Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
J Hepatol. 2011 Aug;55(2):359-68. doi: 10.1016/j.jhep.2010.10.043. Epub 2010 Dec 17.
BACKGROUND & AIMS: Hypoxia-inducible factors (HIFs) and nuclear factor-κB (NF-κB) regulate genes involved in carcinogenesis and progression of cancers including hepatocellular carcinoma (HCC). The von Hippel-Lindau (VHL) protein (pVHL) targets HIFα subunits for destruction and participates in modulating the activity of NF-κB. The present study aimed to investigate whether the overexpression of pVHL synergizes with doxorubicin in the treatment of HCC.
Overexpression of pVHL was induced by infecting mouse HCC Hepa1-6 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-κB were examined. The therapeutic effects of pVHL were also evaluated in orthotopic Hepa1-6 tumors by intraportal delivery of Ad-VHL.
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-1α and HIF-2α expression, and inhibited NF-κB 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 HIFαs, activity of NF-κB, 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.
By targeting HIF and NF-κB, overexpression of pVHL enhances the efficacy of doxorubicin, and warrants consideration as a potential therapeutic strategy for treating HCC.
缺氧诱导因子（HIFs）和核因子-κB（NF-κB）调节包括肝细胞癌（HCC）在内的癌症的致癌和进展相关基因。von Hippel-Lindau（VHL）蛋白（pVHL）靶向 HIFα 亚基进行降解，并参与调节 NF-κB 的活性。本研究旨在探讨 pVHL 的过表达是否与多柔比星协同治疗 HCC。
通过感染小鼠 HCC Hepa1-6 和 H22 细胞，或在 C57BL/c 小鼠中注射皮下 Hepa1-6 肿瘤，用编码小鼠 VHL 基因的腺病毒载体诱导 pVHL 的过表达。检测细胞增殖、凋亡、肿瘤血管生成以及 NF-κB 的基因表达和 DNA 结合活性。还通过门静脉内递送 Ad-VHL 评估 pVHL 在原位 Hepa1-6 肿瘤中的治疗效果。
Ad-VHL 通过抑制细胞增殖、导致细胞周期停滞和凋亡，增强了多柔比星的抗肿瘤活性。Ad-VHL 感染下调了 HIF-1α 和 HIF-2α 的表达，并抑制了 NF-κB 活性以及涉及凋亡、增殖、血管生成、侵袭和转移的基因表达。将 Ad-VHL 注射到 HCC 肿瘤中，通过抑制细胞增殖和肿瘤血管生成以及诱导细胞凋亡，增强了多柔比星诱导的肿瘤生长抑制作用。对 HIFαs 的表达、NF-κB 的活性及其下游基因的影响与体外研究结果一致。门静脉内注射 Ad-VHL 增强了多柔比星抑制原位肝肿瘤生长的疗效。
通过靶向 HIF 和 NF-κB，pVHL 的过表达增强了多柔比星的疗效，是治疗 HCC 的一种有潜力的治疗策略。
