Abstract
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.
Highlights
Colorectal cancer (CRC) is one of the common digestive tract malignancies, and is the third most commonly diagnosed cancer and the fourth cause of cancer death worldwide[1]
Our results demonstrate that a polymorphism rs3742106 in the 3′-UTR of ATP-binding cassette subfamily C member 4 (ABCC4) gene is significantly related to the efficacy of 5-FU/capecitabine-based chemotherapy in colorectal cancer (CRC)
We find that a polymorphism rs3742106 in the 3′-UTR of ABCC4 gene is significantly related to the efficacy of 5-FU and capecitabine-based chemotherapy in CRC
Summary
We find that a polymorphism rs3742106 in the 3′-UTR of ABCC4 gene is significantly related to the efficacy of 5-FU and capecitabine-based chemotherapy in CRC. We discover a novel polymorphism rs3742106 in the 3′-UTR of ABCC4 gene leads to individual efficacy of 5-FU- and capecitabine-based chemotherapy in CRC This polymorphism affects the expression of ABCC4 protein on cancer cells through altering the inhibitory role of miR-3190-5p. We provide evidences to support the conclusion that a polymorphism rs3742106 in the 3′-UTR of ABCC4 through altering the binding of miR-3190-5p to ABCC4 mRNA leads to disrupted expression of ABCC4, intracellular concentration of 5-FU, and individual response to 5-FU and capecitabine chemotherapy in CRC. While in the patients with G/G genotype, ABCC4 is overexpressed on cancer cells and intracellular concentration of 5-FU is decreased, so that the drug resistance is elevated These findings provide a novel molecular marker for individual chemotherapy of 5-FU- and capecitabine-based in CRC, as well as the new regulatory mechanism of polymorphism and miRNA in the expression of ABCC4
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