ArticleMolecular cancer therapeutics2014
microRNAs miR-27a and miR-27b directly regulate liver dihydropyrimidine dehydrogenase expression through two conserved binding sites.
Article in Molecular cancer therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.
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Who cites it
50 citing papers in PubMed, 1 synthesis or guideline pooled it, 87 citations in OpenAlex.
- Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update.Clinical pharmacology and therapeutics · 2018Guideline
- Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).Pharmacogenetics and genomics · 2016Trial
- A rare variant in DPYD c.812delT causes severe adverse events of S-1 in a patient with tongue cancer.Cancer chemotherapy and pharmacology · 2026Article
- Association between miRNA expression profiles and polymorphisms of dihydropyrimidine dehydrogenase drug-metabolizing gene in patients with colorectal cancer receiving 5-fluorouracil.Biomedical reports · 2025Article
- Understanding microRNA-Mediated Chemoresistance in Colorectal Cancer Treatment.International journal of molecular sciences · 2025Review
- Article
- Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Article
- GermlineeLife · 2024Article
- GermlinebioRxiv : the preprint server for biology · 2024Article
- The Critical Function of microRNAs in Developing Resistance against 5- Fluorouracil in Cancer Cells.Mini reviews in medicinal chemistry · 2024Review
- Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD.Current drug metabolism · 2024Review
- Genetic Variation in miR-27a Is Associated with Fluoropyrimidine-Associated Toxicity in Patients with Dihydropyrimidine Dehydrogenase Variants after Genotype-Guided Dose Reduction.International journal of molecular sciences · 2023Article
- Fluoropyrimidine‑induced cardiotoxicity in colorectal cancer patients: a prospective observational trial (CHECKPOINT).Oncology reports · 2023Observational
- Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution.ACS pharmacology & translational science · 2022Review
- SNPs in 3'UTR miRNA Target Sequences Associated with Individual Drug Susceptibility.International journal of molecular sciences · 2022Review
- MALAT1-miRNAs network regulate thymidylate synthase and affect 5FU-based chemotherapy.Molecular medicine (Cambridge, Mass.) · 2022Review
- Review
- Review
- A narrative review of genetic factors affecting fluoropyrimidine toxicity.Precision cancer medicine · 2021Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) is the rate-limiting enzyme in the uracil catabolic pathway and has a pivotal role in the pharmacokinetics of the commonly prescribed anticancer drug 5-fluorouracil (5-FU). Deficiency of DPD, whether due to inadequate expression or deleterious variants in DPYD, has been linked to severe toxic responses to 5-FU. Little is known about the mechanisms governing DPD expression in the liver. In this report, we show increased accumulation of RNA-induced silencing complex (RISC) proteins on DPYD mRNA in cells overexpressing the highly homologous microRNAs (miRNA) miR-27a and miR-27b. These miRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells overexpressing miR-27a or miR-27b was 4.4 μmol/L (both), significantly lower than that for cells expressing a nontargeting (scramble) control miRNA (14.3 μmol/L; P = 3.3 × 10(-5) and P = 1.5 × 10(-7), respectively). Mouse liver DPD enzyme activity was inversely correlated with expression levels of miR-27a (R(2) = 0.49; P = 0.0012) and miR-27b (R(2) = 0.29; P = 0.022). A common variant in the hairpin loop region of hsa-mir-27a (rs895819) was also shown to be associated with elevated expression of the miR-27a in a panel of cell lines (P = 0.029) and in a transgenic overexpression model (P = 0.0011). Furthermore, rs895819 was associated with reduced DPD enzyme activity (P = 0.028) in a cohort of 40 healthy volunteers. Taken together, these results suggest that miR-27a and miR-27b expression may be pharmacologically relevant modulators of DPD enzyme function in the liver. Furthermore, our data suggest that rs895819 may be a potential risk allele for 5-FU sensitivity.
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