FoxM1 in Liver Cancer

The work presented in this thesis elucidates the role of transcription factor FoxM1 in progression of hepatocellular carcinoma. In this work, I provide the genetic evidence that FoxM1 is important for progression and maintenance of liver tumors. Also, high FoxM1 expression leads to accumulation of poorly differentiated tumor cells by inhibition of liver differentiation factors. I show here that deletion of FoxM1 from hepatocytes leads to regression of Ras induced liver tumors. This regression in number of tumor nodules was found to result from decreased proliferation, increased apoptosis and higher accumulation of reactive oxygen species in the HCC cells. Deletion of FoxM1 also leads to a disproportionate loss of liver cancer progenitor cells. The work also shows that the liver cancer stem cells are dependent on the expression of FoxM1. Further, I show that FoxM1 inhibits the expression of liver differentiation genes FoxA1 and FoxA2 by silencing their promoters for transcription. This inhibition of FoxA factors leads to accumulation of poorly differentiated tumor cells and thus helps liver cancer progress to an aggressive phenotype.