Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis |
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| Authors: | 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 |
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| Affiliation: | 1. Laboratory of Diet, Nutrition, and Cancer, Department of Food and Experimental Nutrition, University of S?o Paulo, S?o Paulo, Brazil;2. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR;3. Laboratory of Food Chemistry and Biochemistry, Department of Food and Experimental Nutrition, University of S?o Paulo, S?o Paulo, Brazil;4. Laboratory of Hematology, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of S?o Paulo, S?o Paulo, Brazil;5. Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR;6. Division of Cancer Prevention, National Cancer Institute, Bethesda, MD |
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| 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. |
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| Keywords: | hepatocarcinogenesis chemoprevention angiogenesis folic acid tributyrin |
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