Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy

Lu, Jianwei; Gao, Chang–Ming; Wu, Jianzhong; Cao, Hongyan; Tajima, Kazuo; Feng, Jifeng

doi:10.1007/s10038-005-0339-4

Cited by 41 publications

(30 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Discussion miRNAs are known to inhibit gene expression by binding to the 3Ј UTR of the target transcript. 3Ј UTR polymorphisms are reported to be associated with various diseases that include hereditary thrombophilia (32), ␣-thalassemia (33), insulin sensitivity (34), urolithiasis (35), human papilloma virus infection (36,15), and increased sensitivity to 5-fluorouracil chemotherapy (37,38). Recently, it has been shown that a G-to-A transition in the 3Ј UTR of the myostatin gene in Texel sheep creates a potential illegitimate miRNA target site, which recruits miR1 and miR206 binding and leads to translational inhibition of the gene, resulting in muscular hypertrophy (39).…”

Section: Cells Expressing Snp-829c3 T Adjacent To the Mir-24 Binding mentioning

confidence: 99%

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance

Mishra¹,

Humeniuk

Mishra

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

391

331

View full text Add to dashboard Cite

MicroRNAs are predicted to regulate Ϸ30% of all human genes by targeting sequences in their 3 UTR. Polymorphisms in 3 UTR of several genes have been reported to affect gene expression, but the mechanism is not fully understood. Here, we demonstrate that 829C3 T, a naturally occurring SNP, near the miR-24 binding site in the 3 UTR of human dihydrofolate reductase (DHFR) affects DHFR expression by interfering with miR-24 function, resulting in DHFR overexpression and methotrexate resistance. miR-24 has a conserved binding site in DHFR 3 UTR. DHFR with WT and 3 UTR containing the 829C3 T mutation were expressed in DG44 cells that lack DHFR. Overexpression of miR-24 in cells with WT DHFR resulted in down-regulation of DHFR protein, whereas no effect on DHFR protein expression was observed in the mutant 3 UTRexpressing cells. Inhibition of endogenous miR-24 with a specific inhibitor led to up-regulation of DHFR in WT and not in mutant cells. Cells with the mutant 3 UTR had a 2-fold increase in DHFR mRNA half-life, expressed higher DHFR mRNA and DHFR protein, and were 4-fold more resistant to methotrexate as compared with WT cells. SNP-829C3 T, therefore, leads to a decrease in microRNA binding leading to overexpression of its target and results in resistance to methotrexate. We demonstrate that a naturally occurring miRSNP (a SNP located at or near a microRNA binding site in 3 UTR of the target gene or in a microRNA) is associated with enzyme overproduction and drug resistance.3Ј UTR ͉ drug resistance ͉ single nucleotide polymorphism ͉ translational regulation ͉ mRNA stability

show abstract

Section: Cells Expressing Snp-829c3 T Adjacent To the Mir-24 Binding mentioning

confidence: 99%

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance

Mishra¹,

Humeniuk

Mishra

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

391

331

View full text Add to dashboard Cite

show abstract

“…40 Also SNPs in 3'-UTR are associated with human papilloma virus infection, 41 with increased sensitivity to 5-fluorouracil (5FU) chemotherapy 42,43 and with urolithiasis. 44,45 It has been predicted that a target gene can be regulated by more than one microRNA.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics

Mishra¹,

Mishra²,

Banerjee³

et al. 2008

Cell Cycle

191

138

View full text Add to dashboard Cite

MicroRNAs are evolutionarily conserved small non-coding RNAs known to inhibit the translation of proteins by binding to the target transcript in the 3' untranslated region. Functional polymorphisms in 3' UTRs of several genes have been reported to be associated with diseases by affecting gene expression. The mechanism by which these polymorphisms affect gene expression and induce variability in a cell is not well understood. It has been suggested that these polymorphisms may interfere with regulatory elements that bind to untranslated region of a gene. Recently, a novel class of functional polymorphisms termed miRSNPs/polymorphisms was reported. 1,2 defined as a polymorphism present at or near a microRNA binding sites of functional genes that can affect gene expression by interfering with a miRNA function. The work elucidated the mechanism of a functional miRSNP 829C→ T present in 3' UTR of dihydrofolate reductase, an important drug target. The SNP interferes with the miR24 microRNA function and leads to DHFR over expression and methotrexate resistance. In this article we highlight the importance of these miRSNPs or miR-polymorphisms in gene regulation and the mechanism by which these miRSNPs can induce variability in the SNP expressing mutant cell by using drug resistance as an example.

show abstract

“…5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, which catalyzes the irreversible conversion of 5-10-methylene tetrahydrofolate to 5-methyltetrahydrofolate (5). Because decreased activity of MTHFR may result in accumulation of 5-10-methylene tetrahydrofolate and improve the antitumor efficacy of FU, several studies evaluated genetic polymorphisms of MTHFR, with or without genetic polymorphisms of TYMS in patients with advanced gastric cancer, although the clinical data are still controversial (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Folate Intake along with Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase in Patients with Advanced Gastric Cancer

Shitara

Muro

Ito

et al. 2010

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

View full text Add to dashboard Cite

Background: A relationship between dietary folate intake and efficacy of fluorouracil (FU) is supported by preclinical data. Furthermore, there are several reports that evaluated genetic polymorphisms of MTHFR (methylenetetrahydrofolate reductase) or TYMS (thymidylate synthase) and efficacy of FU. However, to our knowledge, there are no reports that evaluate simultaneously the effects of folate intake and genetic polymorphisms on clinical outcome of gastric cancer patients.Methods: We retrospectively analyzed the survival impact of estimated folate intake by a food frequency questionnaire and MTHFR and TYMS polymorphisms in 132 patients with advanced gastric cancer who were treated with first-line FU-based chemotherapy.Results: Median overall survival was 11.3 months (95% confidence interval, 9.4-13.4 mo) and median progression-free survival was 5.2 months (95% confidence interval, 4.1-6.3 mo). Patients with folate intake of >260 μg/day (n = 88) showed longer overall survival compared with low folate intake (n = 44; overall survival, 12.2 versus 8.4 mo). In a multivariate Cox model, patients who had folate intake of >260 μg/day, MTHFR 677 TT polymorphism, and TYMS-3′ untranslated region 6-bp insertion were associated with better survival. Similar tendency was observed in progression-free survival. No interaction was observed between folate intake and favorable genotypes.Conclusion: Folate intake and genetic polymorphisms of MTHFR and TYMS were associated with better clinical outcome by FU-based chemotherapy in advanced gastric cancer.Impact: Our results suggested folate intake and folate-related genetic polymorphisms may play an important role in efficacy of FU-based chemotherapy in advanced gastric cancer. Cancer Epidemiol Biomarkers Prev;

show abstract

Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy

Cited by 41 publications

References 15 publications

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance

MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics

Folate Intake along with Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase in Patients with Advanced Gastric Cancer

Contact Info

Product

Resources

About