MicroRNA-552 deficiency mediates 5-fluorouracil resistance by targeting SMAD2 signaling in DNA-mismatch-repair-deficient colorectal cancer
Objective 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 rem...
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Veröffentlicht in: | Cancer chemotherapy and pharmacology 2019-08, Vol.84 (2), p.427-439 |
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Sprache: | eng |
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Zusammenfassung: | Objective
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.
Methods
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.
Results
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.
Conclusions
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. |
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ISSN: | 0344-5704 1432-0843 |
DOI: | 10.1007/s00280-019-03866-7 |