![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
3
*
Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University and
Divisions of Clinical Nutrition and Gastroenterology, Tufts University School of Medicine, Boston, MA 02111
3To whom correspondence should be addressed. E-mail: jmason{at}hnrc.tufts.edu.
Many epidemiologic, animal and human studies suggest that folate status modulates carcinogenesis. Although these observations have been made in a number of tissues, the data are clearly most compelling for the colorectum. The mechanism(s) by which this modulation is mediated remains ill defined. Alterations in either genome-wide or gene-specific DNA methylation and/or alterations in DNA stability, resulting from DNA strand breaks or uracil misincorporation, are leading candidates in this regard. Folate has a central role in biological methylation and nucleotide synthesis, and therefore it is not surprising that folate depletion has been observed to alter DNA methylation and diminish DNA stability. The hypothesis that these two pathways are the means by which folate modulates cancer risk is also supported by the epidemiological observation that a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) gene differentially affects the relative risk of colon cancer depending on folate status, because MTHFR catalyzes the reaction that determines whether cellular folate is diverted into biological methylation or nucleotide synthesis. This phenomenon suggests that it is an imbalance between biological methylation and nucleotide synthesis that is responsible for folate-related carcinogenesis. The control of cell proliferation, which also is related to DNA methylation, is another candidate mechanism by which folate status modulates carcinogenesis. In cell culture studies, folate supplementation has been observed to suppress excessive cell proliferation. Understanding the mechanisms by which folate status modulates carcinogenesis is important for advancing insight into cancer biology and for facilitating those efforts to translate research in folate and carcinogenesis into effective and safe public health initiatives.
KEY WORDS: • folate • colon carcinogenesis • methylenetetrahydrofolate reductase • DNA methylation
This article has been cited by other articles:
|
|
 |
|
  G. M. Lindzon, A. Medline, K.-J. Sohn, F. Depeint, R. Croxford, and Y.-I. Kim Effect of folic acid supplementation on the progression of colorectal aberrant crypt foci Carcinogenesis, September 1, 2009; 30(9): 1536 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Figueiredo, M. V. Grau, R. W. Haile, R. S. Sandler, R. W. Summers, R. S. Bresalier, C. A. Burke, G. E. McKeown-Eyssen, and J. A. Baron Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial J Natl Cancer Inst, March 18, 2009; 101(6): 432 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Dong, J. D. Potter, E. White, C. M. Ulrich, L. R. Cardon, and U. Peters Genetic Susceptibility to Cancer: The Role of Polymorphisms in Candidate Genes JAMA, May 28, 2008; 299(20): 2423 - 2436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A D. Smith, Y.-I. Kim, and H. Refsum Is folic acid good for everyone? Am. J. Clinical Nutrition, March 1, 2008; 87(3): 517 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Marsillach, N. Ferre, J. Camps, F. Riu, A. Rull, and J. Joven Moderately High Folic Acid Supplementation Exacerbates Experimentally Induced Liver Fibrosis in Rats Experimental Biology and Medicine, January 1, 2008; 233(1): 38 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Al-Ghnaniem, J. Peters, R. Foresti, N. Heaton, and M. Pufulete Methylation of estrogen receptor {alpha} and mutL homolog 1 in normal colonic mucosa: association with folate and vitamin B-12 status in subjects with and without colorectal neoplasia Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1064 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Hayashi, K.-J. Sohn, J. M. Stempak, R. Croxford, and Y.-I. Kim Folate Deficiency Induces Cell-Specific Changes in the Steady-State Transcript Levels of Genes Involved in Folate Metabolism and 1-Carbon Transfer Reactions in Human Colonic Epithelial Cells J. Nutr., March 1, 2007; 137(3): 607 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Larsson, E. Giovannucci, and A. Wolk Folate and Risk of Breast Cancer: A Meta-analysis J Natl Cancer Inst, January 3, 2007; 99(1): 64 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Melse-Boonstra, P. Verhoef, C. E West, J. A van Rhijn, R. B van Breemen, J. J. Lasaroms, S. D Garbis, M. B Katan, and F. J Kok A dual-isotope-labeling method of studying the bioavailability of hexaglutamyl folic acid relative to that of monoglutamyl folic acid in humans by using multiple orally administered low doses. Am. J. Clinical Nutrition, November 1, 2006; 84(5): 1128 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Leopardi, F. Marcon, S. Caiola, A. Cafolla, E. Siniscalchi, A. Zijno, and R. Crebelli Effects of folic acid deficiency and MTHFR C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes Mutagenesis, September 1, 2006; 21(5): 327 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z Attias, H Werner, and N Vaisman Folic acid and its metabolites modulate IGF-I receptor gene expression in colon cancer cells in a p53-dependent manner. Endocr. Relat. Cancer, June 1, 2006; 13(2): 571 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Novakovic, J. M. Stempak, K.-J. Sohn, and Y.-I. Kim Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells Carcinogenesis, May 1, 2006; 27(5): 916 - 924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z Stolzenberg-Solomon, S.-C. Chang, M. F Leitzmann, K. A Johnson, C. Johnson, S. S Buys, R. N Hoover, and R. G Ziegler Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am. J. Clinical Nutrition, April 1, 2006; 83(4): 895 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jang, J. B. Mason, and S.-W. Choi Genetic and Epigenetic Interactions between Folate and Aging in Carcinogenesis J. Nutr., December 1, 2005; 135(12): 2967S - 2971S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ulrich Nutrigenetics in Cancer Research--Folate Metabolism and Colorectal Cancer J. Nutr., November 1, 2005; 135(11): 2698 - 2702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kotsopoulos, A. Medline, R. Renlund, K.-J. Sohn, R. Martin, S. W. Hwang, S. Lu, M. C. Archer, and Y.-I. Kim Effects of dietary folate on the development and progression of mammary tumors in rats Carcinogenesis, September 1, 2005; 26(9): 1603 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fenech, P. Baghurst, W. Luderer, J. Turner, S. Record, M. Ceppi, and S. Bonassi Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, {beta}-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instability--results from a dietary intake and micronucleus index survey in South Australia Carcinogenesis, May 1, 2005; 26(5): 991 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Stempak, K.-J. Sohn, E.-P. Chiang, B. Shane, and Y.-I. Kim Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model Carcinogenesis, May 1, 2005; 26(5): 981 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-I. Kim Will mandatory folic acid fortification prevent or promote cancer? Am. J. Clinical Nutrition, November 1, 2004; 80(5): 1123 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Davis and E. O. Uthus DNA Methylation, Cancer Susceptibility, and Nutrient Interactions Experimental Biology and Medicine, November 1, 2004; 229(10): 988 - 995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Giovannucci Alcohol, One-Carbon Metabolism, and Colorectal Cancer: Recent Insights from Molecular Studies J. Nutr., September 1, 2004; 134(9): 2475S - 2481S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Huycke and H. R. Gaskins Commensal Bacteria, Redox Stress, and Colorectal Cancer: Mechanisms and Models Experimental Biology and Medicine, July 1, 2004; 229(7): 586 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Roncales, M. Achon, F. Manzarbeitia, C. Maestro de las Casas, C. Ramirez, G. Varela-Moreiras, and J. Perez-Miguelsanz Folic Acid Supplementation for 4 Weeks Affects Liver Morphology in Aged Rats J. Nutr., May 1, 2004; 134(5): 1130 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Martinez, S. M Henning, and D. S Alberts Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence Am. J. Clinical Nutrition, April 1, 2004; 79(4): 691 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-I. Kim Folate and DNA Methylation: A Mechanistic Link between Folate Deficiency and Colorectal Cancer? Cancer Epidemiol. Biomarkers Prev., April 1, 2004; 13(4): 511 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Choi, S. Friso, H. Ghandour, P. J. Bagley, J. Selhub, and J. B. Mason Vitamin B-12 Deficiency Induces Anomalies of Base Substitution and Methylation in the DNA of Rat Colonic Epithelium J. Nutr., April 1, 2004; 134(4): 750 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Townsend, S. R. Davis, A. D. Mackey, and J. F. Gregory III Folate deprivation reduces homocysteine remethylation in a human intestinal epithelial cell culture model: role of serine in one-carbon donation Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G588 - G595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kimura, K. Umegaki, M. Higuchi, P. Thomas, and M. Fenech Methylenetetrahydrofolate Reductase C677T Polymorphism, Folic Acid and Riboflavin Are Important Determinants of Genome Stability in Cultured Human Lymphocytes J. Nutr., January 1, 2004; 134(1): 48 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kawakami, A. Ruszkiewicz, G. Bennett, J. Moore, G. Watanabe, and B. Iacopetta The Folate Pool in Colorectal Cancers Is Associated with DNA Hypermethylation and with a Polymorphism in Methylenetetrahydrofolate Reductase Clin. Cancer Res., December 1, 2003; 9(16): 5860 - 5865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-I. Kim Role of Folate in Colon Cancer Development and Progression J. Nutr., November 1, 2003; 133(11): 3731S - 3739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Satia-Abouta, J. A. Galanko, C. F. Martin, J. D. Potter, A. Ammerman, and R. S. Sandler Associations of Micronutrients with Colon Cancer Risk in African Americans and Whites: Results from the North Carolina Colon Cancer Study Cancer Epidemiol. Biomarkers Prev., August 1, 2003; 12(8): 747 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Wargovich and J. E. Cunningham Diet, Individual Responsiveness and Cancer Prevention J. Nutr., July 1, 2003; 133(7): 2400S - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zijno, C. Andreoli, P. Leopardi, F. Marcon, S. Rossi, S. Caiola, A. Verdina, R. Galati, A. Cafolla, and R. Crebelli Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects Carcinogenesis, June 1, 2003; 24(6): 1097 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lokk News and Views on Folate and Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2003; 58(4): M354 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. B Fallon Commentary: Colon cancer, folate and genetic status Int. J. Epidemiol., February 1, 2003; 32(1): 67 - 70. [Full Text] [PDF]
|
|
