Back to Search Start Over

miR-1226-3p Promotes Sorafenib Sensitivity of Hepatocellular Carcinoma via Downregulation of DUSP4 Expression

Authors :
Jinyi Zhong
Wenxin Li
Wenda Li
Xianqing Chen
Changzhen Shang
Sicong Zhu
Yajin Chen
Wenliang Tan
Source :
Journal of Cancer
Publication Year :
2019
Publisher :
Ivyspring International Publisher, 2019.

Abstract

Background: Sorafenib appears to increase the survival rate of hepatocellular carcinoma (HCC) patients, but its response rate is seriously limited due to drug resistance. Molecular mechanisms underlying sorafenib resistance are still unknown. 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. Cell viabilities to sorafenib were measured by CCK-8 assay. Cell apoptosis and proliferation were detected by flow cytometry and EdU proliferation assay. 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. We confirmed that SK-HEP-1 cells were more resistant to sorafenib compared to 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.

Details

Language :
English
ISSN :
18379664
Volume :
10
Issue :
12
Database :
OpenAIRE
Journal :
Journal of Cancer
Accession number :
edsair.doi.dedup.....b1d8bdb936065ded5591cc3351dc7060