FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer.
FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer.
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DOI：
10.18632/oncotarget.4280
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Fan Q;Cai Q;Xu Y
溶血磷脂酸(LPA)是G蛋白偶联受体的典型配体，Forkhead box Protein M1(FOXM1)是调控多种肿瘤发生发展相关基因表达的转录因子，是上皮性卵巢癌中两个重要的致癌信号分子。我们利用药物抑制剂、信号分子的遗传形式和RNAi介导的基因敲除进行了体外机制研究，以揭示这两个分子如何在EOC细胞中相互作用的分子机制。此外，还进行了小鼠体内研究，以证实FOXM1在EOC肿瘤形成和进展中的功能参与。我们首次发现LPA以时间和剂量依赖的方式上调人卵巢癌细胞株OVCA433、CAOV3和OVCAR5中活性FOXM1剪接变异体的表达。GI-PI3K-AKT和G12/13-Rho-Yap信号通路均参与LPA受体(LPA1-3)在转录水平上上调FOXM1。此外，在CAOV3异种移植瘤中FOXM1的下调显著减少了肿瘤和腹水的形成、转移以及与细胞增殖、迁移或侵袭有关的FOXM1靶基因的表达。总的来说，我们的数据将卵磷脂LPA、癌基因YAP和EOC细胞中细胞增殖/突变的中央调节因子FOXM1联系在一起。此外，这些结果进一步支持了这些通路作为卵巢癌潜在治疗靶点的重要性。
Lysophosphatidic acid (LPA), a prototypical ligand for G protein coupled receptors, and Forkhead box protein M1 (FOXM1), a transcription factor that regulates expression of a wide array of genes involved in cancer initiation and progression, are two important oncogenic signaling molecules in human epithelial ovarian cancers (EOC). We conducted in vitro mechanistic studies using pharmacological inhibitors, genetic forms of the signaling molecules, and RNAi-mediated gene knock-down to uncover the molecular mechanisms of how these two molecules interact in EOC cells. Additionally, in vivo mouse studies were performed to confirm the functional involvement of FOXM1 in EOC tumor formation and progression. We show for the first time that LPA up-regulates expression of active FOXM1 splice variants in a time- and dose-dependent manner in the human EOC cell lines OVCA433, CAOV3, and OVCAR5. Gi-PI3K-AKT and G12/13-Rho-YAP signaling pathways were both involved in the LPA receptor (LPA1–3) mediated up-regulation of FOXM1 at the transcriptional level. In addition, down-regulation of FOXM1 in CAOV3 xenografts significantly reduced tumor and ascites formation, metastasis, and expression of FOXM1 target genes involved in cell proliferation, migration, or invasion. Collectively, our data link the oncolipid LPA, the oncogene YAP, and the central regulator of cell proliferation/mutagenesis FOXM1 in EOC cells. Moreover, these results provide further support for the importance of these pathways as potential therapeutic targets in EOC.