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首页> 外文期刊>Journal of Cellular Physiology >Cyclooxygenase-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 in breast cancer cells
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Cyclooxygenase-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 in breast cancer cells

机译：通过Cyclooxygenase-2让CCR7表达AKT-mediated磷酸化,激活在乳腺癌细胞Sp1

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Up-regulation of cyclooxygenase-2 (COX-2) is frequently found in human cancers and is significantly associated with tumor metastasis. Our previous results demonstrate that COX-2 and its metabolite prostaglandin E2 (PGE2) stimulate the expression of CCR7 chemokine receptor via EP2/EP4 receptors to promote lymphatic invasion in breast cancer cells. In this study, we address the underlying mechanism of COX-2/PGE2-induced CCR7 expression. We find that COX-2/PGE2 increase CCR7 expression via the AKT signaling pathway in breast cancer cells. Promoter deletion and mutation assays identify the Sp1 site located at the -60/-57 region of CCR7 gene promoter is critical for stimulation. Chromatin immunoprecipitation (ChIP) assay confirms that in vivo binding of Sp1 to human CCR7 promoter is increased by COX-2 and PGE2. Knockdown of Sp1 by shRNA reduces the induction of CCR7 by PGE2. We demonstrate for the first time that AKT may directly phosphorylate Sp1 at S42, T679, and S698. Phosphorylation-mimic Sp1 protein harboring S42D, T679D, and S698D mutation strongly activates CCR7 expression. In contrast, change of these three residues to alanine completely blocks the induction of CCR7 by PGE2. Pathological investigation demonstrates that CCR7 expression is strongly associated with phospho-AKT and Sp1 in 120 breast cancer tissues. Collectively, our results demonstrate that COX-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 and this pathway is highly activated in metastatic breast cancer.
机译：老年病的cyclooxygenase-2 (cox - 2)经常发现在人类癌症与肿瘤转移显著相关。我们先前的结果表明cox - 2和其代谢产物前列腺素E2 (PGE2)刺激CCR7表达的趋化因子受体通过EP2 / EP4受体促进淋巴入侵在乳腺癌细胞。cox - 2 / PGE2-induced的底层机制CCR7表达。通过一种蛋白激酶信号通路在CCR7表达乳腺癌细胞。突变检测识别Sp1站点位于-60/-57 CCR7基因启动子区域刺激的关键。免疫沉淀反应(芯片)试验证实体内绑定Sp1人类CCR7启动子增加了cox - 2和PGE2。PGE2 shRNA减少CCR7的感应。首次证明一种蛋白激酶直接使磷酸化Sp1 S42、T679和S698。S42D、T679D S698D变异强烈激活CCR7表达。这三个残基丙氨酸完全块CCR7的PGE2的感应。调查表明,CCR7表达是与phospho-AKT密切相关,Sp1120年乳腺癌组织。结果表明,cox - 2让CCR7通过AKT-mediated磷酸化和表达式这个途径激活Sp1和高度在转移性乳腺癌激活。

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