Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers. The rising incidence of HCC worldwide and its resistance to pharmacotherapy indicate that the prevention of HCC development may be the most impactful strategy to improve HCC-related morbidity and mortality. Among the broad range of chemopreventive agents, the use of dietary and nutritional agents is an attractive and promising approach; however, a better understanding of the mechanisms of their potential cancer suppressive action is needed to justify their use. In the present study, we investigated the underlying molecular pathways associated with the previously observed suppressive effect of butyrate-containing structured lipids (STLs) against liver carcinogenesis using a rat “resistant hepatocyte” model of hepatocarcinogenesis that resembles the development of HCC in humans. Using whole transcriptome analysis, we demonstrate that the HCC suppressive effect of butyrate-containing STLs is associated with the inhibition of the cell migration, cytoskeleton organization, and epithelial-to-mesenchymal transition (EMT), mediated by the reduced levels of RACGAP1 and RAC1 proteins. Mechanistically, the inhibition of the Racgap1 and Rac1 oncogenes is associated with cytosine DNA and histone H3K27 promoter methylation. Inhibition of the RACGAP1/RAC1 oncogenic signaling pathways and EMT may be a valuable approach for liver cancer prevention.

肝细胞癌 (HCC) 是最具侵袭性的人类癌症之一。全球 HCC 发病率的上升及其对药物治疗的抵抗表明，预防 HCC 发展可能是改善 HCC 相关发病率和死亡率的最有效策略。在广泛的化学预防剂中，使用膳食和营养剂是一种有吸引力且有前途的方法；然而，需要更好地了解它们潜在的癌症抑制作用的机制，以证明它们的使用是合理的。在目前的研究中，我们使用类似于人类 HCC 发展的大鼠“抗性肝细胞”肝癌模型研究了与先前观察到的含丁酸盐结构脂质 (STL) 对肝癌发生的抑制作用相关的潜在分子途径。使用全转录组分析，我们证明含丁酸盐的 STL 的 HCC 抑制作用与细胞迁移、细胞骨架组织和上皮间质转化 (EMT) 的抑制有关，由降低的 RACGAP1 和 RAC1 水平介导蛋白质。从机制上讲，抑制 和上皮间质转化 (EMT)，由 RACGAP1 和 RAC1 蛋白水平降低介导。从机制上讲，抑制 和上皮间质转化 (EMT)，由 RACGAP1 和 RAC1 蛋白水平降低介导。从机制上讲，抑制Racgap1和Rac1癌基因与胞嘧啶 DNA 和组蛋白 H3K27 启动子甲基化有关。抑制 RACGAP1/RAC1 致癌信号通路和 EMT 可能是预防肝癌的一种有价值的方法。