Exploiting a novel miR-519c–HuR–ABCG2 regulatory pathway to overcome chemoresistance in colorectal cancer
Abstract
Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. While surgery remains the mainstay of treatment for early stage CRC, adjuvant chemotherapy is usually given to reduce the risk of recurrence after colectomy. Overexpression of a multidrug resistance (MDR) transporter ABCG2 in vitro has been shown to cause resistance to 5-fluorouracil (5-FU) and irinotecan, components of the most commonly adopted regimens for treating CRC. Both anticancer drugs are known ABCG2 substrates. An effective way to predict drug response may provide guidance for better cancer treatment. We investigated the effect of ABCG2 dysregulation on cancer cell sensitivity to chemotherapy using pairs of snap-frozen paraffin-embedded archival blocks of human colorectal cancer tissues and their matched non-cancerous colon tissues from CRC patients. In CRC patients responding to chemotherapy, the tumors were found to have remarkable lower ABCG2 expression than the adjacent normal colon tissues. On the contrary, the tumors from patients not responding to 5-FU-based chemotherapy have higher ABCG2 level than the adjacent normal tissues. The high ABCG2 expression in the tumor is associated with the concomitant overexpression of the mRNA binding protein HuR but a low expression of miR-519c because miR-519c is known to target both ABCG2 and HuR. Further investigation in CRC cell lines revealed that the ABCG2 overexpression was caused by an interplay between miR-519c, HuR and the length of the 3' untranslated region (UTR) of ABCG2. These parameters may be further developed as useful biomarkers to predict patient response to adjuvant chemotherapy. Besides being predictive biomarkers, the microRNAs and mRNA binding protein identified may also be potential drug targets for modulating ABCG2 to combat resistance in CRC chemotherapy.
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miR-519c is highly associated with the reversion of multidrug resistance by targeting ABCG2 mRNA.
“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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- Authors
- To, K. K. W., Leung, W. W., & Ng, S. S. M.
- Affiliations
- Chinese University of Hong Kong (HK)
- Corresponding author
- To, Kenneth K.W.
- Ng, Simon S.M.
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 338
- Issue
- 2
- Pages
- 222-231
- ISSN
- 0014-4827 (ISSN-L)
- OpenAlex
- W1668324142
- Cited by
- 99
- References
- 45
- Citations by year
- 2025: 8 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 15 · 2020: 9 · 2019: 10 · 2018: 10 · 2017: 7 · 2016: 13 · 2015: 1
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- CUHK Direct Grant for Research (2041532, 2041750)
- 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 › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- colorectal cancer, chemoresistance, ABCG2, HuR, 5-fluorouracil, irinotecan, 3' untranslated region, microRNA target regulation, predictive biomarkers, adjuvant chemotherapy response, multidrug resistance, therapeutic target
- MeSH terms
- ELAV-Like Protein 1, ATP Binding Cassette Transporter, Subfamily G, Member 2, Irinotecan, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Camptothecin, Female, Fluorouracil, Humans, Male, Middle Aged, Neoplasm Proteins, RNA, Messenger, Biomarkers, Tumor, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, ATP-Binding Cassette Transporters, Caco-2 Cells, Drug Resistance, Neoplasm, HT29 Cells, 3' Untranslated Regions, MicroRNAs, Cell Line, Tumor
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