The microRNA-429/DUSP4 axis regulates thesensitivity of colorectal cancer cells to nintedanib.

Abstract

Colorectal cancer (CRC) is recognized as one of the most common malignancies, which ranks third among all cancer-related deaths worldwide. Nintedanib is an orally available tyrosine kinase inhibitor that can treat CRC; however, drug resistance to nintedanib leads to unsatisfactory treatments for patients with CRC. The aim of the present study was to explore whether overexpression of miR-429 elevated the sensitivity of CRC cells to nintedanib by downregulating dual specificity protein phosphatase 4 (DUSP4). The nintedanib-resistant CRC cell model was established via the treatment of cells with nintedanib in a dose-dependent manner. Reverse transcription-quantitative PCR was used to detect the expression levels of miR-429 and DUSP4, and to confirm the transfection efficiency of miR-429 mimic and DUSP4 overexpression plasmid. Cell Counting Kit-8 assay was utilized to measure the inhibition rate of cells. Western blotting was conducted to observe the expression levels of DUSP4 protein, apoptosis-related proteins and proteins related to the JNK signaling pathway. Dual-luciferase reporter assay was performed to evaluate luciferase activity and TUNEL assay was conducted to detect the apoptosis of cells. The results revealed that miR-429 mimic elevated the sensitivity of CRC cells to nintedanib. Moreover, by ENCORI prediction, DUSP4 was identified as a target gene of miR-429, and overexpression of DUSP4 reversed the inducing effect of miR-429 overexpression on the sensitivity of CRC cells to nintedanib. In conclusion, overexpression of miR-429 may elevate the sensitivity of CRC cells to nintedanib through inhibition of the JNK signaling pathway by targeting DUSP4. These findings may aid in the prevention of drug resistance of CRC cells to nintedanib.