Thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer and normal mucosa in patients

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Abstract
To compare thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene polymorphism and expression in colorectal cancer (CRC), and normal mucosa in chemotherapy-naïve patients. TS, DPD and TP mRNA expression was analysed by real-time reverse-transcription polymerase chain reaction in primary CRC and adjacent normal tissues from 53 patients with glyceraldehyde-3-phosphate dehydrogenase as housekeeping gene. TS promoter (TSER and C/G SNP) and DPD IVS14+1G>A genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism assays. Moreover, the correlation between TS, DPD and TP expression and cytotoxicity of 5-fluorouracil was evaluated in Colo 320, HT-29, CaCo-2 and SW620 human CRC cell lines. TP and DPD mRNA expression was significantly different in tumour and normal tissue (7.51±13.50 vs. 1.10±0.57, P<0.05 and 0.60±0.63 vs. 1.17±0.55, P<0.0001, respectively), whereas no differences were observed in TS mRNA levels. High-grade, undifferentiated tumours (WHO grade 3) had significantly higher mRNA levels of TS with respect to moderately differentiated (WHO grade 2) carcinomas (0.38±0.37 vs. 0.00±0.44, respectively; P<0.05). Noteworthy, TS mRNA expression was significantly decreased (P<0.05) in homozygous TSER*3G/3G (−0.35±0.35) with respect to pooled homozygous TSER*2/2 and heterozygous TSER*2/3 genotypes (0.14±0.41). In-vitro results showed a higher sensitivity to 5-FU of cell lines with the lowest TS expression. The present results demonstrated significant differences in DPD and TP gene expression between normal mucosa and tumour samples, while TSER*3G/3G and high-grade histology were associated with significant variation in TS gene expression in tumour samples.

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