MicroRNA: a prognostic biomarker and a possible druggable target for circumventing multidrug resistance in cancer chemotherapy

Kenneth Kw To

doi:10.1186/1423-0127-20-99

Abstract

Multidrug resistance (MDR) is a major obstacle to successful cancer treatment. It is often associated with an increased efflux of a variety of structurally unrelated anticancer drugs by ATP-binding cassette (ABC) transporters including P-gp, ABCG2 and MRP1. MicroRNAs (miRNAs) are small non-coding RNAs that govern posttranscriptional regulation of target genes by interacting with specific sequences in their 3′ untranslated region (3′UTR), thereby promoting mRNA degradation or suppressing translation. Accumulating evidence suggests that alterations in miRNAs contribute to resistance to anticancer drugs. While miRNAs are well-known to be dysregulated in cancer, recent literature revealed that miRNA levels in biological samples may be correlated with chemotherapy response. This review summarized the coordinated network by which miRNA regulated MDR transporters. The usefulness of miRNAs as prognostic biomarkers for predicting chemotherapeutic outcome is discussed. MiRNAs may also represent druggable targets for circumvention of MDR.

Highlights

Resistance to anticancer drugs remains a major unresolved obstacle to successful chemotherapy
The most common and extensively studied mechanism is the overexpression of the energy-dependent ATP-binding cassette (ABC) drug efflux transporters such as P-glycoprotein (MDR-1/P-gp/ABCB1), multidrug
Gene regulation by miRNAs is mediated by the formation of imperfect hybrids with the 3′untranslated region (3′UTR) sequences of the target mRNAs, leading to mRNA degradation and/or translational inhibition [3]

Summary

Introduction

Resistance to anticancer drugs remains a major unresolved obstacle to successful chemotherapy. Not long after the identification of the miRNAs regulating ABCG2, a few miRNAs directly repressing ABCB1 through binding to its 3′UTR (miR-27a, -451, -296, -298, -338, -1253) have been reported (Table 1; [14,26,27]) Downregulation of these miRNAs in resistant cancer cells leads to drug resistance. The SNP (829C → T) near the miR-24 binding site in the 3′UTR of human dihydrofolate reductase (DHFR) was found to interfere with miR-24-mediated repression, resulting in DHFR overexpression and methotrexate resistance Similar to this 3′UTR polymorphism, the phenomenon of alternative transcript polyadenylation (leading to shortening of 3′UTR) described above for the regulation of ABCG2 (Figure 1) [17] is another example where miRNA-mediated gene regulation can intersect with genetic variation to mediate anticancer drug resistance. It appears that these hurdles have to be overcome before an effective miRNA-targeted strategy can be realized for circumvention of anticancer drug resistance in cancer patients

Conclusions

Goldman B

Hammond SM

Findings

12. Fojo T