Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α

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 14-3-3 eta maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3 eta stabilizes hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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 14-3-3 eta and thereby inhibits 14-3-3./HIF-1 alpha/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3 eta, HIF-1 alpha, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3 eta expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3 eta 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.