AATF Inhibition Exerts Antiangiogenic Effects Against Human Hepatocellular Carcinoma

ABSTRACT Hepatocellular carcinoma (HCC), a highly fatal cancer with a mortality rate proportional to its incidence, continues to pose a global health care challenge. Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in HCC. We previously showed that the apoptosis antagonizing transcription factor (AATF) affects tumor growth and metastasis in a mouse xenograft model. However, the regulatory role of AATF in tumor angiogenesis and its underlying mechanisms in HCC remain unknown. In the current study, we identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibition of AATF in human HCC cells showed high levels of pigment epithelium-derived factor (PEDF) compared to controls as a resultant of reduced matric metalloproteinases activity. Conditioned media from AATF knockdown (KD) cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Of note, PEDF inhibition by its respective antibody profoundly reversed the anti-angiogenic effect of AATF KD. In conclusion, our study demonstrates that inhibition of AATF suppresses angiogenesis in HCC via PEDF. Thus, a therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may be a promising approach for HCC treatment.