A polymorphism in ABCC4 is related to efficacy of 5-FU/capecitabine-based chemotherapy in colorectal cancer patients

To investigate the association of microRNA (miRNA) binding-site polymorphisms in the drug transporter genes with the efficacy of 5-Fluorouracil (5-FU)/capecitabine-based chemotherapy in colorectal cancer (CRC), 6 polymorphisms were determined in 432 CRC patients by using DNA sequencing method. The impacts of the polymorphisms on the miRNA-mediated regulation of gene expression were evaluated by using the methods including quantitative real-time PCR, western blotting, and luciferase reporter assays. The effects of miRNA on the intracellular concentration and cytotoxicity of 5-FU in CRC cells were measured by high performance liquid chromatography conjected tandem mass spectrometry (HPLC-MS/MS) and MTT methods, respectively. Statistical analysis showed that a polymorphism rs3742106 in the 3′-UTR of ATP-binding cassette subfamily C member 4 (ABCC4) gene was significantly associated with the efficacy of 5-FU/capecitabine-based chemotherapy in CRC. The patients with T/T genotype had significantly higher response rate than those with G/G and G/T genotypes. The expression of ABCC4 was inhibited by miR-3190-5p through binding to the 3′-UTR of the ABCC4 gene. This regulatory role of miR-3190-5p was disrupted by rs3742106. Furthermore, we found that the intracellular concentration of 5-FU was elevated by miR-3190-5p, and consequently the sensitivity of CRC cells to 5-FU was also enhanced. Rs3742106 might be regarded as a genetic biomarker for individualized use of 5-FU and capecitabine in CRC.