MicroRNAs contribute to ATP-binding cassette transporter- and autophagy-mediated chemoresistance in hepatocellular carcinoma

Table 1 miRNAs and ABC transporter-mediated drug resistance in hepatocellular carcinoma cells

miRNA	Expression Level in HCC	Role in ABC transporter expression and/or function	Involvement in cell viability and/or drug resistance	Ref.
miR122	Downregulated in tumors (reduced levels correlate with patient poor prognosis and metastasis) and in human HepG2, HuH-7 and Hep3B HCC cell lines	miR122-overexpressing HCC cells treated with DOX and vincristine showed reduced levels of P-gp mRNA expression, and MRP1 mRNA and protein levels	Adenovirus-transduced cells to overexpress miR122 became more sensitive to DOX- and vincristine-induced death	[12,14]
miR27a	Low in drug-resistant Bel-7402 cells	Negatively correlated with P-gp levels. Upregulation of miR27a reduced P-gp mRNA and protein expression	Cells transfected to overexpress miR27a sensitized resistant cells to 5-FU, mitomycin and DOX	[17]
miR503	Downregulated in HCC tissues (reduced levels correlate with malignant tumor progression), in HCC cell lines (SMMC-7721, Hep3B, HepG2, MHCC97H and LM3) and HepG2 resistant to drugs	Cells transfected to overexpress miR503 showed downregulation of both P-gp and MRP1, at mRNA and protein levels, and accumulated more intracellular rhodamine-123 (extruded through P-gp)	miR503 overexpression restored sensitivity to DOX in HepG2 resistant cells	[19,20]
miR375	Downregulated in patient tumor tissues and cells lines (HepG2, HuH-7, Hep3B)	Delivered within nanoparticles decreased P-gp protein expression	Delivered within nanoparticles improved DOX antitumor effect, prevented tumor cell growth in vitro and in vivo	[21,22,24]
miR133a	Downregulated in patient tumor tissues (its low expression correlated with poor differentiated tumors) and in HepG2, SMMC-77231, Hep3B, HuH-7 HCC cells	Through its binding to the 3’UTR of ABCC1 gene specifically downregulated MRP1 expression	miR133a-overexpressing HepG2 cells were more sensitive to DOX-induced death	[27,28]
miR326	Downregulated in human tissues (its low expression correlated with tumor progression and lymph node metastasis) and in HepG2, SMMC-77231, Hep3B, HuH-7 HCC cells	Specifically targeted MRP1 expression through its binding to the 3’UTR of ABCC1 gene	miR326-overexpressing HepG2 cells were more sensitive to DOX than control cells	[28,31]
miR223	Downregulated in HCC patient sera and liver biopsies	Through its binding to the 3’UTR of ABCB1 gene, it specifically downregulated P-gp expression	miR223 overexpression increased sensitivity to DOX and paclitaxel in SMMC-7721 and HepG2 cells	[34,35]
miR491-3p	Downregulated in HCC tissues and in human cell lines (Hep3B, Bel-7402 and SMMC-7721 cells)	Negatively correlated with P-gp expression. Through its binding to the 3’UTR of ABCB1 gene, it specifically downregulated P-gp expression and increased DOX intracellular concentration. Also, miR491-3p downregulated SP3 expression (transcription factor suggested to induce P-gp expression).	Conferred sensitivity to DOX and vinblastine in Hep3B and SMMC-7721 HCC cells	[38]
miR183	Overexpressed in liver tissues and in drug-resistant Bel-7402 cells	Positively correlated with P-gp and MRP2 protein expression	Conferred resistance to 5-FU in Bel-7402 cells	[41,42]

miRNA: MicroRNA; ABC: ATP-binding cassette; HCC: Hepatocellular carcinoma; DOX: Doxorubicin; 5-FU: 5-Fluoroacil; P-gp/ABCB1: P-glycoprotein; MRP1/ABCC1: Multidrug resistance-associated protein 1; 3’-UTR: 3’-untranslated region; MRP2: Multidrug resistance-associated protein 2.