacyclin synthase (PGIS or PTGIS) is an enzyme that catalyses the conversion of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2). PGI2 promotes cancer growth by activating peroxisome proliferator-activated receptor δ (PPARδ), and increases the expression levels of the pro-angiogenic factor vascular endothelial growth factor (VEGF). We found that the expression of the PGIS gene was enhanced in WI-38, TIG-3-20 and HEL human lung fibroblast cells and two cancer cell lines (NB-1 and G361) under hypoxic conditions. The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI-38 cells. The induced PGIS had an enzymatic activity since the intracellular level of 6-keto-prostaglandin, a useful marker of PGI2 biosynthesis in vivo, was increased with the increasing levels of PGIS. Expression of VEGF was increased in parallel with PGIS induction under hypoxic conditions. PGIS knockdown resulted in the decreased expression of VEGF mRNA. Since VEGF is a known PPARδ target gene, we examined the effects of siRNAs targeting PPARδ on the expression of VEGF under hypoxic conditions. Knockdown of PPARδ suppressed the expression of VEGF under hypoxic conditions in WI-38 cells. These findings suggest that PGIS is induced by hypoxia and regulates the expression of VEGF in fibroblasts. Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis.