Caffeic acid attenuates the autocrine IL-6 in hepatocellular carcinoma via the epigenetic silencing of the NF-kB-IL-6-STAT-3 feedback loop
Caffeic acid attenuates the autocrine IL-6 in hepatocellular carcinoma via the epigenetic silencing of the NF-kB-IL-6-STAT-3 feedback loop
复制标题
咖啡酸通过 NF-kB-IL-6-STAT-3 反馈环的表观遗传沉默减弱肝细胞癌中的自分泌 IL-6
作者：
Lingling Wang;Ming Lu;Mei Yi;Lijun Chen;Jian Shen;Zhong Li;Lei Li;Ye Yang;Jianping Zhang;Yuan Li
肝细胞癌（HCC）是全球癌症相关死亡的第三大原因。自分泌IL-6信号通路在HCC进展中起关键作用。咖啡酸（CaA）是一种新型的抗肿瘤药物，但CaA在肝癌自分泌IL-6中的作用及其分子机制尚不清楚。在我们目前的研究中，我们发现CaA通过microRNA-124（miR-124）介导的NF-κB-IL-6-STAT-3反馈环的衰减来阻断HCC细胞中内源性IL-6的表达/分泌。事实上，CaA通过诱导DNA去甲基化来提高miR-124的表达。miR-124靶向NF-κB/p65和STAT-3 mRNA的3′-UTR，减弱这两种蛋白的表达/激活，并导致IL-6基因的转录抑制。miR-124的敲低逆转了Ca A诱导的NF-κB和STAT-3以及自分泌IL-6的抑制。通过了解CaA抑制HCC中自分泌IL-6的新机制，我们的研究将有助于设计未来发展CaA作为潜在的HCC化学预防剂的策略，无论是单独使用还是与其他现有药物联合使用。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. The autocrine IL-6 signaling pathway plays a key role in HCC progression. Caffeic acid (CaA) is a novel anti-tumor agent; however, the functions of CaA in the regulation of autocrine IL-6 in HCC, and the molecular mechanisms it is involved in remain unclear. In our present study, we found that CaA blocked the expression/secretion of endogenous IL-6 by the microRNA-124 (miR-124)-mediated attenuation of the NF-κB-IL-6-STAT-3 feedback loop in HCC cells. Indeed, CaA elevated the expression of miR-124 by inducing DNA-demethylation. MiR-124, which targeted the 3′-UTR of NF-κB/p65 and STAT-3 mRNAs, attenuated the expressions/activations of these two proteins and led to a transcriptional suppression of the IL-6 gene. Knockdown of miR-124 reversed the CaA-induced inhibitions of NF-κB and STAT-3, as well as autocrine IL-6. By understanding a novel mechanism whereby CaA inhibits the autocrine IL-6 in HCC, our study would help in the design of future strategies of developing CaA as a potential HCC chemo-preventive agent when used alone or in combination with other current drugs.