Prospero-Related Homeobox 1 Drives Angiogenesis of Hepatocellular Carcinoma Through Selectively Activating Interleukin-8 Expression
Prospero-Related Homeobox 1 Drives Angiogenesis of Hepatocellular Carcinoma Through Selectively Activating Interleukin-8 Expression
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Prospero 相关同源框 1 通过选择性激活 IL-8 表达驱动肝细胞癌的血管生成
DOI：
10.1002/hep.29337
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发表时间：
2017-12-01
期刊：
影响因子：
13.5
通讯作者：
Qin, Lun-Xiu
中科院分区：
文献类型：
--
作者：
Liu, Yanfeng;Zhang, Yonglong;Qin, Lun-Xiu
血管生成已被证明在肝细胞癌（HCC）的进展中起重要作用。然而，HCC血管生成的分子机制还不清楚。在这项研究中，普洛斯彼罗相关同源框1（PROX 1）被确定为一种新的促血管生成因子在肝癌细胞系和组织。肝癌组织中PROX 1的表达水平与微血管密度呈正相关。在肝癌细胞中敲低PROX 1表达显著抑制人血管内皮细胞的体外毛细血管形成和肝癌的体内血管生成，而在肝癌细胞中过表达PROX 1则诱导相反的效果。PROX 1和核因子jB p65的表达水平在HCC组织和细胞系中均呈正相关。PROX 1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，PROX 1激活核因子jB信号传导，并通过表观遗传学刺激IL-8启动子选择性地促进促血管生成白细胞介素-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PROX 1表达HCC的进展。结论：我们已经确定PROX 1是HCC血管生成的关键启动子;我们的研究提供了对PROX 1在HCC进展中的功能的深入了解，以及抗IL-8抗体在PROX 1高表达HCC患者中的潜在治疗应用。
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 jB 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 jB 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.