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Medientyp: E-Artikel Titel: Murine MTHFD1‐synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases growth of colorectal tumors Beteiligte: Lévesque, Nancy; Christensen, Karen E.; Van Der Kraak, Lauren; Best, Ana F.; Deng, Liyuan; Caldwell, Don; MacFarlane, Amanda J.; Beauchemin, Nicole; Rozen, Rima Erschienen: Wiley, 2017 Erschienen in: Molecular Carcinogenesis Sprache: Englisch DOI: 10.1002/mc.22568 ISSN: 1098-2744; 0899-1987 Schlagwörter: Cancer Research ; Molecular Biology Entstehung: Anmerkungen: Beschreibung: <jats:sec><jats:label /><jats:p>The common R653Q variant (∼20% homozygosity in Caucasians) in the synthetase domain of the folate‐metabolizing enzyme MTHFD1 reduces purine synthesis. Although this variant does not appear to affect risk for colorectal cancer, we questioned whether it would affect growth of colorectal tumors. We induced tumor formation in a mouse model for MTHFD1‐synthetase deficiency (<jats:italic>Mthfd1S</jats:italic><jats:sup>+/−</jats:sup>) using combined administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild‐type and <jats:italic>Mthfd1S</jats:italic><jats:sup>+/−</jats:sup> mice. Tumor size was significantly smaller in <jats:italic>MthfdS<jats:sup>+/−</jats:sup></jats:italic> mice, particularly in males. A reduction in the proliferation of <jats:italic>MthfdS<jats:sup>+/−</jats:sup></jats:italic> mouse embryonic fibroblast cell lines, compared with wild‐type lines, was also observed. Tumor number was not influenced by genotype. The amount of inflammation observed within tumors from male <jats:italic>Mthfd1S</jats:italic><jats:sup>+/−</jats:sup> mice was lower than that in wild‐type mice. Gene expression analysis in tumor adjacent normal (pre‐neoplastic) tissue identified several genes involved in proliferation (<jats:italic>Fosb, Fos, Ptk6, Esr2, Atf3</jats:italic>) and inflammation (<jats:italic>Atf3, Saa1</jats:italic>, <jats:italic>TNF‐α</jats:italic>) that were downregulated in <jats:italic>MthfdS<jats:sup>+/−</jats:sup></jats:italic> males. In females, <jats:italic>MthfdS<jats:sup>+/−</jats:sup></jats:italic> genotype was not associated with these gene expression changes, or with differences in tumor inflammation. These findings suggest that the mechanisms directing tumor growth differ significantly between males and females. We suggest that restriction of purine synthesis, reduced expression of genes involved in proliferation, and/or reduced inflammation lead to slower tumor growth in MTHFD1‐synthetase deficiency. These findings may have implications for CRC tumor growth and prognosis in individuals with the R653Q variant. © 2016 Wiley Periodicals, Inc.</jats:p></jats:sec>