Murine MTHFD1-synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases growth of colorectal tumors.
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 (Mthfd1S+/-) using combined administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S+/-mice. Tumor size was significantly smaller in MthfdS+/-mice, particularly in males. A reduction in the proliferation of MthfdS+/-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 Mthfd1S+/-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 (Fosb, Fos, Ptk6, Esr2, Atf3) and inflammation (Atf3, Saa1, TNF-α) that were downregulated in MthfdS+/-males. In females, MthfdS+/-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.
Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Nancy
N
Lévesque
Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Karen E
KE
Christensen
Departments of Biochemistry, Goodman Cancer Research Centre, Medicine and Oncology, McGill University, Montreal, Quebec, Canada.
Lauren
L
Van Der Kraak
Department of Mathematics and Statistics, McGill University, Montreal, Quebec, Canada.
Ana F
AF
Best
Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Liyuan
L
Deng
Nutrition Research Division, Health Canada, Ottawa, Ontario, Canada.
Don
D
Caldwell
Nutrition Research Division, Health Canada, Ottawa, Ontario, Canada.
Amanda J
AJ
MacFarlane
Departments of Biochemistry, Goodman Cancer Research Centre, Medicine and Oncology, McGill University, Montreal, Quebec, Canada.
Nicole
N
Beauchemin
Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Rima
R
Rozen
D000619:Aminohydrolases / Q000172:deficiency*; D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D016264:Dextran Sulfate / Q000009:adverse effects; D005260:Female; D005574:Formate-Tetrahydrofolate Ligase / Q000172:deficiency*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000172:deficiency*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D009097:Multienzyme Complexes / Q000172:deficiency*; D064251:Multifunctional Enzymes / Q000172:deficiency*; D020641:Polymorphism, Single Nucleotide
D015778:Minor Histocompatibility Antigens; C000622271:Mthfd1 protein, mouse; D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D016264:Dextran Sulfate; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D045064:Methenyltetrahydrofolate Cyclohydrolase; D005574:Formate-Tetrahydrofolate Ligase; D001397:Azoxymethane
AOM-DSS; MTHFD1; carcinogenesis; colorectal cancer; folate metabolism