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

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

Content Provider	MDPI
Author	Li, Ru Okada, Hikari Yamashita, Taro Nio, Kouki Chen, Han Li, Yingyi Shimakami, Tetsuro Takatori, Hajime Arai, Kuniaki Sakai, Yoshio Yamashita, Tatsuya Mizukoshi, Eishiro Honda, Masao Kaneko, Shuichi
Copyright Year	2022
Description	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.
Starting Page	8305
e-ISSN	14220067
DOI	10.3390/ijms23158305
Journal	International Journal of Molecular Sciences
Issue Number	15
Volume Number	23
Language	English
Publisher	MDPI
Publisher Date	2022-07-27
Access Restriction	Open
Subject Keyword	International Journal of Molecular Sciences Oncology Alpha-fetoprotein Forkhead Box M1 Carfilzomib Hepatocellular Carcinoma Vascular Endothelial Growth Factor Receptor 2
Content Type	Text
Resource Type	Article

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