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Differential gene expression and methylation in the retinoid/ PPARA pathway and of tumor suppressors may modify intestinal tumorigenesis induced by low folate in mice
Author(s) -
Leclerc Daniel,
Cao Yuanhang,
Deng Liyuan,
Mikael Leonie G.,
Wu Qing,
Rozen Rima
Publication year - 2013
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201200212
Subject(s) - carcinogenesis , downregulation and upregulation , dna methylation , biology , methylation , gene expression , microbiology and biotechnology , cecum , cancer research , gene , biochemistry , ecology
Scope 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 C 57 BL /6 mice. We suggested that DNA damage, altered methylation, and reduced apoptosis could contribute to tumorigenesis in this model. Methods and results To identify genes involved in tumorigenesis, we compared gene expression profiles in preneoplastic intestine of BALB /c and C57 BL /6 mice‐fed low folate. We identified 74 upregulated and 90 downregulated genes in BALB /c compared to C 57 BL /6 mice. We validated decreased expression of B cmo1 and increased expression of A ldh1a , which would be expected to upregulate the peroxisome proliferator‐activated receptor alpha ( PPARA ) pathway, and confirmed the expected upregulation of several P para downstream genes. We verified, in BALB /c mice, reduced expression of S prr2a , a gene that increases resistance to oxidative damage, and of two oncosuppressors ( B mp5 and A rntl ). Low folate increased P para and A ldh1a1 expression, and decreased B cmo1, S prr2a, and B mp5 expression in BALB /c, compared to BALB /c on control diets. B cmo1, P para , and B mp5 showed differential DNA methylation related to strain, diet, and/or M thfr genotype. Conclusion 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.