Overexpression of von Hippel-Lindau protein synergizes with doxorubicin to suppress hepatocellular carcinoma in mice
Overexpression of von Hippel-Lindau protein synergizes with doxorubicin to suppress hepatocellular carcinoma in mice
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DOI：
10.1016/j.jhep.2010.10.043
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发表时间：
2011-08-01
影响因子：
25.7
通讯作者：
Sun, Xueying
中科院分区：
文献类型：
--
作者：
Wang, Jizhou;Ma, Yong;Sun, Xueying
背景82目的：低氧诱导因子(HIF)和核因子-kappaB(NF-kappa B)调控与包括肝细胞癌在内的肿瘤发生和发展有关的基因。Von Hippel Lindau蛋白(von Hippel Lindau，VHL)针对HIFα亚基进行破坏，参与调节核因子-kappa B的活性。本研究旨在探讨pVHL的过表达是否与阿霉素在治疗肝癌中具有协同作用。方法：通过感染小鼠肝癌尼泊尔6和H22细胞或将携带VHL基因的腺病毒载体注射到C57BL/c小鼠皮下，诱导pVHL过表达。检测细胞增殖、细胞凋亡、肿瘤血管生成、核因子-kappaB基因表达及DNA结合活性。结果：Ad-VHL通过抑制细胞增殖，引起细胞周期停滞和细胞凋亡，增强了阿霉素的抗肿瘤活性。Ad-VHL感染可下调HIF-1α和HIF-2α的表达，抑制NF-kappa B活性和参与细胞凋亡、增殖、血管生成、侵袭和转移相关基因的表达。瘤内注射Ad-VHL可通过抑制细胞增殖和肿瘤血管生成，并诱导细胞凋亡，增强阿霉素对肿瘤生长的抑制作用。对缺氧诱导因子αS表达、核因子-kappaB活性及其下游基因的影响与体外实验结果一致。结论：通过靶向HIF和核因子-kappaB，pVHL的过表达增强了阿霉素对肝细胞癌的疗效，值得考虑作为一种潜在的治疗策略。(C)2010年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background 82 Aims: Hypoxia-inducible factors (HIFs) and nuclear factor-kappa B (NF-kappa B) regulate genes involved in carcinogenesis and progression of cancers including hepatocellular carcinoma (HCC). The von Hippel Lindau (VHL) protein (pVHL) targets HIF alpha subunits for destruction and participates in modulating the activity of NF-kappa B. The present study aimed to investigate whether the overexpression of pVHL synergizes with doxorubicin in the treatment of HCC.Methods: Overexpression of pVHL was induced by infecting mouse HCC Nepal 6 and H22 cells, or injecting subcutaneous Hepa1-6 tumors in C57BL/c mice, with adenoviral vectors encoding mouse VHL gene. Cell proliferation, apoptosis, tumoral angiogenesis, and gene expression and DNA-binding activity of NF-kappa B were examined. The therapeutic effects of pVHL were also evaluated in orthotopic Hepa1-6 tumors by intraportal delivery of Ad-VHL.Results: Ad-VHL enhanced the anti-tumor activity of doxorubicin by inhibiting cell proliferation, and causing cell cycle arrest and apoptosis. The Ad-VHL infection downregulated HIF-1 alpha and HIF-2 alpha expression, and inhibited NF-kappa B activity and the expression of genes involved in apoptosis, proliferation, angiogenesis, invasion, and metastasis. Injection of Ad-VHL into HCC tumors augmented doxorubicin-induced suppression of tumor growth by inhibiting cell proliferation and tumor angiogenesis, and by inducing cell apoptosis. Effects on the expression of HIF alpha s, activity of NF-kappa B, and their downstream genes were in accordance with the in vitro findings. Intraportal injection of Ad-VHL enhanced the efficacy of doxorubicin to suppress the growth of orthotopic liver tumors.Conclusions: By targeting HIF and NF-kappa B, overexpression of pVHL enhances the efficacy of doxorubicin, and warrants consideration as a potential therapeutic strategy for treating HCC. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.