Prospero-related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating IL-8 expression

ABSTRACT

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 pro-angiogenic 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 NF-κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 could enhance the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin specific protease 7 (USP7) to prevent p65 ubiquitination. Consequently, PROX1 activated the NF-κB signaling and selectively promoted the expression of the pro-angiogenic 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 mAb. Conclusions: We have identified PROX1 as a crucial promoter of HCC angiogenesis. Our study provides a novel insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. This article is protected by copyright. All rights reserved.

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