Copyright ©The Author(s) 2019.
World J Hepatol. Apr 27, 2019; 11(4): 344-358
Published online Apr 27, 2019. doi: 10.4254/wjh.v11.i4.344
Table 1 miRNAs and ABC transporter-mediated drug resistance in hepatocellular carcinoma cells
miRNAExpression Level in HCCRole in ABC transporter expression and/or functionInvolvement in cell viability and/or drug resistanceRef.
miR122Downregulated in tumors (reduced levels correlate with patient poor prognosis and metastasis) and in human HepG2, HuH-7 and Hep3B HCC cell linesmiR122-overexpressing HCC cells treated with DOX and vincristine showed reduced levels of P-gp mRNA expression, and MRP1 mRNA and protein levelsAdenovirus-transduced cells to overexpress miR122 became more sensitive to DOX- and vincristine-induced death[12,14]
miR27aLow in drug-resistant Bel-7402 cellsNegatively correlated with P-gp levels. Upregulation of miR27a reduced P-gp mRNA and protein expressionCells transfected to overexpress miR27a sensitized resistant cells to 5-FU, mitomycin and DOX[17]
miR503Downregulated 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 drugsCells 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]
miR375Downregulated in patient tumor tissues and cells lines (HepG2, HuH-7, Hep3B)Delivered within nanoparticles decreased P-gp protein expressionDelivered within nanoparticles improved DOX antitumor effect, prevented tumor cell growth in vitro and in vivo[21,22,24]
miR133aDownregulated in patient tumor tissues (its low expression correlated with poor differentiated tumors) and in HepG2, SMMC-77231, Hep3B, HuH-7 HCC cellsThrough its binding to the 3’UTR of ABCC1 gene specifically downregulated MRP1 expressionmiR133a-overexpressing HepG2 cells were more sensitive to DOX-induced death[27,28]
miR326Downregulated in human tissues (its low expression correlated with tumor progression and lymph node metastasis) and in HepG2, SMMC-77231, Hep3B, HuH-7 HCC cellsSpecifically targeted MRP1 expression through its binding to the 3’UTR of ABCC1 genemiR326-overexpressing HepG2 cells were more sensitive to DOX than control cells[28,31]
miR223Downregulated in HCC patient sera and liver biopsiesThrough its binding to the 3’UTR of ABCB1 gene, it specifically downregulated P-gp expressionmiR223 overexpression increased sensitivity to DOX and paclitaxel in SMMC-7721 and HepG2 cells[34,35]
miR491-3pDownregulated 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]
miR183Overexpressed in liver tissues and in drug-resistant Bel-7402 cellsPositively correlated with P-gp and MRP2 protein expressionConferred resistance to 5-FU in Bel-7402 cells[41,42]