Folic acid supplementation during early hepatocarcinogenesis: Cellular and molecular effects

• Published in: International journal of cancer Vol. 129; no. 9; pp. 2073 - 2082
• Main Authors: Chagas, Carlos Eduardo Andrade, Bassoli, Bruna Kempfer, de Souza, Camila Alexandre Soares, Deminice, Rafael, Júnior, Alceu Afonso Jordão, Paiva, Sérgio Alberto Rupp, Dagli, Maria Lúcia Zaidan, Ong, Thomas Prates, Moreno, Fernando Salvador
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2011; Wiley-Blackwell
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Body Weight - drug effects; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Chemoprevention; Dietary Supplements; DNA Damage; DNA Methylation; Folic Acid - pharmacology; folic acid supplementation; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Genes, myc; Glutathione Transferase - metabolism; hepatocarcinogenesis; Liver - anatomy & histology; Liver - metabolism; Liver - pathology; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - prevention & control; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Organ Size - drug effects; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - prevention & control; preneoplastic lesions; Rats; Rats, Wistar; S-Adenosylhomocysteine - metabolism; S-Adenosylmethionine - metabolism; Tumors; Chemoprophylaxis; Premalignant lesion; Vitamin; Hepatic disease; folic acid supplementation; Malignant tumor; hepatocarcinogenesis; Carcinogenesis; Folic acid; Prevention; Liver cancer; Chemotherapy; Treatment; Cancerology; chemoprevention; preneoplastic lesions; Digestive diseases; Early; Supplementation; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25886

Folic acid (FA) supplementation during carcinogenesis is controversial. Considering the impact of liver cancer as a public health problem and mandatory FA fortification in several countries, the role of FA supplementation in hepatocarcinogenesis should be elucidated. We evaluated FA supplementation during early hepatocarcinogenesis. Rats received daily 0.08 mg (FA8 group) or 0.16 mg (FA16 group) of FA/100 g body weight or water (CO group, controls). After a 2‐week treatment, animals were subjected to the “resistant hepatocyte” model of hepatocarcinogenesis (initiation with diethylnitrosamine, selection/promotion with 2‐acetylaminofluorene and partial hepatectomy) and euthanized after 8 weeks of treatment. Compared to the CO group, the FA16 group presented: reduced (p < 0.05) number of persistent and increased (p < 0.05) number of remodeling glutathione S‐transferase (GST‐P) positive preneoplastic lesions (PNL); reduced (p < 0.05) cell proliferation in persistent GST‐P positive PNL; decreased (p < 0.05) hepatic DNA damage; and a tendency (p < 0.10) for decreased c‐myc expression in microdissected PNL. Regarding all these parameters, no differences (p > 0.05) were observed between CO and FA8 groups. FA‐treated groups presented increased hepatic levels of S‐adenosylmethionine but only FA16 group presented increased S‐adenosylmethionine/S‐adenosylhomocysteine ratio. No differences (p > 0.05) were observed between experimental groups regarding apoptosis in persistent and remodeling GST‐P positive PNL, and global DNA methylation pattern in microdissected PNL. Altogether, the FA16 group, but not the FA8 group, presented chemopreventive activity. Reversion of PNL phenotype and inhibition of DNA damage and of c‐myc expression represent relevant FA cellular and molecular effects.