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]
Table 2 miRNAs and autophagy in hepatocellular carcinoma cell drug resistance
miRNAExpression Level in HCCEffect on autophagyInvolvement in drug resistanceRef.
miR26a/bDownregulated in tissues and cell lines (HepG2, Hep3B, MHCC97-H and SMCC-7721), also by chemotherapeutic drugs and autophagy inhibitorsInhibited autophagy, by targeting the expression of ULK1, the key initiator of autophagySensitized HepG2 cells and tumors to apoptosis induced by DOX through targeting autophagy[53,54]
miR199a-5pDownregulated in HepG2 and HuH-7 cells and tissues, also by chemotherapeutic drugsInhibited cisplatin-induced autophagy, by interacting with the 3’UTR region of ATG7 transcript (an autophagy related gene)Protected HepG2 and HuH-7 cells from cisplatin-induced resistance[56,58]
miR101Downregulated in cell lines (SMMC-7721, HepG2, Bel-4404, and 97L) and tissues, associated with distant metastasis and related to poor prognosisInhibited autophagy, by reducing STMN1, RAB5A, ATG4D and mTOR expression (involved in the phagosome formation)Sensitized HepG2 cells to apoptosis induced by cisplatin[61,62]
miR216bDownregulated in patient plasma and tissues, related to poor prognosisInhibited autophagy, by targeting . MALAT1 (an oncogenic long non-coding RNA generally upregulated in HCC that modulates chemosensitivity)Sensitized BEL-7402/5-FU resistant cells to 5-FU-, DOX- and mitomycin-induced death[65,66]
miR142-3pDownregulated in tissues, also by sorafenib treatmentInhibited sorafenib-induced autophagy by binding to the 3’-UTR of ATG5 and ATG16L1Sensitized SMCC-7721 and HepG2 cells to sorafenib-induced death[69,70]
miR21Overexpressed in patient tissues and in drug-resistant cellsInhibited autophagy, and downregulated PTEN pathwaymiR21-dependent autophagy inhibition contributed to sorafenib resistance in Huh7 and HepG2 cells and HCC tumors developed in mice[72-74]
miR423-5pOverexpressed in tissues, also elevated in serum of sorafenib-treated patients, and secreted in high levels from sorafenib-treated cellsInduced autophagyProposed as a helpful tool to predict patient response to sorafenib treatment[77,78]