Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial-mesenchymal transition of metastatic ovarian cancer cells
Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial-mesenchymal transition of metastatic ovarian cancer cells
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DOI：
10.3892/or.2017.5533
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发表时间：
2017-05-01
期刊：
影响因子：
4.2
通讯作者：
Kim, Daejin
中科院分区：
文献类型：
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作者：
Park, Ga Bin;Chung, Yoon Hee;Kim, Daejin
肿瘤细胞上不同Toll样受体（TLR）的表达与疾病侵袭性、治疗抗性和不良预后相关。磷脂酰肌醇3-激酶（PI 3 K）/AKT通路被认为是癌细胞存活和增殖的关键。因此，我们在本研究中研究了TLR刺激的PI 3 K活化对原发性（Caov-3）和转移性（SK-0 V-3）上皮性卵巢癌细胞系的上皮向间充质转化（EMT）的影响。TLR与各种配体的结合促进了SK-OV-3细胞中IA类PI 3 K（p110 α、p110 β和p110 δ）的表达，并增加了间充质标志物（N-钙粘蛋白、Slug、波形蛋白、Snail、α-SMA和TCF）的表达。经TLR激动剂激活后，SK-OV-3的迁移活性和EMT相关细胞因子的分泌均显著高于Caov-3。虽然LPS刺激的SK-OV-3细胞的侵袭能力和EMT相关细胞因子的产生被p110亚型的所有药理学抑制剂显著抑制，但Syk/Src依赖性p1101 β亚型显著减弱迁移活性。相比之下，IL-10和半乳凝素-1的产生主要受p110 δ亚型的影响。用siRNA沉默TLR 4和galectin-1的基因降低了LPS处理的SK-OV-3细胞中基质金属蛋白酶2（MMP 2）和MMP 9的表达，并减少了间充质标志物。这项研究表明，TLR介导的PI 3 K活化通过产生半乳糖凝集素-1调节卵巢癌的侵袭和转移，这表明抑制p110亚型是一种有前途的治疗转移性卵巢癌的方法。
The expression of different toll -like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK-OV-3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110 alpha, p110 beta and p110 delta) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, alpha-SMA, and TCF) in SK-OV-3 cells. The migratory activity and secretion of EMT-related cytokines of SK-OV-3 were significantly higher compared to those of Caov-3 after activation with TLR agonist. Although the invasive capacity and production of EMT-related cytokines of LPS-stimulated SK-OV-3 cells were significantly suppressed by all pharmacological inhibitors of the p110 isoform, the Syk/Src-dependent p1101 beta isoform prominently attenuated migration activity. In contrast, the production of IL-10 and galectin-1 was mainly affected by the p110 delta isoform. Gene silencing of TLR4 and galectin-1 with siRNA decreased the expression of matrix metalloproteinase-2 (MMP2) and MMP9 and reduced mesenchymal markers in LPS-treated SK-OV-3 cells. This study demonstrated that TLR-mediated PI3K activation modulated the invasion and metastasis of ovarian cancer through the production of galectin-1, suggesting that inhibition of the p110 isoform is a promising therapeutic approach against metastatic ovarian cancer.