C/EBPα inhibits hepatocellular carcinoma by reducing Notch3/Hes1/p27 cascades

Background and aims: CCAAT/enhancer binding protein α is one of the key transcription factors of the hepatocyte nuclear factors family, which plays a critical role in liver cell proliferation and differentiation. However, the role of CCAAT/enhancer binding protein α in hepatocarcinogenesis remains to be defined. Methods: A recombinant adenovirus carrying the C/EBPα gene was constructed to determine its effect on hepatocarcinogenesis in vitro and in vivo. Results: We demonstrated that overexpression of CCAAT/enhancer binding protein α inhibited the tumourigenicity of Huh7 cells, re-established the expression of certain liver-specific genes and induced G0/G1 arrest. Overexpression of CCAAT/enhancer binding protein α significantly suppressed the proliferation of primary hepatocarcinogenesis cells and tumour associated fibroblasts in vitro. Additionally, intratumoural injection of adenovirus carrying the C/EBPα reduced the growth of subcutaneous hepatocarcinogenesis xenografts in nude mice. Systemic administration of adenovirus carrying the C/EBPα resulted in the eradication of orthotopic liver hepatocarcinogenesis nodules in nude mice. Further, up-regulation of CCAAT/enhancer binding protein α reduced the expression of Notch3, thereby suppressing Hes1 transactivation activity and leading to decreased p27 expression. Overexpression of Hes1 partially abolished the anti-proliferation effect of CCAAT/enhancer binding protein α on Huh7 cells. Conclusion: These results suggested that the effect of CCAAT/enhancer binding protein α on hepatocarcinogenesis is partially through by reducing Notch3/Hes1/p27 cascades and CCAAT/enhancer binding protein α may possess a novel therapeutic potential for human hepatocarcinogenesis.