Journal of Gastroenterology

, Volume 32, Issue 2, pp 171–175 | Cite as

Relationship of plasma folic acid and status of DNA methylation in human gastric cancer

  • Jing-Yuan Fang
  • Shu-Dong Xiao
  • Shun-Shi Zhu
  • Ji-Min Yuan
  • Dai-Kai Qiu
  • Shao-Ji Jiang
Alimentary Tract


To evaluate the anti-cancer effects of folic acid at the molecular level, we determined plasma folic acid concentration by radioimmuno-assay and the degree of total genomic DNA methylation by incubating DNA with3H-S-adenosylmethionine (3H-SAM) in the presence of a methylase, and analyzed the methylation status of the c-myc and c-Ha-ras oncogenes by Southern blotting in 21 patients with advanced gastric cancer. The degree of total genomic DNA methylation of cancerous tissues was significantly lower than that of paracancerous and non-cancerous tissues; c-myc and c-Ha-ras oncogenes from cancerous (10/21, 5/10) and paracancerous (13/21, 4/10) tissues were hypomethylated. The plasma folic acid concentration in patients who showed hypomethylation was lower than that patients showing normal methylation. These findings suggest that a decrease in folic acid, and the subsequent DNA hypomethylation, may be involved in human gastric carcinogenesis.

Key words

gastric cancer folic acid DNA methylation oncogene 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cravo ML, Mason JB, Dagal Y, et al. Folate deficiency enhances the development of colonic neoplasia in dimethylhydeazinetreated rats. Cancer Res 1992;52:5002–5006.PubMedGoogle Scholar
  2. 2.
    Giovannucci E, Rimm EB, Ascherio A, et al. Alcohol, lowmethionine-low folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;87:265–273.PubMedCrossRefGoogle Scholar
  3. 3.
    Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875–883.PubMedCrossRefGoogle Scholar
  4. 4.
    Kim YI, Christman JK, Fleet JC, et al. Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. Am J Clin Nutr 1995;61:1083–1090.PubMedGoogle Scholar
  5. 5.
    Heimburger DC, Krumidieck CL, Alerxander B, et al. Localized folic acid deficiency and bronchial metaplasia in snorers: Hypothesis and preliminary report. Nutr Int 1987;3:54–60.Google Scholar
  6. 6.
    Butterworth CE, Hatch KD, Macaluso M, et al. Folate deficiency and cervical dysplasis. JAMA 1992;267:528–533.PubMedCrossRefGoogle Scholar
  7. 7.
    Gazarian D, Ghoshal AK, Farber E. In vivo free radical generation in the rat liver by a choline-devoid diet and its role in cell death in relation to phospholipase A2. Proc Am Assoc Cancer Res 1992;35:102.Google Scholar
  8. 8.
    Cliford A, Heid M, Muller H, et al. Tissue distribution and prediction of total body folate of rats. J Nutr 1990;120:1633–1639.Google Scholar
  9. 9.
    Tatematsu M, Ichinose M, Tsukada S, et al. DNA methylation of the pepsinogen 1 gene during rat glandular stomach carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine of catechol. Carcinogenesis 1993;14:1415–1419.PubMedCrossRefGoogle Scholar
  10. 10.
    Dizk M, Christman JK, Wainfan E. Alteration in expression and methylation of specific genes in livers of rats fed a cancerpromoting methyl-deficient diet. Carcinogenesis 1991;12:1307–1312.CrossRefGoogle Scholar
  11. 11.
    Hass BS, Hart RW, Lu MH, et al. Effect of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vito. Mutat Res 1993;295:281–289.PubMedGoogle Scholar
  12. 12.
    Bross IDJ. How to use ridit analysis. Biometrics 1958;14:18–38.CrossRefGoogle Scholar
  13. 13.
    Kim YI, Giuliano A, Hatch KD, et al. Global DNA hypomethylation increases progressively in cervical dysplasia and carcinoma. Cancer 1994;74:893–899.PubMedCrossRefGoogle Scholar
  14. 14.
    Pascale RM, Simile MM, Feo F. Genomic abnormalities in hepatocarcinogenesis: Implications for a chemopreventive strategy. Anticancer Res 1993;13(5A):1341–1356.PubMedGoogle Scholar
  15. 15.
    Doerfier W, Toth M, Kochanek S, et al. Eukaryotic DNA methylation: Facts and problems. FEBS 1990;268:329–333.CrossRefGoogle Scholar
  16. 16.
    Balaghi M, Wagner C. DNA methylation in folate deficiency: Use of CpG methylase. Biochem Biophys Res Commun 1993;193:1184–1190.PubMedCrossRefGoogle Scholar
  17. 17.
    Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and carcinogenesis of the colon and rectum. Internation J Epidemiol 1991;20:368–374.CrossRefGoogle Scholar
  18. 18.
    Lavecchia VC, Ferraroni M, D'Avanzo B, et al. Selected micronutrient intake and the risk of gastric cancer. Cancer Epidemiol Biomarkers Prev 1994;3:393–398.Google Scholar
  19. 19.
    Ming T, Teh M, Lee YS. An immunohistochemical study ofras oncoprotein expression in gastric carcinoma. Cancer 1993;72:1846–1848.CrossRefGoogle Scholar
  20. 20.
    Ninomiya I, Yonemura Y, Matsumoto H, et al. Expression of c-myc gene product in gastric carcinoma. Oncol 1991;48:149–152.CrossRefGoogle Scholar
  21. 21.
    Suwady J, Friedman MI, Latvin WE, et al. Role of transitional mucosa of the colon in differentiating primary adenocarcinoma from carcinomas metastatic to the colon. An immunohistochemical study. Am J Surg Pathol 1991;15:136–144.CrossRefGoogle Scholar
  22. 22.
    Lashner BA. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol 1993;119:549–554.PubMedCrossRefGoogle Scholar
  23. 23.
    Mason JB. Folate and colonic carcinogenesis: Searching for a mechanistic understanding. J Nutr Biochem 1995;5:170–175.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • Jing-Yuan Fang
    • 1
  • Shu-Dong Xiao
    • 1
  • Shun-Shi Zhu
    • 1
  • Ji-Min Yuan
    • 1
  • Dai-Kai Qiu
    • 1
  • Shao-Ji Jiang
    • 1
  1. 1.Shanghai Ren-Ji Hospital, Shanghai Institute of Digestive Disease (200001)Shanghai Second Medical UniversityShanghaiPeople's Republic of China

Personalised recommendations