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AATF inhibition exerts antiangiogenic effects against human hepatocellular carcinoma
Diwakar Suresh1, Akshatha N Srinivas1, Akila Prashant1
1Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India.
Background And Aims:
Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in hepatocellular carcinoma (HCC). In this study, we aim to identify the key role of apoptosis antagonizing transcription factor (AATF) in tumor angiogenesis and its underlying mechanisms in HCC.
Methods:
HCC tissues were analyzed for AATF expression by qRT-PCR and immunohistochemistry. Stable clones of control and AATF knockdown (KD) were established in human HCC cells. The effect of AATF inhibition on the angiogenic processes was determined by proliferation, invasion, migration, chick chorioallantoic membrane (CAM) assay, zymography, and immunoblotting techniques.
Results:
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. Inhibiting AATF in QGY-7703 cells resulted in higher levels of pigment epithelium-derived factor (PEDF) than controls due to decreased matric metalloproteinase activity. Conditioned media from AATF 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. Notably, PEDF inhibition effectively reversed the anti-angiogenic effect of AATF KD.
Conclusion:
Our study reports the first evidence that the therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may serve as a promising approach for HCC treatment.
Insights
Inhibiting apoptosis antagonizing transcription factor (AATF) suppresses hepatocellular carcinoma (HCC) angiogenesis by increasing pigment epithelium-derived factor (PEDF). This strategy shows promise for HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Angiogenesis is crucial for hepatic tumor growth and metastasis in hepatocellular carcinoma (HCC).
- Apoptosis antagonizing transcription factor (AATF) is a potential therapeutic target in HCC.
- Understanding AATF's role in tumor angiogenesis is essential for developing novel HCC treatments.
Purpose of the Study:
- To investigate the role of AATF in HCC tumor angiogenesis.
- To elucidate the underlying mechanisms by which AATF influences angiogenesis in HCC.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) and immunohistochemistry to analyze AATF expression in HCC tissues.
- Establishment of AATF knockdown (KD) in human HCC cells.
- Assays for proliferation, invasion, migration, chick chorioallantoic membrane (CAM) assay, zymography, and immunoblotting to assess angiogenic processes.
Main Results:
- AATF expression is elevated in HCC tissues and correlates with tumor stage and grade.
- AATF inhibition increases pigment epithelium-derived factor (PEDF) and decreases matrix metalloproteinase activity.
- AATF knockdown suppresses endothelial cell proliferation, migration, invasion, and vascularization, mediated by inhibiting VEGF signaling.
- PEDF inhibition reverses the anti-angiogenic effects of AATF knockdown.
Conclusions:
- AATF plays a significant role in promoting HCC tumor angiogenesis.
- Inhibiting AATF disrupts angiogenesis by modulating PEDF levels and suppressing VEGF signaling.
- Targeting AATF represents a promising therapeutic strategy for hepatocellular carcinoma treatment.
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