MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression

We investigated MAPK14-dependent resistance to sorafenib in hepatocellular carcinoma (HCC). Bioinformatics analysis and dual luciferase reporter assays in HCC cell lines showed that miR-216a-3p directly binds to the 3'UTR of MAPK14 mRNA and downregulates MAPK14 protein expression. Consequently, miR-216a-3p expression correlates inversely with MAPK14 protein levels in HCC patient tissues. miR-216a-3p overexpression significantly increases the sorafenib sensitivity of HCC cells by suppressing MAPK14 expression and reducing the subsequent activation of the MEK/ERK and ATF2 signaling pathways. The growth of xenograft tumors derived from miR-216a-3p-overexpression HCC cells was significantly diminished in sorafenib-treated Balb/c nude mice compared to controls. High miR-216a-3p levels in HCC tissue samples prior to treatment correlated with a better sorafenib response and favorable prognosis. Our findings thus demonstrate that miR-216a-3p enhances sorafenib sensitivity in HCC cells and tumor tissues by decreasing MAPK14 levels, thereby inhibiting the MAPK14-dependent MEK/ERK and ATF2 signaling.