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- Title
MicroRNA-552 deficiency mediates 5-fluorouracil resistance by targeting SMAD2 signaling in DNA-mismatch-repair-deficient colorectal cancer.
- Authors
Zhao, Ping; Ma, Yu-guang; Zhao, Yang; Liu, Di; Dai, Zhi-jun; Yan, Chang-you; Guan, Hai-tao
- Abstract
<bold>Objective: </bold>Although DNA-mismatch-repair-deficient (dMMR) status and aberrant expression of miRNAs are both critically implicated in the pathogenesis of resistance to 5-fluorouracil (5-FU) in colorectal cancer (CRC), whether these two factors regulate tumor response to 5-FU in a coordinated manner remains unknown. This study is designed to elucidate whether changes in miR-552 expression levels correlate to 5-FU-based chemoresistance in CRC, and to further identify the putative targets of miR-552 using multiple approaches.<bold>Methods: </bold>miR-552 expression was assessed in 5-FU-resistant CRC tissues and cells using real-time PCR. Effects of miR-552 dysregulation on 5-FU resistance in CRC cells were determined by measuring cell viability, apoptosis and in vivo oncogenic capacity. Finally, we studied the posttranscriptional regulation of SMAD2 by miR-552 using multiple approaches including luciferase reporter assay, site-directed mutagenesis and transient/stable transfection, at molecular and functional levels.<bold>Results: </bold>Expression of miR-552 was significantly downregulated in 5-FU-resistant CRC tissues and cells, and this downregulation, regulated by dMMR, was associated with poor postchemotherapy prognosis. Functionally, forced expression of miR-552 exhibited a proapoptotic effect and attenuated 5-FU resistance, whereas inhibition of miR-552 expression potentiated 5-FU resistance in CRC cells. Mechanically, miR-552 directly targeted the 3'-UTR of SMAD2, and stable ablation of SMAD2 neutralized the promoting effects of miR-552 deficiency-induced 5-FU resistance.<bold>Conclusions: </bold>Overall, our findings have revealed a critical role of miR-552/SMAD2 cascade in modulating cellular response to 5-FU chemotherapy. miR-552 may act as an efficient mechanistic link synchronizing dMMR and 5-FU resistance in CRC.
- Subjects
COLORECTAL cancer; SITE-specific mutagenesis; DIHYDROPYRIMIDINE dehydrogenase; MICRORNA; FLUOROURACIL; CELL survival; RNA metabolism; COLON tumors; BIOLOGICAL models; DNA; RECTUM tumors; ANIMAL experimentation; CELLULAR signal transduction; CARRIER proteins; MICE; PHARMACODYNAMICS
- Publication
Cancer Chemotherapy & Pharmacology, 2019, Vol 84, Issue 2, p427
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-019-03866-7