Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA.
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA.
Hepatology. 2019 Apr;69(4):1520-1534. doi: 10.1002/hep.30346. Epub 2019 Mar 4.
Hepatocellular carcinoma (HCC) is increasing as a cause of liver-related mortality largely because of the growing burden of nonalcoholic steatohepatitis (NASH). The mechanisms of HCC development in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. We initially identified apoptosis antagonizing transcription factor (AATF) to be associated with HCC in a mouse model of NASH that develops HCC without the addition of specific carcinogens. AATF, also called che-1, is a transcriptional factor that is highly conserved among eukaryotes. AATF is known to be a central mediator of the cellular responses as it promotes cell proliferation and survival by inducing cell cycle arrest, autophagy, DNA repair, and inhibition of apoptosis. However, the role of AATF in NASH and HCC remains unknown. Here, we provide evidence for AATF as a contributory factor for HCC in NAFLD. AATF overexpression was further verified in human NASH and HCC and multiple human HCC cell lines. Tumor necrosis factor-α (TNFα), known to be increased in NASH, induced AATF expression. Promoter analysis of AATF revealed a sterol regulatory element binding transcription factor 1-c (SREBP-1c) binding site; inhibition of SREBP-1 by using specific inhibitors as well as small interfering RNA decreased TNFα-induced AATF expression. AATF interacted with signal transducer and activator of transcription 3 to increase monocyte chemoattractant protein-1 expression. AATF knockdown decreased cell proliferation, migration, invasion, colony formation, and anchorage-dependent growth in HCC cell lines. Xenograft of QGY-7703 HCC cells with AATF stably knocked down into nonobese diabetic scid gamma mice demonstrated reduced tumorigenesis and metastases. Conclusion: AATF drives NAFLD and hepatocarcinogenesis, offering a potential target for therapeutic intervention.
肝细胞癌（HCC）作为肝脏相关死亡率增加的主要原因，在很大程度上是由于非酒精性脂肪性肝炎（NASH）的负担不断增加。非酒精性脂肪性肝病（NAFLD）中 HCC 发展的机制尚未完全阐明。我们最初在一种发生 HCC 而无需添加特定致癌剂的 NASH 小鼠模型中发现凋亡拮抗转录因子（AATF）与 HCC 相关。AATF，也称为 che-1，是一种在真核生物中高度保守的转录因子。已知 AATF 是细胞反应的中央介质，因为它通过诱导细胞周期停滞、自噬、DNA 修复和抑制细胞凋亡来促进细胞增殖和存活。然而，AATF 在 NASH 和 HCC 中的作用尚不清楚。在这里，我们提供了证据表明 AATF 是 NAFLD 中 HCC 的一个促成因素。AATF 的过表达在人类 NASH 和 HCC 以及多种人类 HCC 细胞系中得到进一步验证。已知在 NASH 中增加的肿瘤坏死因子-α（TNFα）诱导了 AATF 的表达。AATF 的启动子分析显示了固醇调节元件结合转录因子 1-c（SREBP-1c）结合位点；使用特异性抑制剂和小干扰 RNA 抑制 SREBP-1 减少了 TNFα诱导的 AATF 表达。AATF 与信号转导和转录激活因子 3 相互作用以增加单核细胞趋化蛋白-1 的表达。AATF 敲低减少了 HCC 细胞系中的细胞增殖、迁移、侵袭、集落形成和锚定依赖性生长。用稳定敲低 AATF 的 QGY-7703 HCC 细胞异种移植到非肥胖糖尿病 scid 伽马小鼠中，显示出肿瘤发生和转移减少。结论：AATF 驱动 NAFLD 和肝癌发生，为治疗干预提供了一个潜在的靶点。
