Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin-specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin-8 (IL-8) by epigenetically stimulating the IL-8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti-IL-8 monoclonal antibody. Conclusions: We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894–1909)

中文翻译：

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Prospero相关的同源盒1通过选择性激活白介素8表达来驱动肝细​​胞癌的血管生成

血管生成已被证明在肝细胞癌（HCC）的进展中起重要作用。但是，尚不清楚HCC血管生成的分子机制。在这项研究中，与Prospero相关的同源盒1（PROX1）被确定为HCC细胞系和组织中的新型促血管生成因子。在肝癌组织中，PROX1的水平与微血管密度之间存在很强的正相关性。敲低HCC细胞中PROX1表达的表达可显着抑制人血管内皮细胞的体外毛细血管形成和HCC的体内血管生成，而PROX1的过表达在HCC细胞中诱导相反的作用。在肝癌组织和细胞系中，PROX1和核因子κBp65表达水平呈正相关。PROX1通过募集泛素特异性蛋白酶7来防止p65泛素化，从而增强p65的核积累并稳定p65。因此，PROX1通过表观遗传刺激IL-8启动子激活了核因子κB信号传导并选择性地促进了促血管生成白介素8（IL-8）的表达。最后，抗IL-8单克隆抗体可以有效地抑制肿瘤异种移植小鼠中高PROX1表达HCC的进程。结论：我们已经确定PROX1是HCC血管生成的关键启动子；我们的研究提供了PROX1在HCC进展中的功能以及抗IL-8抗体在高表达PROX1的HCC患者中的潜在治疗应用的见识。（H epatology 2017; 66：1894-1909）