MiR-223 modulates multidrug resistance via downregulation of ABCB1 in hepatocellular carcinoma cells

Abstract

Multidrug resistance (MDR) has become a major impediment to a successful treatment for liver cancer patients, and one of the common reasons for MDR is the activation of ABCB1 gene, leading to the over-expression of P-glycoprotein (P-gp), which conferred cancer cells be resistant to a broad range of anticancer drugs. MicroRNAs (miRNAs) are a class of short, non-coding RNA moleculars that can regulate gene expression at the post-transcriptional level. In the current study, the aim is to explore whether miRNA participates in the regulation of MDR mediated by ABCB1. We found that the expression of ABCB1 was correlated with the doxorubicin IC50 dose in eight hepatocellular carcinoma (HCC) cell lines: Hep3B, HCC3, LM-6, SMMC7721, Huh-7, SK-Hep-1, HepG2 and BEL-7402. Using the bioinformatics, we discovered that there were several miRNAs that can bind to the 3'UTR of ABCB1 gene. Among these candidate miRNAs, miR-223 was chosen for further study. Then, EGFP reporter assay, real-time PCR and Western blot were performed to verify that miR-223 targeted ABCB1 3'UTR directly, and miR-223 downregulated ABCB1 at both mRNA and protein levels. Finally, we found that the over-expression of miR-223 increased the HCC cell sensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencing of ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition, respectively. In conclusion, our findings indicated that miR-223 played an important role in the regulation of MDR mediated by ABCB1, and it suggests that miR-223 may be considered as a therapeutic biomarker for HCC patients who had MDR problems induced by high expression of ABCB1.

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…The re-expression of miR-223 in HBV-, HCV-, and non-HBV-non-HCV-related HCC cell lines revealed a consistent inhibitory effect on cell viability (Wong et al, 2008). Furthermore, Yang et al (2013) demonstrated that miR-223 overexpression plays an important role in the regulation of multidrug resistance (MDR) through downregulation of the ABCB1 expression by increasing the HCC cell sensitivity to anticancer drugs. Therefore, miR-223 may act as a potential therapeutic biomarker for HCC patients who show MDR resistancecaused by increased ABCB1 expression.…”

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

“…Two separate studies show that restoration of miR-122 in HCC cells increases their sensitivity to doxorubicin due to suppression of cell cycle progression, anti-apoptosis effectors and ABC transporter proteins [106,107]. miR-223 was also shown to increase doxorubicin sensitivity by suppressing MDR1 expression in HCC cells [108]. miR-26b is another miRNA that is downregulated in HCC.…”

Significant biomarkers for the management of hepatocellular carcinoma

“…In addition, the OS rate of the high miR-221 expression group was significantly lower than that of the low miR-221 expression group [70]. Increasing numbers of miRNAs could be significant biomarkers for the management of HCC (Table 4) [71][72][73][74].…”