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PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability.
- Source :
-
Hepatology (Baltimore, Md.) [Hepatology] 2013 Aug; Vol. 58 (2), pp. 692-705. - Publication Year :
- 2013
-
Abstract
- Unlabelled: 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 1α (HIF-1α) transcription and stabilization of HIF-1α protein by recruiting histone deacetylase 1 (HDAC1) to prevent the acetylation of HIF-1α, 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.<br />Conclusion: PROX1 is a critical factor that promotes HCC metastasis.<br /> (Copyright © 2013 by the American Association for the Study of Liver Diseases.)
- Subjects :
- Animals
Carcinoma, Hepatocellular mortality
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Cell Movement physiology
Cohort Studies
Disease Models, Animal
Female
Follow-Up Studies
Heterografts
Histone Deacetylase 1 physiology
Homeodomain Proteins genetics
Humans
Liver Neoplasms mortality
Liver Neoplasms pathology
Male
Mice
Mice, Nude
Middle Aged
Neoplasm Invasiveness pathology
Neoplasm Invasiveness physiopathology
Neoplasm Metastasis pathology
Neoplasm Recurrence, Local pathology
Neoplasm Recurrence, Local physiopathology
Prognosis
Protein Stability
Survival Rate
Tumor Suppressor Proteins genetics
Carcinoma, Hepatocellular physiopathology
Gene Expression Regulation, Neoplastic physiology
Homeodomain Proteins physiology
Hypoxia-Inducible Factor 1, alpha Subunit physiology
Liver Neoplasms physiopathology
Neoplasm Metastasis physiopathology
Tumor Suppressor Proteins physiology
Up-Regulation physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1527-3350
- Volume :
- 58
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Hepatology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 23505027
- Full Text :
- https://doi.org/10.1002/hep.26398