Butyrate-containing structured lipids inhibit RAC1 and epithelial-to-mesenchymal transition markers: a chemopreventive mechanism against hepatocarcinogenesis.
Butyrate-containing structured lipids inhibit RAC1 and epithelial-to-mesenchymal transition markers: a chemopreventive mechanism against hepatocarcinogenesis.
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DOI：
10.1016/j.jnutbio.2020.108496
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Pogribny IP
中科院分区：
文献类型：
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作者：
de Conti A;Tryndyak V;Heidor R;Jimenez L;Moreno FS;Beland FA;Rusyn I;Pogribny IP
肝细胞癌是人类最具侵袭性的癌症之一。世界范围内肝癌发病率的上升及其对药物治疗的耐药性表明，预防肝癌的发展可能是改善肝癌相关发病率和死亡率的最有效的策略。在广泛的化学预防药物中，使用饮食和营养制剂是一种有吸引力和前景的方法；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。在本研究中，我们利用类似于人类肝细胞癌发展的大鼠“耐药肝细胞”模型，研究了与先前观察到的含丁酸结构脂(STL)抑制肝癌发生相关的潜在分子途径。通过全转录组分析，我们证明了含有丁酸的STL对肝癌的抑制作用与抑制细胞迁移、细胞骨架组织和上皮向间充质转化(EMT)有关，这种抑制是通过降低RACGAP1和RAC1蛋白的水平来实现的。从机制上讲，racgap1和rac1癌基因的抑制与胞嘧啶DNA和组蛋白H3K27启动子甲基化有关。抑制RACGAP1/RAC1癌基因信号通路和EMT可能是预防肝癌的有价值的途径。
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.