title: Differential gene expression and methylation in the retinoid/PPARA pathway and of tumor suppressors may modify intestinal tumorigenesis induced by low folate in mice.
abstract: METHODS
  Inadequate folate intake increases risk for colorectal cancer. We previously showed that low-folate diets induced intestinal tumors in BALB/c mice, but not in C57BL/6 mice. We suggested that DNA damage, altered methylation, and reduced apoptosis could contribute to tumorigenesis in this model.
  
  
  RESULTS
  To identify genes involved in tumorigenesis, we compared gene expression profiles in preneoplastic intestine of BALB/c and C57BL/6 mice-fed low folate. We identified 74 upregulated and 90 downregulated genes in BALB/c compared to C57BL/6 mice. We validated decreased expression of Bcmo1 and increased expression of Aldh1a, which would be expected to upregulate the peroxisome proliferator-activated receptor alpha (PPARA) pathway, and confirmed the expected upregulation of several Ppara downstream genes. We verified, in BALB/c mice, reduced expression of Sprr2a, a gene that increases resistance to oxidative damage, and of two oncosuppressors (Bmp5 and Arntl). Low folate increased Ppara and Aldh1a1 expression, and decreased Bcmo1, Sprr2a, and Bmp5 expression in BALB/c, compared to BALB/c on control diets. Bcmo1, Ppara, and Bmp5 showed differential DNA methylation related to strain, diet, and/or Mthfr genotype.
  
  
  CONCLUSIONS
  Disturbed regulation of the retinoid/PPARA pathway, which influences oxidative damage, and altered expression of tumor suppressors may contribute to intestinal tumorigenesis induced by low-folate intake.
authors.affiliation: Department of Human Genetics, Montreal Children's Hospital Research Institute, McGill University, Montreal, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.forename: Yuanhang
authors.initials: Y
authors.lastname: Cao
authors.forename: Liyuan
authors.initials: L
authors.lastname: Deng
authors.forename: Leonie G
authors.initials: LG
authors.lastname: Mikael
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D055417:Bone Morphogenetic Protein 5 / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D004032:Diet; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005494:Folic Acid Deficiency / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D005838:Genotype; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology; D007422:Intestines / Q000187:drug effects*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D050697:Retinal Dehydrogenase; D012176:Retinoids / Q000032:analysis / Q000378:metabolism; D015854:Up-Regulation; D050559:beta-Carotene 15,15'-Monooxygenase / Q000187:drug effects / Q000378:metabolism
chemical_list: C525815:Bmp5 protein, mouse; D055417:Bone Morphogenetic Protein 5; D055233:Cornified Envelope Proline-Rich Proteins; D047493:PPAR alpha; D012176:Retinoids; C491091:Sprr2a1 protein, mouse; D005492:Folic Acid; C493359:Bco1 protein, mouse; D050559:beta-Carotene 15,15'-Monooxygenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D042965:Methylenetetrahydrofolate Reductase (NADPH2)