Possible Use of miR-223-3p as a Prognostic Marker in Transarterial Chemoembolization Treatment of Hepatocellular Carcinoma Patients

INTRODUCTION AND OBJECTIVES: Transcatheter chemoembolization (TACE) is the recommended therapy for intermediate stage hepatocellular carcinoma patients. Unfortunately, one of the main reasons for its failure is the emergence of multidrug resistance (MDR). Therefore, this study explored the possibility of using MDR-related miRNA as a response biomarker in HCC patients treated with doxorubicin drug-eluting bead TACE (DEB-TACE). PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to evaluate the expression level of 14 MDR-related miRNAs in doxorubicin-resistant HepG2 cells (HepG2/Dox) developed by single-dose of doxorubicin mimicking the situation of liver cells surviving TACE. The sera level of miR-223-3p, which was the most significantly downregulated in the HepG2 cells, was determined in 60 primary HCC patients undergoing TACE. Restoring miR-223-3p in HepG2/Dox cell line was achieved by its mimic transfection. Cell sensitivity was measured by SRB assay. Cell apoptosis and doxorubicin uptake were assessed by flow cytometry. The expression of miR-223-3p target protein, P-glycoprotein, was evaluated using qRT-PCR and western blotting. RESULTS: We detected a significant downregulation of circulating miR-223-3p in patients non-responders to TACE treatment compared with responders. The expression of miR-223-3p was markedly decreased in resistant HepG2/Dox cells compared to the parental control. In addition, the expression of miR-223-3p was found to be inversely correlated with P-glycoprotein expression thus confirming the role of miR-223-3p in MDR. Furthermore, overexpression of miR-223-3p suppressed P-glycoprotein which promoted cellular uptake of doxorubicin and increased apoptosis. CONCLUSIONS: Our data suggest a potential role for miR-233-3p as a prognostic as well as a therapeutic target for HCC.