Inhibition of hypoxia-inducible factor via upregulation of von Hippel-Lindau protein induces "angiogenic switch off" in a hepatoma mouse model.
Inhibition of hypoxia-inducible factor via upregulation of von Hippel-Lindau protein induces "angiogenic switch off" in a hepatoma mouse model.
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DOI：
10.1038/mto.2015.20
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Torimura T
中科院分区：
文献类型：
--
作者：
Iwamoto H;Nakamura T;Koga H;Izaguirre-Carbonell J;Kamisuki S;Sugawara F;Abe M;Iwabata K;Ikezono Y;Sakaue T;Masuda A;Yano H;Ohta K;Nakano M;Shimose S;Shirono T;Torimura T
“血管生成关闭”是治疗癌症的理想治疗理念之一。然而，在肿瘤中诱导血管生成关闭的特异性分子还没有确定。本研究以肝细胞癌中的von Hippel-Lindau蛋白(PVHL)为研究对象，研究了新型磺基糖脂--磺基喹诺酮-丙二醇(SQAP)对肝细胞癌的治疗作用。我们用30例肝癌标本检测了VHL基因在肝癌中的突变率，并对移植瘤小鼠进行了SQAP治疗。30例临床标本均未发现肝细胞癌VHL基因突变。在小鼠肝癌模型中，SQAP通过抑制血管生成显著抑制肿瘤生长。参麦多糖通过上调pVHL，降低缺氧诱导因子-1，2α蛋白表达，从而导致肿瘤血管生成关闭。PVHL上调通过多种机制降低HIFα蛋白水平：(1)增加依赖于pVHL的HIFα蛋白降解；(2)减少HIFα合成，同时降低NF-κB的表达；(3)通过血管正常化减少肿瘤缺氧。我们通过功能丧失实验证实了SQAP的这些抗肿瘤作用。我们发现SQAP直接与转谷氨酰胺酶2结合并抑制转谷氨酰胺酶2。本研究提供了证据，表明上调肿瘤pVHL是一个有希望的靶点，可以诱导肝癌血管生成关闭。
“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.