Microsomal prostaglandin E synthase-1 inhibits PTEN and promotes experimental cholangiocarcinogenesis and tumor progression.
Microsomal prostaglandin E synthase-1 inhibits PTEN and promotes experimental cholangiocarcinogenesis and tumor progression.
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DOI：
10.1053/j.gastro.2011.02.056
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发表时间：
2011-06
期刊：
影响因子：
29.4
通讯作者：
Wu T
中科院分区：
文献类型：
--
作者：
Lu D;Han C;Wu T
微粒体前列腺素E合酶-1（mPGES-1）是一种限速酶，在前列腺素E2（PGE 2）的合成中与环氧合酶-2（考克斯-2）偶联。尽管考克斯-2参与多种人类癌症的发生和发展，但mPGES-1在癌发生中的作用尚未确定。我们研究了mPGES-1在人胆管癌生长中的作用。我们采用免疫组化分析来检测mPGES-1在福尔马林固定、石蜡包埋的人胆管癌组织中的表达。在体外和在SCID小鼠中测定mPGES-1对人胆管癌细胞的作用。通过免疫印迹和免疫沉淀法测定mPGES-1过表达或敲低的人胆管癌细胞中PTEN和相关信号分子的水平。mPGES-1在人胆管癌组织中过表达。人胆管癌细胞中mPGES-1的过表达增加了肿瘤细胞的增殖、迁移、侵袭和集落形成;相反，mPGES-1的RNAi敲低抑制了肿瘤生长参数。mPGES-1过表达可促进SCID小鼠肿瘤形成并增加肿瘤重量（P<0.01），而mPGES-1敲低可延迟肿瘤形成并减少肿瘤重量（P<0.01）。mPGES-1可抑制PTEN的表达，激活胆管癌细胞中EGFR-PI 3 K-AKT-mTOR信号通路。mPGES-1介导的对PTEN的抑制通过阻断EGR-1类小泛素化和与PTEN基因的5′-UTR结合来调节。mPGES-1通过抑制PTEN促进实验性胆管癌发生和肿瘤进展。
Microsomal prostaglandin E synthase-1 (mPGES-1) is a rate-limiting enzyme that is coupled with cyclooxygenase-2 (COX-2) in the synthesis of prostaglandin E2 (PGE2). Although COX-2 is involved in development and progression of various human cancers, the role of mPGES-1 in carcinogenesis has not been determined. We investigated the role of mPGES-1 in human cholangiocarcinoma growth. We used immunohistochemical analyses to examine the expression of mPGES-1 in formalin-fixed, paraffin-embedded human cholangiocarcinoma tissues. The effects of mPGES-1 on human cholangiocarcinoma cells were determined in vitro and in SCID mice. Immunoblotting and immunoprecipitation assays were performed to determine the levels of PTEN and related signaling molecules in human cholangiocarcinoma cells with overexpression or knockdown of mPGES-1. mPGES-1 is overexpressed in human cholangiocarcinoma tissues. Overexpression of mPGES-1 in human cholangiocarcinoma cells increased tumor cell proliferation, migration, invasion, and colony formation; in contrast, RNAi knockdown of mPGES-1 inhibited tumor growth parameters. In SCID mice with tumor xenografts, mPGES-1 overexpression accelerated tumor formation and increased tumor weight (P<0.01), whereas mPGES-1 knockdown delayed tumor formation and reduced tumor weight (P<0.01). mPGES-1 inhibited the expression of PTEN, leading to activation of the EGFR–PI3K–AKT–mTOR signaling pathways in cholangiocarcinoma cells. mPGES-1–mediated inhibition of PTEN is regulated through blocking of EGR-1 sumoylation and binding to the 5′-UTR of the PTEN gene. mPGES-1 promotes experimental cholangiocarcinogenesis and tumor progression by inhibiting PTEN.
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