COX-2 Forms Regulatory Loop with YAP to Promote Proliferation and Tumorigenesis of Hepatocellular Carcinoma Cells.
COX-2 Forms Regulatory Loop with YAP to Promote Proliferation and Tumorigenesis of Hepatocellular Carcinoma Cells.
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COX-2与YAP形成调节环促进肝癌细胞增殖和肿瘤发生
DOI：
10.1016/j.neo.2017.12.004
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Xu G;Wang Y;Li W;Cao Y;Xu J;Hu Z;Hao Y;Hu L;Sun Y
研究表明，COX-2和YAP与肝细胞癌高度相关，并在肿瘤形成过程中频繁上调。然而，尽管它们很重要，但COX-2和YAP之间是否存在相互作用以及它们如何相互调节尚不清楚。在这篇文章中，我们发现COX-2在肝癌细胞系中的过表达导致YAP mRNA、蛋白及其靶基因水平的增加。COX-2促进肝癌细胞系的增殖，YAP的基因敲除可拮抗这一作用。此外，我们的结果表明，EP2和Wnt/β-catenin介导了COX-2对YAP的转录诱导。另一方面，YAP在转录水平上增加了COX-2的表达，需要COX-2启动子上完整的tead结合位点。综上所述，这些发现表明，COX-2不仅是YAP的刺激物，而且是河马-YAP通路的靶点，从而形成一个正反馈回路，COX-2-PGE_2-EP2-GαS-β-连环蛋白-YAP-COX-2。在进一步的研究中，我们发现抑制YAP和COX-2的作用是协同的，比单独抑制YAP和COX-2更有效地减少肝癌细胞的生长和肿瘤的形成，这表明YAP和COX-2的双重调控可能通过阻断这一正反馈回路而导致发现有前景的肝癌患者的治疗策略。
COX-2 and YAP are shown to be highly associated with hepatocellular carcinoma (HCC) and frequently upregulated during tumor formation. However, despite their importance, whether there is a mutual interaction between COX-2 and YAP and how they regulate each other are not clear. In this paper, we showed that COX-2 overexpression in HCC cell lines resulted in increased levels of YAP mRNA, protein, and its target genes. COX-2 promoted proliferation of HCC cell lines, and knockdown of YAP antagonized this effect. In addition, our results indicated that EP2 and Wnt/β-Catenin mediate the transcriptional induction of YAP by COX-2. On the other hand, YAP increased COX-2 expression at the level of transcription requiring intact TEAD binding sites in the COX-2 promoter. Collectively, these findings indicated that COX-2 is not only a stimulus of YAP but also a target of Hippo-YAP pathway, thus forming a positive feedback circuit, COX-2-PGE2-EP2-Gαs-β-catenin-YAP-COX-2. In a further study, we showed that inhibition of YAP and COX-2 acted synergistically and more efficiently reduced the growth of HCC cells and tumor formation than either of them alone, suggesting that dual governing of YAP and COX-2 may lead to the discovery of promising therapeutic strategies for HCC patients via blocking this positive feedback loop.
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