Sorafenib resistance is one of the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC). Here, sorafenib-resistant HCC cells and xenografts in nude mice were used as experimental models. A cohort of patients with advanced recurrent HCC who were receiving sorafenib therapy was used to assess the clinical significance of this therapy. Our data showed that 14-3-3η maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3η stabilizes hypoxia-inducible factor 1α (HIF-1α) through the inhibition of ubiquitin-dependent proteasome protein degradation, which leads to the maintenance of cancer stem cell (CSC) properties. We further found that microRNA-16 (miR-16) is a competent miRNA that reverses sorafenib resistance by targeting the 3′-UTR of 14-3-3η and thereby inhibits 14-3-3η/HIF-1α/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3η, HIF-1α, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3η expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3η is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment.

BackgroundMulti-drug resistance (MDR) is one of the main obstacles for treatment of advanced/recurrent hepatocellular carcinoma (HCC). We have previously identified arsenic trioxide (ATO) as an effective metastasis/angiogenesis inhibitor in HCC. Here, we further found that MDR-HCC cells were more sensitive to ATO.MethodsThe MDR-HCC cells were used as experimental models. Biological functions were investigated using cell transfection, polymerase chain reaction, western blot, southwestern blot, immunostaining, immunoprecipitation plus atomic fluorescence spectrometry, and so on.ResultsThe MDR-HCC cells underwent high oxidative stress condition, and employed adaptive mechanisms for them to survive; while ATO abolished such mechanisms via targeting the 14–3-3η/nuclear factor kappa B (NF-κB) feedback Loop. Briefly, in MDR cells, the increase of ROS activated NF-κB signaling, which transcriptionally activated 14–3-3η. Meanwhile, the activation of NF-κB can be constitutively maintained by 14–3-3η. As a NF-κB inhibitor, ATO transcriptionally inhibited the 14–3-3η mRNA level. Meanwhile, ATO was also validated to directly bind to 14–3-3η, enhancing the degradation of 14–3-3η protein in an ubiquitination-dependent manner. Knockdown of 14–3-3η reduced the ATO-induced reversal extents of drug resistance in MDR cells.Conclusion14–3-3η/NF-κB feedback loop plays an important role in maintaining the MDR phenotype in HCC. Moreover, via targeting such feedback loop, ATO could be considered as a potential molecular targeted agent for the treatment of HCC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1005-y) contains supplementary material, which is available to authorized users.