Author information
1
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, 23298, USA.
2
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
3
Department of Pathology, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Abstract
Hepatocellular carcinoma (HCC) is increasing as a cause of liver-related mortality largely due to 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 also 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. TNFα, known to be increased in NASH, induced AATF expression. Promoter analysis of AATF revealed a SREBP-1c binding site; inhibition of SREBP-1 by using specific inhibitors as well as siRNA decreased TNFα-induced AATF expression. AATF interacted with STAT3 to increase MCP-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 in to NSG mice demonstrated reduced tumorigenesis and metastases. Conclusion AATF drives NAFLD and hepatocarcinogenesis, offering a potential target for therapeutic intervention.