Journal article
microRNAs miR-27a and miR-27b Directly Regulate Liver Dihydropyrimidine Dehydrogenase Expression through Two Conserved Binding Sites
Molecular cancer therapeutics, Vol.13(3), pp.742-751
03/01/2014
DOI: 10.1158/1535-7163.MCT-13-0878
PMCID: PMC3954441
PMID: 24401318
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 miR27a or miR-27b was 4.4 mu mol/L (both), significantly lower than that for cells expressing a nontargeting (scramble) control miRNA (14.3 mu mol/L; P 3.3 x 10(-5) and P = 1.5 x 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 miR27b (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. (C)2014 AACR.
Details
- Title: Subtitle
- microRNAs miR-27a and miR-27b Directly Regulate Liver Dihydropyrimidine Dehydrogenase Expression through Two Conserved Binding Sites
- Creators
- Steven M. Offer - Mayo ClinicGabriel L. Butterfield - Mayo ClinicCalvin R. Jerde - Mayo ClinicCroix C. Fossum - Mayo ClinicNatalie J. Wegner - Mayo ClinicRobert B. Diasio - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.13(3), pp.742-751
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/1535-7163.MCT-13-0878
- PMID
- 24401318
- PMCID
- PMC3954441
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Number of pages
- 10
- Grant note
- 5P30 CA15083-37; R01 CA062164; P30 CA015083; R01 CA116964; CA116964; CA62164 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30CA015083 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 03/01/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984618521002771
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