Table 1 miRNAs reported to regulate MDR transporters to mediate chemoresistance
Transporter targets | MicroRNA dysregulation | Direct binding site(s) on target gene? | Prediction by miRNA database(s) | Identification method | Cancer type | Study in patient samples? | Reference |
|---|---|---|---|---|---|---|---|
ABCB1 | miR-27a↑ | Indirect regulation-targets HIPK2 (a transcriptional corepressor that inhibits HIF-1αactivity), thereby indirectly activating MDR-1/P-gp | TargetScan suggests that HIPK2 is a possible target for miR-27a | Serendipitous testing of miR-27a in the development of drug resistance in ovarian cancer cell lines | Ovarian | No | [23] |
miR-27a↑, miR-451↑ | Likely indirect regulation | -- | miRNA microarray profiling | Ovarian | No | [24] | |
(i.e. not via ABCB1 3′UTR) | |||||||
miR-27a & miR-451 mimics elevate ABCB1 mRNA | |||||||
miR-122↓ | NO attempt to verify binding of miR-122 on MDR-1 3′UTR | NOT performed | Serendipitous testing of downregulation of MDR related genes (MDR-1, MRP & GST-π) by miR-122 | Hepatocellular carcinoma | No | [25] | |
miR-296↑ | Likely indirect regulation | -- | miRNA microarray profiling | Esophageal squamous cell carcinoma | Yes | [26] | |
(i.e. not via ABCB1 3′UTR) | |||||||
- antagomir of miR-296 decrease ABCB1 promoter activity | |||||||
miR-298↓ | Confirmed by luciferase reporter assay / MDR-1 3′UTR miRNA site deletion / miRNA mimic / miRNA inhibitor | miRanda | miRNA microarray | Breast cancer | No | [27] | |
miR-1253↓ | |||||||
let-7 g↓ | Indirect regulation |  |  | Ovarian | Yes | [28] | |
• targets IMP-1 (a RNA-binding protein) | |||||||
• IMP-1 is known to stabilize MDR1 mRNA | |||||||
• loss of let-7 g commonly observed in various cancers could therefore allow overexpression of IMP-1 and stability of MDR-1/P-gp to mediate drug resistance | |||||||
ABCC1 | miR-326↓ | Confirmed by luciferase reporter assay / ABCC1 3′UTR miRNA site deletion / gene expression analysis after transfection with miR-326 mimic | TargetScan | miRNA microarray profiling | Breast cell line + early/advanced breast cancer tissue | Yes | [29] |
miR-1291↓ | Confirmed by luciferase reporter/miRNA mimic/miRNA inhibitor | RNAhybrid, TargetScan, miRanda, PITA | Serendipitous study of the role of SNORA34 to generate miR-1291, which subsequently controls chemosensitivity | Pancreatic | No | [30] | |
ABCC2 | miR-297↓ | Luciferase reporter/miRNA mimic/miRNA inhibitor | TargetScan | miRNA microarray profiling | Colorectal | Yes | [31] |
ABCC3 & ABCC6 | miR-9*↓ | Indirect regulation – | PicTar, TargetScan, miRBase, miRanda | Serendipitous study of the role of ID4 in chemoresistance of induced glioma stem cells | Glioma | Yes | [32] |
• miR-9* is a SOX2-targeting miRNA | |||||||
• novel ID4-miR-9*-SOX2-ABCC3/ABCC6 regulatory pathway | |||||||
• ID4 was found to confer chemoresistance to glioma stem cells by inducing the expression of two SOX2-mediated ABC transporters (ABCC3 & ABCC6) through suppression of miR-9* | |||||||
ABCG2 | miR-212↓, miR-328↓ | Effect of miR-212 & miR-328 on ABCG2 expression was evaluated by gene expression analysis and luciferase reporter gene assay | -- | miRNA microarray profiling in imatinib-selected K562 cells | Leukemia (short-term /long-term imatinib treatmet) | No | [33] |
miR-328↓ | Confirmed by luciferase reporter assay / ABCG2 3′UTR miRNA site deletion / miRNA mimic / miRNA antagomir | PITA; TargetScan | Bioinformatic analysis | Breast | No | [18] | |
miR-328↓ | Confirmed by luciferase reporter assay / gene expression analysis after transfection with miRNA mimic or inhibitor | -- | miRNA microarray analysis on SP# vs non-SP# cells | Colorectal cell lines + primary biopsies | Yes | [34] | |
miR-328↓, miR-519c↓, miR-520 h↓ | Confirmed by luciferase reporter assay with site-directed gene mutagenesis / gene expression analysis after transfection with miRNA mimics | TargetScan, PITA, MicroCosm Targets, RNA22 | Bioinformatic analysis | Breast, Stem-like cells from human retinoblastoma | No | [35] | |
miR-519c (shortening of ABCG2 3′UTR escape miR-519c repression) | Confirmed by luciferase reporter assay with site-directed gene mutagensis on ABCG2 3′UTR miRNA site / gene expression analysis after transfection with miRNA mimics or inhibitor | miRBase TARGETS, RNAHybrid, UTRScan program | Bioinformatic analysis | Colon | No | ||
miR-520 h↓ | Confirmed by luciferase reporter assay +/- miRNA mimic & inhibitor | PicTar, miRanda, TargetScan | miRNA microarray profiling of CD34+ hematopoietic cells | Leukemia | No | [36] | |
miR-520 h↓ | Confirmed by gene expression analysis after miRNA mimic transfection | miRanda, TargetScan, TarBase | Bioinformatic analysis | Pancreatic | No | [37] | |
miR-181a↓ | Confirmed by luciferase reporter assay and gene expression analysis +/- miRNA mimic & inhibitor | RNAhybrid | miRNA microarray analysis to compare sensitive and resistant cells | Breast | No | [38] | |
|  | miR-487a↓ | Confirmed by luciferase reporter assay and gene expression analysis +/- miRNA mimic & inhibitor Confirmed by luciferase reporter assay and gene expression analysis +/- miRNA mimic & inhibitor | TargetScan, PITA, RNAhybrid | Bioinformatic analysis | Breast | No | [39] |