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miR-1226-3p Promotes Sorafenib Sensitivity of Hepatocellular Carcinoma via Downregulation of DUSP4 Expression
- 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.
- Subjects :
- 0301 basic medicine
Sorafenib
Cell
DUSP4
Flow cytometry
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
medicine
neoplasms
Gene knockdown
medicine.diagnostic_test
business.industry
sorafenib resistance
hepatocellular carcinoma
medicine.disease
digestive system diseases
030104 developmental biology
medicine.anatomical_structure
Oncology
Apoptosis
Cell culture
030220 oncology & carcinogenesis
Hepatocellular carcinoma
miR-1226-3p
Cancer research
business
medicine.drug
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 18379664
- Volume :
- 10
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Journal of Cancer
- Accession number :
- edsair.doi.dedup.....b1d8bdb936065ded5591cc3351dc7060