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Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2
Open accessPublished version of a preprint
Abstract
Overexpression of ABCG2 has been reported in cell lines selected for drug resistance and it is widely believed to be important in the clinical pharmacology of anticancer drugs. We and others have previously identified and validated two microRNAs (miRNA; hsa-miR-519c and hsa-miR-520h) targeting ABCG2. In this study, the shortening of the ABCG2 3′ untranslated region (3′UTR) was found to be a common phenomenon in several ABCG2-overexpressing resistant cell lines, which as a result removes the hsa-miR-519c binding site and its repressive effects on mRNA stability and translation blockade, thereby contributing to drug resistance. On the other hand, reduced expression of hsa-miR-520h, previously thought to have allowed ABCG2 overexpression, was found to be caused by the sequestering of the miRNA by the highly expressed ABCG2. In drug-sensitive cells, inhibitors against hsa-miR-519c and hsa-miR-520h could augment the cytotoxic effect of mitoxantrone, suggesting a substantial role for both miRNAs in controlling ABCG2 level and thereby anticancer drug response. However, in drug-resistant cells, altering the levels of the two miRNAs did not have any effect on sensitivity to mitoxantrone. Taken together, these studies suggest that in ABCG2-overexpressing drug-resistant cells, hsa-miR-519c is unable to affect ABCG2 expression because the mRNA lacks its binding site, whereas hsa-miR-520h is sequestered and unable to limit ABCG2 expression. Given the recent observation that a truncated 3′UTR is also observed in ABCG2-overexpressing human embryonic stem cells, our results in drug-resistant cell lines suggest that 3′UTR truncation is a relatively common mechanism of ABCG2 regulation. [Mol Cancer Ther 2009;8(10):2959–68]
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“where miR-519c has been demonstrated to be highly associated with the reversion of MDR by targeting the ABCG2 mRNA.19–21”
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Metadata
- Authors
- To, K. K. W., Robey, R. W., Knutsen, T., Zhan, Z., Ried, T., & Bates, S. E.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- To, Kenneth K.W.
- Venue
- Molecular Cancer Therapeutics
- Published
- 2009-10-01
- Volume
- 8
- Issue
- 10
- Pages
- 2959-2968
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC3680354
- OpenAlex
- W2137545438
- Cited by
- 112
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 7 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 9 · 2015: 6 · 2014: 16 · 2013: 11 · 2012: 13
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC010622)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Keywords
- ABCG2, microRNA regulation, drug resistance, mitoxantrone, mRNA stability, microRNA sequestration, anticancer drug response
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Chromosomes, Human, Drug Screening Assays, Antitumor, Humans, Mitoxantrone, Neoplasm Proteins, RNA, Messenger, Gene Rearrangement, Gene Expression Regulation, Neoplastic, Sequence Analysis, DNA, ATP-Binding Cassette Transporters, Drug Resistance, Neoplasm, 3' Untranslated Regions, Gene Silencing, RNA Stability, MicroRNAs, Cell Line, Tumor
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