Anti-angiogenic activity of tributyrin and potential molecular mechanisms involved when it is administered to rats during the early promotion of hepatocarcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, the sixth most prevalent type of cancer in the world and the third and fourth leading cause of death related to this condition in the world and in Brazil, respectively. HCC is also one of the most hypervascular solid tumors in which the process of angiogenesis contributes to its malignant biological features such as vascular invasion associated with a high rate of recurrence even after surgical resection. Different than previously thought, angiogenesis can be induced at early stages of carcinogenesis, as in pre- neoplastic lesions, suggesting that its blockade may be a promising strategy in preventing the development of cancer. Bioactive compounds from food (CBAs) with anti - angiogenic action are potent chemopreventive agents. Recently, it was observed that tributyrin (TB) when administered during the early promotion of rat hepatocarcinogenesis, inhibited the process of angiogenesis in premalignant states, including early premalignant liver lesions. However, little is known about the mechanisms involved in anti-angiogenic effects by TB. In this context, this project aims to evaluate the kinetics of the process of angiogenesis in the early promotion stage of hepatocarcinogenesis in rats submitted to the "resistant hepatocyte" model and evaluate the anti - angiogenic activity of TB and possible molecular mechanisms involved, as such as modulation of the levels of angiogenic factors ( HIF - 1± , VEGFA , Flk - 1) and tumor suppressor genes with anti - angiogenic actions (VHL and PTEN ) through the regulation of epigenetic mechanisms such as histone acetylation and DNA methylation. We expect that the results obtained from this study contribute to elucidation of the chemopreventive activity of TB through its anti-angiogenic action so that in the future it can be used in the prevention and even treatment of liver cancer. (AU)