Tian Yuan, Mok Myth T S, Yang Pengyuan, Cheng Alfred S L
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Cancers (Basel). 2016 Aug 20;8(8):76. doi: 10.3390/cancers8080076.
Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
非酒精性脂肪性肝病（NAFLD）以肝脏脂肪堆积为特征，与中心性肥胖、营养过剩及代谢综合征的其他特征密切相关，这些因素会增加肝细胞癌（HCC）的发生风险。Wnt/β-连环蛋白信号通路在肝脏的生理和病理过程中发挥着重要作用。高达半数的HCC患者存在Wnt/β-连环蛋白信号的激活。然而，HCC患者中CTNNB1（编码β-连环蛋白）或其他靶向Wnt/β-连环蛋白信号的拮抗剂的突变频率较低，这表明基因突变并非驱动HCC中β-连环蛋白异常活性的主要因素。新出现的证据表明，肥胖诱导的代谢途径可使染色质修饰因子（如组蛋白去乙酰化酶8）失调，从而引发不良的整体表观遗传变化，进而改变有助于致癌信号传导的基因表达程序。本综述聚焦于NAFLD相关HCC发生发展过程中Wnt/β-连环蛋白的异常表观遗传激活。对这种失调潜在分子机制的深入理解，可能有助于为肥胖和糖尿病患者预防和/或治疗HCC确定新的可药物化表观遗传靶点。
