PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1 expression and protein stability
PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1 expression and protein stability
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PROX1通过上调缺氧诱导因子1表达和蛋白稳定性促进肝细胞癌转移
DOI：
10.1002/hep.26398
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发表时间：
2013-08-01
期刊：
影响因子：
13.5
通讯作者：
Xie, Youhua
中科院分区：
文献类型：
--
作者：
Liu, Yanfeng;Zhang, Ju-Bo;Xie, Youhua
肝细胞癌（HCC）是世界范围内最常见的癌症之一，也是第三大癌症死亡原因。由于肝癌的侵袭性、肝内扩散和肝外转移，其预后非常差。肝癌侵袭和转移的分子机制还不清楚。同源框蛋白PROX 1是小鼠胚胎肝发育过程中肝细胞迁移所必需的。在这项研究中，我们发现原发性肝癌组织中PROX 1蛋白的高表达与术后肝癌患者的生存率和早期肿瘤复发显著相关。肝癌细胞中PROX 1表达的敲低抑制了细胞的体外迁移和侵袭以及裸鼠肝癌转移，而肝癌细胞中PROX 1的过表达促进了这些过程。PROX 1的促转移活性最可能归因于其通过募集组蛋白脱乙酰酶1（HDAC 1）来上调缺氧诱导因子1（HIF-1）转录和稳定HIF-1蛋白，以防止HIF-1的乙酰化，其随后诱导HCC细胞中的上皮-间充质转化反应。我们进一步证明了联合应用PROX 1和HDAC 1水平预测HCC术后生存率和早期复发的预后价值。结论：PROX 1是促进肝癌转移的关键因子。（肝病学2013;58：692-705）
Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death from cancer worldwide. HCC has a very poor prognosis because of tumor invasiveness, frequent intrahepatic spread, and extrahepatic metastasis. The molecular mechanism of HCC invasiveness and metastasis is poorly understood. The homeobox protein PROX1 is required for hepatocyte migration during mouse embryonic liver development. In this study, we show that high PROX1 protein expression in primary HCC tissues is associated with significantly worse survival and early tumor recurrence in postoperative HCC patients. Knockdown of PROX1 expression in HCC cells inhibited cell migration and invasiveness in vitro and HCC metastasis in nude mice while overexpression of PROX1 in HCC cells promoted these processes. PROX1's pro-metastasis activity is most likely attributed to its up-regulation of hypoxia-inducible factor 1 (HIF-1) transcription and stabilization of HIF-1 protein by recruiting histone deacetylase 1 (HDAC1) to prevent the acetylation of HIF-1, which subsequently induces an epithelial-mesenchymal transition response in HCC cells. We further demonstrated the prognostic value of using the combination of PROX1 and HDAC1 levels to predict postoperative survival and early recurrence of HCC. Conclusion: PROX1 is a critical factor that promotes HCC metastasis. (Hepatology 2013;58:692-705)