Inhibition of hypoxia-inducible factor via upregulation of von Hippel-Lindau protein induces "angiogenic switch off" in a hepatoma mouse model.
"Angiogenic switch off" is one of the ideal therapeutic concepts in the treatment of cancer. However, the specific molecules which can induce "angiogenic switch off" in tumor have not been identified yet. In this study, we focused on von Hippel-Lindau protein (pVHL) in hepatocellular carcinoma (HCC) and investigated the effects of sulfoquinovosyl-acylpropanediol (SQAP), a novel synthetic sulfoglycolipid, for HCC. We examined mutation ratio of VHL gene in HCC using 30 HCC samples and we treated the HCC-implanted mice with SQAP. Thirty clinical samples showed no VHL genetic mutation in HCC. SQAP significantly inhibited tumor growth by inhibiting angiogenesis in a hepatoma mouse model. SQAP induced tumor "angiogenic switch off" by decreasing hypoxia-inducible factor (HIF)-1, 2α protein via pVHL upregulation. pVHL upregulation decreased HIFα protein levels through different multiple mechanisms: (i) increasing pVHL-dependent HIFα protein degradation; (ii) decreasing HIFα synthesis with decrease of NF-κB expression; and (iii) decrease of tumor hypoxia by vascular normalization. We confirmed these antitumor effects of SQAP by the loss-of-function experiments. We found that SQAP directly bound to and inhibited transglutaminase 2. This study provides evidence that upregulation of tumor pVHL is a promising target, which can induce "angiogenic switch off" in HCC.
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Hideki
H
Iwamoto
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Toru
T
Nakamura
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Hironori
H
Koga
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science , Tokyo, Japan.
Jesus
J
Izaguirre-Carbonell
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science , Tokyo, Japan.
Shinji
S
Kamisuki
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science , Tokyo, Japan.
Fumio
F
Sugawara
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Mitsuhiko
M
Abe
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science , Tokyo, Japan.
Kazuki
K
Iwabata
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Yu
Y
Ikezono
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Takahiko
T
Sakaue
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Atsutaka
A
Masuda
Department of Pathology, Kurume University School of Medicine , Kurume, Japan.
Hirohisa
H
Yano
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science , Tokyo, Japan.
Keisuke
K
Ohta
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine , Kurume, Japan.
Masahito
M
Nakano
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine , Kurume, Japan.
Shigeo
S
Shimose
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine , Kurume, Japan.
Tomotake
T
Shirono
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Takuji
T
Torimura