Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus.
Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus.
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DOI：
10.18632/oncotarget.9224
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发表时间：
2016-06-21
期刊：
影响因子：
--
通讯作者：
Dhanasekaran DN
中科院分区：
文献类型：
--
作者：
Ha JH;Ward JD;Radhakrishnan R;Jayaraman M;Song YS;Dhanasekaran DN
最近的研究已经确定了溶血磷脂酸（LPA）在卵巢癌进展中的关键作用。利用转录因子激活报告因子阵列，分析了45种不同的转录因子，发现LPA在SKOV3中显著激活转录因子缺氧诱导因子-1α (HIF1α)。IP卵巢癌细胞。与未经治疗的对照组相比，HIF1α的激活谱增加了150倍。阵列分析的验证表明，LPA刺激卵巢癌细胞中HIF1α水平的快速升高，在4小时内观察到HIF1α-诱导的最高水平。我们的报告表明，LPA通过g - αi2刺激HIF1α水平的升高。与HIF1α在癌细胞上皮向间充质转化（EMT）中的作用一致，LPA刺激EMT和相关的侵袭性细胞迁移，同时增加N-cadherin和Slug/Snail2的表达水平。利用Slug/Snail2的表达作为EMT的标记物，我们证明抑制Gαi2、HIF1α或Src会减弱这种反应。与EMT在促进侵袭性细胞迁移中的作用一致，我们的数据表明，临床使用的HIF1α抑制剂PX-478抑制HIF1α可以显著减弱lpa刺激SKOV3的侵袭性迁移。ip细胞。因此，我们目前的研究表明，LPA通过Src激酶通过g αi2介导的信号通路刺激HIF1α水平和下游emt特异性因子（如Slug）的增加，导致卵巢癌细胞的侵袭性迁移。
Recent studies have identified a critical role for lysophosphatidic acid (LPA) in the progression of ovarian cancer. Using a transcription factor activation reporter array, which analyzes 45 distinct transcription factors, it has been observed that LPA observed robustly activates the transcription factor hypoxia-induced factor-1α (HIF1α) in SKOV3.ip ovarian cancer cells. HIF1α showed 150-fold increase in its activation profile compared to the untreated control. Validation of the array analysis indicated that LPA stimulates a rapid increase in the levels of HIF1α in ovarian cancer cells, with an observed maximum level of HIF1α-induction by 4 hours. Our report demonstrates that LPA stimulates the increase in HIF1α levels via Gαi2. Consistent with the role of HIF1α in epithelial to mesenchymal transition (EMT) of cancer cells, LPA stimulates EMT and associated invasive cell migration along with an increase in the expression levels N-cadherin and Slug/Snail2. Using the expression of Slug/Snail2 as a marker for EMT, we demonstrate that the inhibition of Gαi2, HIF1α or Src attenuates this response. In line with the established role of EMT in promoting invasive cell migration, our data demonstrates that the inhibition of HIF1α with the clinically used HIF1α inhibitor, PX-478, drastically attenuates LPA-stimulates invasive migration of SKOV3.ip cells. Thus, our present study demonstrates that LPA utilizes a Gαi2-mediated signaling pathway via Src kinase to stimulate an increase in HIF1α levels and downstream EMT-specific factors such as Slug, leading to invasive migration of ovarian cancer cells.
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影响因子：
4.8
作者：
Ha, Ji Hee;Ward, Jeremy D.;Dhanasekaran, Danny N.
通讯作者：
Dhanasekaran, Danny N.
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
4.8
作者：
Burkhalter, Rebecca J.;Westfall, Suzanne D.;Stack, M. Sharon
通讯作者：
Stack, M. Sharon
影响因子：
4
作者：
Bolós, V;Peinado, H;Cano, A
通讯作者：
Cano, A