miR-1226-3p Promotes Sorafenib Sensitivity of Hepatocellular Carcinoma via Downregulation of DUSP4 Expression.Background: Sorafenib appears to increase the survival rate of hepatocellular carcinoma (HCC) patients, but its response rate is seriously limited due to drug resistance.  Herein, we explored the possible role of miR-1226-3p in sorafenib resistance of HCC.  Methods: The miR-1226-3p expression level in HCC cell lines was evaluated by qRT-PCR.  A luciferase reporter of DUSP4 3'-UTR was used for validation as a target gene of miR-1226-3p.  Finally, the effects of in vivo antitumor efficacy of miR-1226-3p combined with sorafenib were evaluated by HCC tumor xenografts in nude mice.  Results: Bioinformatics analysis from Gene Expression Omnibus (GEO) datasets GSE56059 suggested that miR-1226-3p expression was downregulated in HCC patients who showed progressive disease (PD) after sorafenib treatment.  SK-HEP-1 cells expressed lower levels of miR-1226-3p than HepG2 cells.  In addition, miR-1226-3p mimic increased cell apoptosis of SK-HEP-1 cells, whereas miR-1226-3p inhibitor significantly impaired cell apoptosis of HepG2 cells after sorafenib treatment.  Moreover, we validated that miR-1226-3p directly targeted dual specificity phosphatase 4 (DUSP4), and further demonstrated that knockdown of DUSP4 reduced sorafenib resistance by regulating the JNK-Bcl-2 axis.  Conclusions: miR-1226-3p promotes sorafenib sensitivity of HCC through downregulation of DUSP4 expression, and targeting miR-1226-3p may be a novel therapeutic strategy for overcoming sorafenib resistance.
miR-1226-3p
miR-1226-3p Promotes Sorafenib Sensitivity of Hepatocellular Carcinoma via Downregulation of DUSP4 Expression.Background: Sorafenib appears to increase the survival rate of hepatocellular carcinoma (HCC) patients, but its response rate is seriously limited due to drug resistance.  A luciferase reporter of DUSP4 3'-UTR was used for validation as a target gene of miR-1226-3p.  Moreover, we validated that miR-1226-3p directly targeted dual specificity phosphatase 4 (DUSP4), and further demonstrated that knockdown of DUSP4 reduced sorafenib resistance by regulating the JNK-Bcl-2 axis.  Conclusions: miR-1226-3p promotes sorafenib sensitivity of HCC through downregulation of DUSP4 expression, and targeting miR-1226-3p may be a novel therapeutic strategy for overcoming sorafenib resistance.
DUSP4
Results: Bioinformatics analysis from Gene Expression Omnibus (GEO) datasets GSE56059 suggested that miR-1226-3p expression was downregulated in HCC patients who showed progressive disease (PD) after sorafenib treatment. 
Gene Expression Omnibus (GEO)
Cell viabilities to sorafenib were measured by CCK-8 assay. 
CCK-8 assay
Cell apoptosis and proliferation were detected by flow cytometry and EdU proliferation assay. 
flow cytometry
Cell apoptosis and proliferation were detected by flow cytometry and EdU proliferation assay. 
EdU proliferation assay
A luciferase reporter of DUSP4 3'-UTR was used for validation as a target gene of miR-1226-3p. 
luciferase reporter
Finally, the effects of in vivo antitumor efficacy of miR-1226-3p combined with sorafenib were evaluated by HCC tumor xenografts in nude mice. 
HCC tumor xenografts in nude mice