1. Overexpressing microRNA-34a overcomes ABCG2-mediated drug resistance to 5-FU in side population cells from colon cancer via suppressing DLL1.
- Author
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Xie ZY, Wang FF, Xiao ZH, Liu SF, Tang SL, and Lai YL
- Subjects
- 3' Untranslated Regions, Animals, Calcium-Binding Proteins genetics, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Down-Regulation genetics, Female, Humans, Membrane Proteins genetics, Mice, Mice, Inbred NOD, Mice, SCID, MicroRNAs genetics, RNA, Messenger metabolism, Signal Transduction genetics, Transfection, Tumor Burden drug effects, Tumor Burden genetics, Xenograft Model Antitumor Assays, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Calcium-Binding Proteins metabolism, Colonic Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, Fluorouracil administration & dosage, Fluorouracil pharmacology, Membrane Proteins metabolism, MicroRNAs metabolism, Neoplasm Proteins metabolism, Side-Population Cells drug effects
- Abstract
Colon cancer side population (SP) cells are a small subset of cancer cells that have cancer stemness capacity and enhanced drug resistance. ABCG2 is a multidrug resistance-related protein in SP cells and has been demonstrated to be regulated by Notch signalling pathway. Recently, microRNAs are reported to play a critical role in SP cell fate. However, their role in ABCG2-mediated drug resistance in colon cancer SP cells remains unclear. In the current study, the different expressions of miR-552, miR-611, miR-34a and miR-5000-3p were compared within SP and non-SP cells, which were separated from human colon cancer cell lines (SW480 and LoVo). We found that miR-34a was significantly down-regulated in SP cells and that overexpressing miR-34a overcame drug resistance to 5-fluorouracil (5-FU). The luciferase reporter assay indicated that miR-34a negatively regulated DLL1, a ligand of Notch signalling pathway, via binding with 3'-untranslated region of its messenger RNA. In addition, overexpressing miR-34a overcame ABCG2-mediated resistance to 5-FU via DLL1/Notch pathway in vitro, and suppressed tumour growth under 5-FU treatment in vivo. In conclusion, our findings suggest that miR-34a acts as a tumour suppressor via enhancing chemosensitivity to 5-FU in SP cells, which provides a novel therapeutic target in chemotherapy-resistant colon cancer., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)
- Published
- 2020
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