Outfoxing liver cancer with p19ARF tumor suppressor?
Article first published online: 7 MAR 2007
Copyright © 2004 American Association for the Study of Liver Diseases
Volume 40, Issue 4, pages 1010–1012, October 2004
How to Cite
Thorgeirsson, S. S. (2004), Outfoxing liver cancer with p19ARF tumor suppressor?. Hepatology, 40: 1010–1012. doi: 10.1002/hep.1840400433
- Issue published online: 7 MAR 2007
- Article first published online: 7 MAR 2007
Hepatocellular carcinoma (HCC) is a leading cause of cancerrelated deaths worldwide. Here, we provide evidence that the Forkhead Box (Fox) m1b (Foxm1b or Foxm1) transcription factor is essential for the development of HCC. Conditionally deleted Foxm1b mouse hepatocytes fail to proliferate and are highly resistant to developing HCC in response to a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor-induction protocol. The mechanism of resistance to HCC development is associated with nuclear accumulation of the cell cycle inhibitor p27 Kip1 protein and reduced expression of the Cdk1-activator Cdc25B phosphatase. We showed that the Foxm1b transcription factor is a novel inhibitory target of the p19ARF tumor suppressor. Furthermore, we demonstrated that conditional overexpression of Foxm1b protein in osteosarcoma U2OS cells greatly enhances anchorage-independent growth of cell colonies on soft agar. A p19ARF 26-44 peptide containing nine D-Arg to enhance cellular uptake of the peptide was sufficient to significantly reduce both Foxm1b transcriptional activity and Foxm1b-induced growth of U2OS cell colonies on soft agar. These results suggest that this (D-Arg)9-p19ARF 26-44 peptide is a potential therapeutic inhibitor of Foxm1b function during cellular transformation. Our studies demonstrate that the Foxm1b transcription factor is required for proliferative expansion during tumor progression and constitutes a potential new target for therapy of human HCC tumors.