An Integrating Approach for Genome-Wide Screening of MicroRNA Polymorphisms Mediated Drug Response Alterations

Wang, Xianyue; Jiang, Hong; Wu, Wei; Zhang, Rongxin; Wu, Lingxiang; Chen, Huan; Nie, Yumin; Shao, Jiaofang; Li, Yan; Lü, Xue; Lv, Sali; Wang, Qh; Hu, Jie

doi:10.1155/2017/1674827

Cited by 5 publications

(3 citation statements)

References 36 publications

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“…Upon significant differences, Mir2Drug associates these SNPs as either direct or indirect drug targets. Therefore, it provides comprehensive annotation information on miRSNP belonging to drug target genes (Wang X. et al, 2017 ).…”

Section: Mirsnpmentioning

confidence: 99%

microRNAs Make the Call in Cancer Personalized Medicine

Detassis

Grasso

Vescovo

et al. 2017

Front. Cell Dev. Biol.

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Since their discovery and the advent of RNA interference, microRNAs have drawn enormous attention because of their ubiquitous involvement in cellular pathways from life to death, from metabolism to communication. It is also widely accepted that they possess an undeniable role in cancer both as tumor suppressors and tumor promoters modulating cell proliferation and migration, epithelial-mesenchymal transition and tumor cell invasion and metastasis. Moreover, microRNAs can even affect the tumor surrounding environment influencing angiogenesis and immune system activation and recruitment. The tight association of microRNAs with several cancer-related processes makes them undoubtedly connected to the effect of specific cancer drugs inducing either resistance or sensitization. In this context, personalized medicine through microRNAs arose recently with the discovery of single nucleotide polymorphisms in the target binding sites, in the sequence of the microRNA itself or in microRNA biogenesis related genes, increasing risk, susceptibility and progression of multiple types of cancer in different sets of the population. The depicted scenario implies that the overall variation displayed by these small non-coding RNAs have an impact on patient-specific pharmacokinetics and pharmacodynamics of cancer drugs, pushing on a rising need of personalized treatment. Indeed, microRNAs from either tissues or liquid biopsies are also extensively studied as valuable biomarkers for disease early recognition, progression and prognosis. Despite microRNAs being intensively studied in recent years, a comprehensive review describing these topics all in one is missing. Here we report an up-to-date and critical summary of microRNAs as tools for better understanding personalized cancer biogenesis, evolution, diagnosis and treatment.

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Section: Mirsnpmentioning

confidence: 99%

microRNAs Make the Call in Cancer Personalized Medicine

Detassis

Grasso

Vescovo

et al. 2017

Front. Cell Dev. Biol.

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“…In animals, the miRNA::mRNA base-pairing is usually limited to the so-called “seed region”, i.e., the miRNA sequence (often between the 2 nd and the 8 th nucleotide) that provides most of the pairing specificity [7]. The mRNA region complementary to the miRNA seed is called “seed match” and its genetic alteration could have important phenotypic consequences in terms of risk of developing cancer [8], myocardial infarction [9] and chemo-resistance [10]. The identification of the miRNA:mRNA pairing has been widely addressed using publically available bioinformatics tools followed by experimental validation [11].…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel functional miR-143-5p recognition element in the Cystic Fibrosis Transmembrane Conductance Regulator 3’UTR

et al. 2018

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MicroRNAs (miRNAs) are small non-coding RNAs involved in regulation of gene expression. They bind in a sequence-specific manner to miRNA recognition elements (MREs) located in the 3′ untranslated region (UTR) of target mRNAs and prevent mRNA translation. MiRNA expression is dysregulated in cystic fibrosis (CF), affecting several biological processes including ion conductance in the epithelial cells of the lung. We previously reported that miR-143 is up-regulated in CF bronchial brushings compared to non-CF. Here we identified two predicted binding sites for miR-143-5p (starting at residues 558 and 644) on the CFTR mRNA, and aimed to assess whether CFTR is a true molecular target of miR-143-5p. Expression of miR-143-5p was found to be up-regulated in a panel of CF vs non-CF cell lines (1.7-fold, P = 0.0165), and its levels were increased in vitro after 20 hours treatment with bronchoalveolar lavage fluid from CF patients compared to vehicle-treated cells (3.3-fold, P = 0.0319). Luciferase assays were performed to elucidate direct miRNA::target interactions and showed that miR-143-5p significantly decreased the reporter activity when carrying the wild-type full length sequence of CFTR 3′UTR (minus 15%, P = 0.005). This repression was rescued by the disruption of the first, but not the second, predicted MRE, suggesting that the residue starting at 558 was the actual active binding site. In conclusion, we here showed that miR-143-5p modestly but significantly inhibits CFTR, improving the knowledge on functional MREs within the CFTR 3′UTR. This could lead to the development of novel therapeutic strategies where miRNA-mediated CFTR repression is blocked thereby possibly increasing the efficacy of the currently available CFTR modulators.

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“…The miRNAs are also known to regulate genes involved in response to drug‐induced hepatocyte injury 4 and death 5 . Dysfunction in this post‐transcriptional regulation of pharmacogenes appears to contribute to the interindividual variability in drug response phenotypes 6–9 . Dysfunction can be caused by genetic variants in miRNA binding sites (mirSNPs) that increase or decrease the miRNA binding strength and, therefore, alter the abundance of the functional protein.…”

mentioning

confidence: 99%

Mapping the miRNA‐mRNA Interactome in Human Hepatocytes and Identification of Functional mirSNPs in Pharmacogenes

Powell

Ipe

et al. 2021

Clin Pharma and Therapeutics

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MiRNAs regulate the expression of hepatic genes involved in pharmacokinetics and pharmacodynamics. Genetic variants affecting miRNA binding (mirSNPs) have been associated with altered drug response, but previously used methods to identify miRNA binding sites and functional mirSNPs in pharmacogenes are indirect and limited by low throughput. We utilized the high‐throughput chimeric‐eCLIP assay to directly map thousands of miRNA‐mRNA interactions and define the miRNA binding sites in primary hepatocytes. We then used the high‐throughput PASSPORT‐seq assay to functionally test 262 potential mirSNPs with coordinates overlapping the identified miRNA binding sites. Using chimeric‐eCLIP, we identified a network of 448 miRNAs that collectively target 11,263 unique genes in primary hepatocytes pooled from 100 donors. Our data provide an extensive map of miRNA binding of each gene, including pharmacogenes, expressed in primary hepatocytes. For example, we identified the hsa‐mir‐27b‐DPYD interaction at a previously validated binding site. A second example is our identification of 19 unique miRNAs that bind to CYP2B6 across 20 putative binding sites on the transcript. Using PASSPORT‐seq, we then identified 24 mirSNPs that functionally impacted reporter mRNA levels. To our knowledge, this is the most comprehensive identification of miRNA binding sites in pharmacogenes. Combining chimeric‐eCLIP with PASSPORT‐seq successfully identified functional mirSNPs in pharmacogenes that may affect transcript levels through altered miRNA binding. These results provide additional insights into potential mechanisms contributing to interindividual variability in drug response.

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An Integrating Approach for Genome-Wide Screening of MicroRNA Polymorphisms Mediated Drug Response Alterations

Cited by 5 publications

References 36 publications

microRNAs Make the Call in Cancer Personalized Medicine

microRNAs Make the Call in Cancer Personalized Medicine

Identification of a novel functional miR-143-5p recognition element in the Cystic Fibrosis Transmembrane Conductance Regulator 3’UTR

Mapping the miRNA‐mRNA Interactome in Human Hepatocytes and Identification of Functional mirSNPs in Pharmacogenes

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