FOXM1 Is a Novel Molecular Target of AFP-Positive Hepatocellular Carcinoma Abrogated by Proteasome Inhibition

Int J Mol Sci. 2022 Jul 27;23(15):8305. doi: 10.3390/ijms23158305.

Abstract

Alpha-fetoprotein (AFP) is an oncofetal protein that is elevated in a subset of hepatocellular carcinoma (HCC) with poor prognosis, but the molecular target activated in AFP-positive HCC remains elusive. Here, we demonstrated that the transcription factor forkhead box M1 (FOXM1) is upregulated in AFP-positive HCC. We found that FOXM1 expression was highly elevated in approximately 40% of HCC cases, and FOXM1-high HCC was associated with high serum AFP levels, a high frequency of microscopic portal vein invasion, and poor prognosis. A transcriptome and pathway analysis revealed the activation of the mitotic cell cycle and the inactivation of mature hepatocyte metabolism function in FOXM1-high HCC. The knockdown of FOXM1 reduced AFP expression and induced G2/M cell cycle arrest. We further identified that the proteasome inhibitor carfilzomib attenuated FOXM1 protein expression and suppressed cell proliferation in AFP-positive HCC cells. Carfilzomib in combination with vascular endothelial growth factor receptor 2 (VEGFR2) blockade significantly prolonged survival by suppressing AFP-positive HCC growth in a subcutaneous tumor xenotransplantation model. These data indicated that FOXM1 plays a pivotal role in the proliferation of AFP-positive liver cancer cells. Carfilzomib can effectively inhibit FOXM1 expression to inhibit tumor growth and could be a novel therapeutic option in patients with AFP-positive HCC who receive anti-VEGFR2 antibodies.

Keywords: alpha-fetoprotein; carfilzomib; forkhead box M1; hepatocellular carcinoma; vascular endothelial growth factor receptor 2.

MeSH terms

  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • alpha-Fetoproteins / genetics
  • alpha-Fetoproteins / metabolism

Substances

  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Vascular Endothelial Growth Factor A
  • alpha-Fetoproteins
  • Proteasome Endopeptidase Complex