Indirect regulatory mechanisms of MDR-1/P-gp by miRNAs. (a) let-7 g downregulation is commonly observed in various cancers. It is known to target the RNA binding protein, IMP-1, which stabilizes MDR-1 mRNA. Therefore, let-7 g loss in resistant cells allows overexpression of IMP-1 and stability of MDR-1/P-gp to mediate drug resistance . (b) Homeodomain-interacting protein kinase-2 (HIPK2) is a known target of miR-27a. HIPK2 has also been reported to inhibit HIF-1α. Increased expression of miR-27a in resistant cells leads to downregulation of HIPK2, which indirectly allows HIF-1α-mediated stimulation of MDR-1/P-gp and chemoresistance . (c) A hypothetical miRNAs-DNA methylation machinery-MDR-1 promoter methylation pathway. Increased expression of these miRNAs in resistant cells represses various DNA methylation mediators, thereby facilitating MDR-1 promoter demethylation and increasing P-gp efflux activity to mediate chemoresistance.