Caffeic acid attenuates the autocrine IL-6 in hepatocellular carcinoma via the epigenetic silencing of the NF-κB-IL-6-STAT-3 feedback loop†
Abstract
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.
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