Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice

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• 作者：Femke Heindryckx¹ ; Anna Kuchnio² ; ³ ; Christophe Casteleyn⁴ ; Stephanie Coulon¹ ; Kim Olievier¹ ; Isabelle Colle¹ ; Anja Geerts¹ ; Louis Libbrecht⁵ ; Peter Carmeliet² ; ³ ; Hans Van Vlierberghe¹ ; ^{Hans.VanVlierberghe@UGent.be}
• 关键词：HCC ; hepatocellular carcinoma ; CC ; cholangiocarcinoma ; HIF ; hypoxia inducible factors ; PHD ; prolyl hydroxylase domains ; HPC ; hepatic progenitor cells ; VEGF ; vascular endothelial growth factor ; PlGF ; placental growth factor ; DEN ; diethylnitrosamine ; CK19
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：July, 2012
• 卷：57
• 期：1
• 页码：61-68
• 文件大小：1329 K

摘要

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Background & Aims

The two major primary liver cancers in adults are hepatocellular carcinoma and cholangiocarcinoma. These tumors rapidly outgrow their vascular supply and become hypoxic, resulting in the production of hypoxia inducible factors. Recently, interest has grown in the regulators of these factors. Several reports have been published describing the role of prolyl hydroxylase domains - the key oxygen sensor responsible for the degradation of hypoxia inducible factors - in tumor progression and vascularisation. The effect of prolyl hydroxylase domain 2 on the pathogenesis of liver cancer has never been studied.

Methods

A diethylnitrosamine-induced mouse model was used in this study, allowing primary hepatic tumors to occur as a result of chronic liver damage. Several parameters of prolyl hydroxylase domain 2-haplodeficient mice were compared to those of wild type mice, thereby focussing on the expression of angiogenic factors and on the hepatic progenitor cell activation and differentiation.

Results

This study shows that inhibiting prolyl hydroxylase domain 2 increases the hepatocarcinogenesis and stimulates the development of cholangiocarcinoma. Furthermore, PHD2 deficiency and the accompanying continuous HIF activation, selected for a more metastatic tumor phenotype.

Conclusions

The effect of prolyl hydroxylase domain 2 deficiency on hepatocarcinogenesis hold a great potential for therapeutic intervention, since hypoxia and the selection for a more aggressive cholangiocarcinoma phenotype might also have a repercussion on patients receiving long-term treatment with anti-angiogenic compounds.