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Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis.

International journal of cancer (2013-12-05)
Aline H Guariento, Kelly S Furtado, Aline de Conti, Adriana Campos, Eduardo Purgatto, Jéssica Carrilho, Elvira Maria Guerra Shinohara, Volodymyr Tryndyak, Tao Han, James C Fuscoe, Sharon A Ross, Frederick A Beland, Igor P Pogribny, Fernando S Moreno
ABSTRACT

The steady increase in the incidence and mortality of hepatocellular carcinoma (HCC) signifies a crucial need to understand better its pathogenesis to improve clinical management and prevention of the disease. The aim of this study was to investigate molecular mechanisms for the chemopreventive effects of folic acid and tributyrin alone or in combination on rat hepatocarcinogenesis. Male Wistar rats were subjected to a classic "resistant hepatocyte" model of liver carcinogenesis and treated with folic acid and tributyrin alone or in combination for 5 weeks during promotion stage. Treatment with folic acid and tributyrin alone or in combination strongly inhibited the development of glutathione-S-transferase placental form (GSTP)-positive foci. Microarray analysis showed significant changes in gene expression. A total of 498, 655 and 940 of differentially expressed genes, involved in cell cycle, p53-signaling, angiogenesis and Wnt pathways, was identified in the livers of rats treated with folic acid, tributyrin or folic acid and tributyrin. A detailed analysis of these differentially expressed genes revealed that treatments inhibited angiogenesis in the preneoplastic livers. This was evidenced by the fact that 30 out of 77 differentially expressed genes common to all three treatments are involved in the regulation of the angiogenesis pathway. The inhibition of angiogenesis was confirmed by reduced levels of CD34 protein. In conclusion, the tumor-suppressing activity of folic acid and tributyrin is associated with inhibition of angiogenesis at early stages of rat liver carcinogenesis. Importantly, the combination of folic acid and tributyrin has stronger chemopreventive effect than each of the compounds alone.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Folic acid, ≥97%
Sigma-Aldrich
Folic acid, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥97%
Supelco
Folic acid, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
N-Nitrosodiethylamine, ISOPAC®
Supelco
N-Nitrosodiethylamine solution, certified reference material, 5000 μg/mL in methanol
Sigma-Aldrich
Glyceryl tributyrate, ≥99%
Sigma-Aldrich
N-Nitrosodiethylamine, liquid
Sigma-Aldrich
Tributyrin, 97%, FG
Sigma-Aldrich
N-Nitrosodiethylamine, ≥99.0% (GC)
Sigma-Aldrich
Glutathione S-Transferase from equine liver, lyophilized powder, ≥25 units/mg protein
Sigma-Aldrich
Folic acid, meets USP testing specifications
Supelco
N-Nitrosodiethylamine, analytical standard
Sigma-Aldrich
Glyceryl tributyrate, puriss., ≥98.5% (GC)
USP
Folic acid, United States Pharmacopeia (USP) Reference Standard