PROX1 Promotes Hepatocellular Carcinoma Metastasis Via Up-Regulating Hypoxia-inducible Factor 1α Expression And Protein Stability

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death from cancer worldwide. HCC has an extremely poor prognosis because of a high potential for vascular invasion, metastasis and recurrence. The mechanism of HCC metastasis is not well understood. Epithelial-mesenchymal transition (EMT) has a crucial role in the progression and metastasis of multiple cancers including HCC. EMT is a process in which epithelial cells lose polarity and cell-cell adhesion, and are converted to a mesenchymal phenotype. EMT is triggered and controlled by signals cancer cells receive from their microenvironment. One of the major EMT triggers in cancers is the signaling through hypoxia-inducible factor 1 (HIF-1), activated via hypoxia-dependent or hypoxia-independent pathways. Enhanced HIF-1 activities have been reported to promote angiogenesis and invasiveness in HCC. HIF-1 is composed of a hypoxia-inducible a subunit (HIF-1 a) and a constitutively expressing β subunit (HIF-1β). The majority of HCC patients are high HIF-1 a expression, promoting HCC invasion and lymph node metastasis.Prospero-related homeobox 1 (PROX1) is an essential regulator for the development of multiple organs and tissues including central nervous system, heart, eye, lymphatic vessel, pancreas, and liver. Homozygous PROX1 knockout mice are embryonic lethal due to multiple developmental defects. PROX1 is essential for embryonic liver development in which it is required for hepatocyte migration. The correlation between PROX1 and human cancer development has been studied in several cancers. PROX1 exhibits tumor suppressor activity or oncogenic activity depending on cancer types, suggesting that PROX1’s role in cancer development is complex and depends on tissue and cellular context. In this report, we for the first time demonstrate PROX1 as a driving factor for HCC metastasis. HCC patients with high PROX1 protein expression in tumors are associated with significantly worse postoperative survival and more frequent recurrence. Knockdown of PROX1 expression in HCC cells inhibits cell migration and invasiveness in vitro and HCC metastasis in tumor xenograft mice while overexpression of PROX1 in HCC cells exerts the opposite effects. PROX1 up-regulates the transcription of hypoxia-inducible factor 1 (HIF-la) and stabilizes HIF-1α protein by recruiting histone deacetylase 1 (HDAC1) to prevent HIF-la acetylation. Consequently, PROX1 promotes the epithelial-mesenchymal transition of HCC cells. We further demonstrate that the combination of PROX1 and HDAC1 can serve as a promising predictor for postoperative survival and early recurrence in HCC patients. Conclusion:PROX1 is a critical factor that promotes HCC metastasis.