Prostaglandin E2 receptor EP1 phosphorylate CREB and mediates MMP2 expression in human cholangiocarcinoma cells
Prostaglandin E2 receptor EP1 phosphorylate CREB and mediates MMP2 expression in human cholangiocarcinoma cells
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DOI：
10.1007/s11010-013-1610-1
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发表时间：
2013-03
影响因子：
4.3
通讯作者：
Bo Sun;Rong Rong-Rong;Hai-tao Jiang;Hai Zhang;Yipin Wang;Xiao-ming Bai;Min Zhang;Juan Ma;Shukai Xia;W. Shu;Li Zhang;J. Leng
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文献类型：
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作者：
Bo Sun;Rong Rong-Rong;Hai-tao Jiang;Hai Zhang;Yipin Wang;Xiao-ming Bai;Min Zhang;Juan Ma;Shukai Xia;W. Shu;Li Zhang;J. Leng
环氧合酶-2（考克斯-2）和考克斯-2诱导的前列腺素E2（PGE 2）参与恶性肿瘤发生的各个阶段。虽然基质金属蛋白酶2（MMP 2）在肿瘤侵袭中的作用已被研究，但PGE 2诱导MMP 2过度产生的确切机制尚未明确。我们以前已经证明，PGE 2增强细胞外信号调节激酶（Erk）的磷酸化通过EP 1信号通路参与PGE 2诱导的细胞增殖。基于对转录因子环磷酸腺苷反应元件结合蛋白（CREB）作为MMP 2的重要调节因子的鉴定以及Erk使CREB的ser 133磷酸化，我们推测CREB可能通过EP 1受体参与PGE 2刺激MMP 2过度产生的信号传导。在本研究中，我们研究了EP 1受体在PGE 2诱导的MMP 2表达中的作用，并阐明了EP 1受体调节MMP 2在人胆管癌细胞中的信号通路。我们发现，PGE 2或选择性EP 1受体激动剂17-P-T-PGE 2刺激MMP 2的表达，而选择性EP 1受体拮抗剂SC-51322或EP 1受体siRNA阻断了PGE 2诱导的MMP 2表达。细胞内钙离子螯合剂BAPTA-AM、EGFR AG 1478的选择性抑制剂和Erk PD 98059的选择性抑制剂阻断EP 1受体激活诱导的CREB磷酸化和MMP 2表达。一种新的显性负性（D-N）抑制蛋白的CREB，称为A-CREB，衰减EP 1受体激活诱导MMP 2的表达。我们的研究结果表明，前列腺素E2增强MMP 2的表达，至少部分是通过EP 1受体和钙信号通路介导的CREB磷酸化在人胆管癌细胞。
Cyclooxygenase-2 (COX-2) and COX-2-induced prostaglandin E2 (PGE2) have been implicated in all stages of malignant tumorigenesis. Although many aspects of matrix metalloproteinase (MMP2) on tumor invasion have been studied, the exact mechanism of PGE2-induced MMP2 overproduction has not been clearly defined. We have previously demonstrated that PGE2-enhanced extracellular signal-regulated kinase (Erk) phosphorylation via EP1 signaling pathway involved in PGE2-induced cell proliferation. Based on the identification of the transcription factor cyclic AMP response element-binding protein (CREB) as an important regulator of MMP2 and Erk phosphorylate CREB at ser133, we hypothesize that CREB may be implicated in the signaling of PGE2 stimulation to MMP2 overproduction via EP1 receptor. In the study, we investigated the role of EP1 receptor on PGE2-induced MMP2 expression and delineated the signaling pathway that contributes to EP1 receptor modulation of MMP2 in human cholangiocarcinoma cells. We found PGE2 or selective EP1 receptor agonist 17-P-T-PGE2-stimulated MMP2 expression and selective EP1 receptor antagonist SC-51322 or EP1 receptor siRNA abrogated PGE2-induced MMP2 expression. Intracellular calcium chelator BAPTA-AM, the selective inhibitor of EGFR AG1478 and the selective inhibitor of Erk PD98059 blocked EP1 receptor activation-induced CREB phosphorylation and MMP2 expression. A novel dominant-negative (D-N) inhibitor protein of the CREB, termed A-CREB, attenuated EP1 receptor activation-induced MMP2 expression. Our findings suggest that PGE2-enhanced MMP2 expression is, at least in part, mediated through EP1 receptors and calcium signaling pathway-induced CREB phosphorylation in human cholangiocarcinoma cells.