ETS-1 Protein Regulates Vascular Endothelial Growth Factor-induced Matrix Metalloproteinase-9 and Matrix Metalloproteinase-13 Expression in Human Ovarian Carcinoma Cell Line SKOV-3 (Retracted article. See vol. 295, pg. 17887, 2020)
ETS-1 Protein Regulates Vascular Endothelial Growth Factor-induced Matrix Metalloproteinase-9 and Matrix Metalloproteinase-13 Expression in Human Ovarian Carcinoma Cell Line SKOV-3 (Retracted article. See vol. 295, pg. 17887, 2020)
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DOI：
10.1074/jbc.m111.284034
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发表时间：
2012-04-27
影响因子：
4.8
通讯作者：
Roy, Sib Sankar
中科院分区：
文献类型：
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作者：
Ghosh, Sonali;Basu, Moitri;Roy, Sib Sankar
基质金属蛋白酶介导的细胞外基质降解是恶性细胞侵袭和转移的重要事件。基质金属蛋白酶(MMPs)的表达受不同细胞因子和生长因子的调节。血管内皮生长因子是一种强大的血管生成细胞因子，通过激活MMPs诱导卵巢癌细胞的侵袭。在这里，我们证明了血管内皮生长因子通过激活p38MAPK和PI3K/AKT通路来诱导SKOV-3细胞的侵袭和分散。VEGF可诱导卵巢癌细胞MMP2、MMP9和MMP13的表达，从而调节SKOV-3细胞的转移，抑制PI3K/AKT和p38MAPK通路后，这些MMPs的活性降低。有趣的是，血管内皮生长因子诱导了Ets-1因子的表达，Ets-1因子是不同基质金属蛋白酶基因的重要反式调节因子。Ets-1可与基质金属蛋白酶-9和基质金属蛋白酶-13启动子结合。此外，血管内皮生长因子通过其受体发挥上述功能。此外，Ets-1基因敲除后，血管内皮生长因子诱导的基质金属蛋白酶-9和基质金属蛋白酶-13的表达及体外细胞侵袭力显著降低。在ETS-1 siRNA转染细胞中，血管内皮生长因子诱导的基质金属蛋白酶-9和基质金属蛋白酶-13启动子活性再次下调。血管内皮细胞生长因子以剂量依赖的方式使Ets-1在细胞核中的含量增加。PI3K和p38MAPK信号通路的特异性抑制剂可阻断血管内皮生长因子诱导的Ets-1表达及其核定位。因此，根据这些观察结果，推测血管内皮生长因子激活PI3K/AKT和p38MAPK导致Ets-1基因表达，进而激活MMP9和MMP13，从而导致SKOV-3细胞的侵袭和分散。本研究从机制上深入探讨了血管内皮细胞生长因子诱导相关MMPs表达的转移功能。
Matrix metalloproteinase-mediated degradation of extracellular matrix is a crucial event for invasion and metastasis of malignant cells. The expressions of matrix metalloproteinases (MMPs) are regulated by different cytokines and growth factors. VEGF, a potent angiogenic cytokine, induces invasion of ovarian cancer cells through activation of MMPs. Here, we demonstrate that invasion and scattering in SKOV-3 cells were induced by VEGF through the activation of p38 MAPK and PI3K/AKT pathways. VEGF induced the expression of MMP-2, MMP-9, and MMP-13 and hence regulated the metastasis of SKOV-3 ovarian cancer cells, and the activities of these MMPs were reduced after inhibition of PI3K/AKT and p38 MAPK pathways. Interestingly, VEGF induced expression of ETS-1 factor, an important trans-regulator of different MMP genes. ETS-1 bound to both MMP-9 and MMP-13 promoters. Furthermore, VEGF acted through its receptor to perform the said functions. In addition, VEGF-induced MMP-9 and MMP-13 expression and in vitro cell invasion were significantly reduced after knockdown of ETS-1 gene. Again, VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. VEGF enriched ETS-1 in the nuclear fraction in a dose-dependent manner. VEGF induced expression of ETS-1 and its nuclear localization were blocked by specific inhibitors of the PI3K and p38 MAPK pathways. Therefore, based on these observations, it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. The study provides a mechanistic insight into the prometastatic functions of VEGF-induced expression of relevant MMPs.