TAZ Mediates Lysophosphatidic Acid-Induced Migration and Proliferation of Epithelial Ovarian Cancer Cells
TAZ Mediates Lysophosphatidic Acid-Induced Migration and Proliferation of Epithelial Ovarian Cancer Cells
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DOI：
10.1159/000354434
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发表时间：
2013-01-01
影响因子：
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通讯作者：
Kim, Jae Ho
中科院分区：
文献类型：
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作者：
Jeong, Geun Ok;Shin, Sang Hun;Kim, Jae Ho
背景资料：具有PDZ结合基序（TAZ）的转录共激活因子（Transcriptional co-activator）是Hippo通路的下游效应子，已报道其通过充当转录共激活因子来调节器官大小、组织稳态和肿瘤发生。溶血磷脂酸（LPA）是一种生物活性脂质，通过激活G蛋白偶联受体参与卵巢癌的发生和转移。然而，TAZ参与LPA诱导的卵巢癌肿瘤发生尚未阐明。研究方法：为了证明TAZ在LPA刺激的肿瘤发生中的作用，通过蛋白质印迹和趋化性分析在R182人上皮性卵巢癌细胞中确定了LPA对TAZ表达和细胞迁移的影响。结果与结论：LPA受体抑制剂Ki 16425处理R182细胞可阻断LPA诱导的细胞迁移。此外，用LPA受体1特异性的小干扰RNA转染R182细胞导致LPA刺激的细胞迁移的消除。LPA诱导R182细胞中ERK和p38 MAP激酶磷酸化，MEK-ERK通路抑制剂U 0126预处理细胞，而不是p38 MAPK抑制剂SB 202190，导致LPA诱导的细胞迁移消失。用U 0126预处理R182细胞可减弱LPA诱导的TAZ及其转录靶基因（如CTGF和CYR 61）的mRNA水平，而不影响雅普的磷酸化水平。这些结果表明，MEK-ERK通路在LPA诱导的R182细胞迁移和TAZ mRNA表达中起关键作用，而不影响TAZ蛋白的稳定性。此外，小干扰RNA介导的TAZ表达沉默减弱了LPA刺激的R182细胞迁移。这些结果表明，TAZ在LPA刺激的上皮性卵巢癌细胞迁移中起着关键作用。版权所有（c）2013 S. Karger AG，巴塞尔。
Background: Transcriptional co-activator with PDZ-binding motif (TAZ), a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co-activator. Lysophosphatidic acid (LPA) is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein-coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated. Methods: In order to demonstrate the role of TAZ in LPA-stimulated tumorigenesis, the effects of LPA on TAZ expression and cell migration were determined by Western blotting and chemotaxis analyses in R182 human epithelial ovarian cancer cells. Results and Conclusion: Treatment of R182 cells with the LPA receptor inhibitor Ki16425 blocked LPA-induced cell migration. In addition, transfection of R182 cells with small interfering RNA specific for LPA receptor 1 resulted in abrogation of LPA-stimulated cell migration. LPA induced phosphorylation of ERK and p38 MAP kinase in R182 cells and pretreatment of cells with the MEK-ERK pathway inhibitor U0126, but not the p38 MAPK inhibitor SB202190, resulted in abrogation of LPA-induced cell migration. Pretreatment of R182 cells with U0126 attenuated LPA-induced mRNA levels of TAZ and its transcriptional target genes, such as CTGF and CYR61, without affecting phosphorylation level of YAP. These results suggest that MEK-ERK pathway plays a key role in LPA-induced cell migration and mRNA expression of TAZ in R182 cells, without affecting stability of TAZ protein. In addition, small interfering RNA-mediated silencing of TAZ expression attenuated LPA-stimulated migration of R182 cells. These results suggest that TAZ plays a key role in LPA-stimulated migration of epithelial ovarian cancer cells. Copyright (c) 2013 S. Karger AG, Basel.