Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis.
Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis.
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DOI：
10.1042/bj20090045
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发表时间：
2009-12-23
期刊：
影响因子：
--
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;Sasaki Y;Nakatani Y;Majima M;Ishikawa Y;Ishii T;Uematsu S;Akira S;Hara S;Kudo I
mPGES-1（微粒体前列腺素 E 合酶-1）是一种刺激诱导型酶，在 PGE2（前列腺素 E2）生物合成途径中的 COX（环加氧酶）-2 下游发挥作用。尽管已知 COX-2 衍生的 PGE2 在各种肿瘤的发展中发挥作用，但 mPGES-1 在癌发生中的作用尚未完全了解。在本研究中，我们使用 mPGES-1 敲低或过表达的 LLC（刘易斯肺癌）细胞以及 mPGES-1 缺陷小鼠来研究癌细胞和宿主相关的 mPGES-1 在体外和体内肿瘤发生过程中的作用。我们发现，LLC 细胞中 mPGES-1 的 siRNA（小干扰 RNA）沉默显着减少了 PGE2 合成，伴随着细胞增殖减少、Matrigel™ 侵袭性减弱和细胞外基质粘附增加。相反，过表达 mPGES-1 的 LLC 细胞显示出增殖和侵袭能力增强。当皮下植入野生型小鼠时，mPGES-1沉默的细胞形成比对照细胞更小的异种移植肿瘤。此外，皮下移植到 mPGES-1 敲除小鼠体内的 LLC 肿瘤比移植到同窝野生型小鼠体内的 LLC 肿瘤生长得更慢，同时微血管网络密度、促血管生成血管内皮生长因子的表达和基质金属蛋白酶 2 的活性降低。与野生型小鼠相比，mPGES-1缺失小鼠中静脉注射LLC细胞的肺转移也明显不那么明显。因此，我们目前的方法为 mPGES-1 依赖性 PGE2 生物合成途径在癌细胞和宿主微环境中在肿瘤生长和转移中的关键作用提供了明确的证据。
mPGES-1 (microsomal prostaglandin E synthase-1) is a stimulus-inducible enzyme that functions downstream of COX (cyclo-oxygenase)-2 in the PGE2 (prostaglandin E2)-biosynthesis pathway. Although COX-2-derived PGE2 is known to play a role in the development of various tumours, the involvement of mPGES-1 in carcinogenesis has not yet been fully understood. In the present study, we used LLC (Lewis lung carcinoma) cells with mPGES-1 knockdown or overexpression, as well as mPGES-1-deficient mice to examine the roles of cancer cell- and host-associated mPGES-1 in the processes of tumorigenesis in vitro and in vivo. We found that siRNA (small interfering RNA) silencing of mPGES-1 in LLC cells decreased PGE2 synthesis markedly, accompanied by reduced cell proliferation, attenuated Matrigel™ invasiveness and increased extracellular matrix adhesion. Conversely, mPGES-1-overexpressing LLC cells showed increased proliferating and invasive capacities. When implanted subcutaneously into wild-type mice, mPGES-1-silenced cells formed smaller xenograft tumours than did control cells. Furthermore, LLC tumours grafted subcutaneously into mPGES-1-knockout mice grew more slowly than did those grafted into littermate wild-type mice, with concomitant decreases in the density of microvascular networks, the expression of pro-angiogenic vascular endothelial growth factor, and the activity of matrix metalloproteinase-2. Lung metastasis of intravenously injected LLC cells was also significantly less obvious in mPGES-1-null mice than in wild-type mice. Thus our present approaches provide unequivocal evidence for critical roles of the mPGES-1-dependent PGE2 biosynthetic pathway in both cancer cells and host microenvironments in tumour growth and metastasis.