Caffeic acid attenuates the angiogenic function of hepatocellular carcinoma cells via reduction in JNK-1-mediated HIF-1α stabilization in hypoxia
Caffeic acid attenuates the angiogenic function of hepatocellular carcinoma cells via reduction in JNK-1-mediated HIF-1α stabilization in hypoxia
复制标题
咖啡酸通过减少缺氧条件下 JNK-1 介导的 HIF-1 α 稳定性来减弱肝细胞癌细胞的血管生成功能
DOI：
10.1039/c6ra07703j
复制
发表时间：
2016-01-01
期刊：
影响因子：
3.9
通讯作者：
Dong, Huibin
中科院分区：
文献类型：
--
作者：
Gu, Weiting;Yang, Ye;Dong, Huibin
肝细胞癌（HCC）是全球肿瘤相关死亡的第三大原因。血管生成在HCC进展中起着至关重要的作用。咖啡酸（CaA）是一种新型的抗肿瘤药物，但其在肝癌血管生成中的作用及其分子机制尚不清楚。在此，我们发现，在CoCl 2（一种低氧模拟物）存在下，CaA通过降低JNK-1介导的HIF-1 α稳定性来减弱HCC细胞的血管生成功能。简言之，CaA减弱了CoCl 2诱导的HCC细胞自分泌血管内皮生长因子（VEGF）和血管生成。在分子机制上，CoCl 2处理增加了HIF-1 α和磷酸化信号转导子和转录激活子-3（p-STAT 3）的表达。然后，通过直接与VEGF基因的启动子结合，HIF-1 α有效地激活了VEGF。然而，CaA可能通过降低JNK 1活化和降低HIF-1 α稳定性来减弱CoCl 2诱导的HIF-1 α活化。此外，CaA降低CoCl 2诱导的p-STAT-3表达增加。这两种功能导致HIF-1 α向VEGF启动子的募集减弱。通过了解CaA抑制HCC血管生成的新机制，我们的研究扩展了对CaA诱导的抗癌潜力所涉及的分子机制的理解。
Hepatocellular carcinoma (HCC) is the third leading cause of tumor-related mortality worldwide. Angiogenesis plays a crucial role in HCC progression. Caffeic acid (CaA) is a novel anti-tumor agent, however, the functions of CaA in the regulation of angiogenesis in HCC, and the molecular mechanisms involved, remain largely uninvestigated. Here, we found that, in the presence of CoCl2 (a hypoxia mimic), CaA attenuates the angiogenic function of HCC cells via reduction in JNK-1-mediated HIF-1 alpha stabilization. Briefly, CaA attenuated the CoCl2-induced autocrine vascular endothelial growth factor (VEGF) and angiogenesis in HCC cells. For the molecular mechanisms, CoCl2 treatment increased the expressions of HIF-1 alpha and phosphorylated signal transducers and activators of transcription-3 (p-STAT3). Then, by directly binding to the promoter of the VEGF gene, HIF-1 alpha effectively activated VEGF. However, CaA attenuated the CoCl2-induced activation of HIF-1 alpha likely by reducing JNK1 activation and reducing HIF-1 alpha stabilization. Moreover, CaA decreased the CoCl2-induced increased expression of p-STAT-3. These two functions resulted in an attenuated recruiting of the HIF-1 alpha to the VEGF promoter. By understanding a novel mechanism whereby CaA inhibits the angiogenesis in HCC, our study expands the understanding of the molecular mechanisms involved in the anti-cancer potential induced by CaA.