Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis
Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis
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DOI：
10.1074/jbc.m213290200
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发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Kudo, I
中科院分区：
文献类型：
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作者：
Kamei, D;Murakami, M;Kudo, I
微粒体前列腺素E-2合酶-1（mPGES-1）是一种刺激诱导的酶，在PGE（2）生物合成途径中位于环氧化酶（考克斯）-2的下游。鉴于越来越多的证据表明，考克斯-2衍生的PGE（2）参与了各种肿瘤的发展，包括结肠直肠癌，我们在此研究了mPGES-1在肿瘤发生中的潜在参与。免疫组化结果显示考克斯-2和mPGES-1在人结肠癌组织中均有表达。HCA-7是一种表现出考克斯-2和PGE（2）依赖性增殖的人结直肠腺癌细胞系，其组成性表达考克斯-2和mPGES-1。用mPGES-1抑制剂或反义寡核苷酸处理HCA-7细胞减弱了PGE 2的产生和细胞增殖，而mPGES-1的过表达加速了PGE 2的产生和细胞增殖。此外，共转染考克斯-2和mPGES-1到HEK 293细胞中导致细胞转化，表现为软琼脂培养中的集落形成和裸鼠皮下植入时的肿瘤形成。cDNA阵列分析显示，这种mPGES-1定向细胞转化伴随着与增殖，形态，粘附和细胞周期相关的各种基因表达的变化。这些结果共同表明，mPGES-1与考克斯-2的异常表达可促进肿瘤发生。
Microsomal prostaglandin E-2 synthase-1 (mPGES-1) is a stimulus-inducible enzyme that functions downstream of cyclooxygenase ( COX)-2 in the PGE(2)-biosynthetic pathway. Given the accumulating evidence that COX-2-derived PGE(2) participates in the development of various tumors, including colorectal cancer, we herein examined the potential involvement of mPGES-1 in tumorigenesis. Immunohistochemical analyses demonstrated the expression of both COX-2 and mPGES-1 in human colon cancer tissues. HCA-7, a human colorectal adenocarcinoma cell line that displays COX-2- and PGE(2)-dependent proliferation, expressed both COX-2 and mPGES-1 constitutively. Treatment of HCA-7 cells with an mPGES-1 inhibitor or antisense oligonucleotide attenuated, whereas overexpression of mPGES-1 accelerated, PGE2 production and cell proliferation. Moreover, cotransfection of COX-2 and mPGES-1 into HEK293 cells resulted in cellular transformation manifested by colony formation in soft agar culture and tumor formation when implanted subcutaneously into nude mice. cDNA array analyses revealed that this mPGES-1-directed cellular transformation was accompanied by changes in the expression of a variety of genes related to proliferation, morphology, adhesion, and the cell cycle. These results collectively suggest that aberrant expression of mPGES-1 in combination with COX-2 can contribute to tumorigenesis.