Suppression of CYP2C9 by MicroRNA hsa-miR-128-3p in Human Liver Cells and Association with Hepatocellular Carcinoma

Yu, Dianke; Green, Bridgett; Marrone, April K.; Guo, Yongli; Kadlubar, Susan; Lin, Dongxin; Fuscoe, James C.; Pogribny, Igor P.; Ning, Baitang

doi:10.1038/srep08534

Cited by 100 publications

(95 citation statements)

References 41 publications

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“…miRNAs were selected for in silico analysis according to two criteria: (1) miRNAs that down-regulate the cognate genes in a opposite direction, and (2) the free energy of the miRNA:mRNA hybridization was ≤ −20 kcal/mol (based on our previous studies (Yu et al 2015a, c)). As shown in Table 1, 29 miRNAs were predicted to target 97 genes, and detailed prediction results are summarized in Supplementary Table 5.…”

Section: Resultsmentioning

confidence: 99%

“…The pGL3-CU vector that expresses Firefly luciferase and described in our previous reports (Yu et al 2015a, c) was used to create reporter gene plasmids. Firstly, the core 3′-UTRs of CYP3A4 , HNF1A , HNF4A and NR1I2 genes that contain the targeting elements for cognate miRNAs were produced by PCR amplification (all primers or oligonucleotides used in this study were purchased from Integrated DNA Technologies (Coraville, IA), and listed in Supplementary Table 7), and subcloned into the linearized nicked pGL3-CU vector to create CYP3A4-CU, HNF1A-CU, HNF4A-CU, and NR1I2-CU constructs, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have shown that miRNAs influence the expression of drug metabolizing enzymes (DMEs) (Jin et al 2016; Mohri et al 2010; Tsuchiya et al 2006; Wang et al 2017; Yu et al 2010, 2015a, b, c; Zeng et al 2017), which may thereby influence drug efficacy and safety (Koturbash et al 2015). miRNAs have been linked to liver injury and represent candidate biomarkers of liver injury because they are sufficiently stable in a wide range of biofluids, including serum (Baraniskin et al 2012; Chen et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

Gill

et al. 2017

Arch Toxicol

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Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) Hep-aRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6–559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

Gill

et al. 2017

Arch Toxicol

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“…From our previous study, we realized that the free energy associated with binding between miRNAs and mRNA targets is a critical parameter for predicting the interactional efficiency and stability of miRNA/mRNA complexes [23]. Here, in silico target prediction and free energy calculations indicated that hsa-miR-29a-3p could potentially target the coding region of CYP2C19 transcripts with a free energy of −23.3 kcal/mol.…”

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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“…There are also many other experimentally evaluated CYP gene regulation by miRNAs (Table 1), including CYP1A1 by miR-892a (Choi et al, 2012), CYP2C8 by miR-103 and miR-107 , CYP2C9 by miR-128-3p and miR-130b (Rieger et al, 2015;Yu et al, 2015a), CYP2E1 by miR-378 and miR-570 (Mohri et al, 2010;Nakano et al, 2015), CYP2J2 by let-7b (Chen et al, 2012a), and CYP24A1 by miR-125b . The effects of miR130b on endogenous CYP2C9 enzymatic activity (e.g., tolbutamide hydroxylation) in HepaRG cells were demonstrated by selective liquid chromatography-coupled tandem mass spectrometry assay (Rieger et al, 2015).…”

Section: Micrornas In Posttranscriptional Gene Regulationmentioning

confidence: 99%

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

Tian

et al. 2015

Drug Metabolism and Disposition

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Knowledge of drug absorption, distribution, metabolism, and excretion (ADME) or pharmacokinetics properties is essential for drug development and safe use of medicine. Varied or altered ADME may lead to a loss of efficacy or adverse drug effects. Understanding the causes of variations in drug disposition and response has proven critical for the practice of personalized or precision medicine. The rise of noncoding microRNA (miRNA) pharmacoepigenetics and pharmacoepigenomics has come with accumulating evidence supporting the role of miRNAs in the modulation of ADME gene expression and then drug disposition and response. In this article, we review the advances in miRNA pharmacoepigenetics including the mechanistic actions of miRNAs in the modulation of Phase I and II drug-metabolizing enzymes, efflux and uptake transporters, and xenobiotic receptors or transcription factors after briefly introducing the characteristics of miRNA-mediated posttranscriptional gene regulation. Consequently, miRNAs may have significant influence on drug disposition and response. Therefore, research on miRNA pharmacoepigenetics shall not only improve mechanistic understanding of variations in pharmacotherapy but also provide novel insights into developing more effective therapeutic strategies.

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Suppression of CYP2C9 by MicroRNA hsa-miR-128-3p in Human Liver Cells and Association with Hepatocellular Carcinoma

Cited by 100 publications

References 41 publications

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

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

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

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