MicroRNA pharmacogenomics: Post-transcriptional regulation of drug response

Rukov, Jakob Lewin; Shomron, Noam

doi:10.1016/j.molmed.2011.04.003

Cited by 115 publications

(75 citation statements)

References 81 publications

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“…In recent years, accumulating evidence has shown that miRNAs also play important roles in drug response of human cancers. While most studies on drug response focus on individual miRNAs, genome-wide evaluation of each miRNA in the background of the entire miRNome is largely uncharacterized [48]. By functional screening, we identified 22 miRNAs that promote drug sensitivity in liver cancer cells.…”

Section: Discussionmentioning

confidence: 99%

miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression

Zhang

et al. 2015

Cell Res

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Liver and kidney cancers are notorious for drug resistance. Due to the complexity, redundancy and interpatient heterogeneity of resistance mechanisms, most efforts targeting a single pathway were unsuccessful. Novel personalized therapies targeting multiple essential drug resistance pathways in parallel hold a promise for future cancer treatment. Exploiting the multitarget characteristic of microRNAs (miRNAs), we developed a new therapeutic strategy by the combinational use of miRNA and anticancer drugs to increase drug response. By a systems approach, we identified that miR-27b, a miRNA deleted in liver and kidney cancers, sensitizes cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo. Functionally, miR-27b enhances drug response by activating p53-dependent apoptosis and reducing CYP1B1-mediated drug detoxification. Notably, miR-27b promotes drug response specifically in patients carrying p53-wild-type or CYP1B1-high signature. Together, we propose that miR-27b synergizes with anticancer drugs in a defined subgroup of liver and kidney cancer patients.

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Section: Discussionmentioning

confidence: 99%

miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression

Zhang

et al. 2015

Cell Res

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“…Evidence documented that miRNAs play an important role in the modulation of the production of drug metabolizing enzymes and transporters through multi-directional interactions among environmental stimuli, the expression of miRNA molecules and genetic polymorphisms [26][27][28][29][30][31][32][33]. As miRNA expression has been reported to be affected by drugs and since miRNAs themselves may affect drug metabolism and toxicity, miRNA expression possesses a significant potential for affecting drug efficacy and drug safety.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Green

Tolleson

et al. 2015

Biochemical Pharmacology

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Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of −27.5 kcal/mol and −23.3 kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsamiR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression.

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“…53,165 Other mechanisms may include variation in nuclear receptors, altered phos phoryl ation and glycosylation states, posttranslational modifications, microRNA and epigenetic control of expression. [166][167][168] Differential regulation of CYP expression may also occur through indirect effects, such as altered hormonal levels.…”

Section: Mechanisms Of Brain Cyp Inductionmentioning

confidence: 99%