PROX1 Promotes Hepatocellular Carcinoma Metastasis By Way of Up-Regulating Hypoxia-Inducible Factor 1α Expression and Protein Stability
Abstract
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. Conclusion : PROX1 is a critical factor that promotes HCC metastasis. (Hepatology 2013;58:692-705)
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Both tumor-promoting and suppressor roles have been reported for PROX1 in liver cancer models.
“but both tumor-promoting and suppressor roles have been reported in liver cancer models22,23”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [22]
Prox1 overexpression in tumor cells induced migratory and metastatic potential upon transplantation in prior studies.
“This contrasts studies where Prox1 OE in tumor cells induced migratory and metastatic potential upon transplantation22,63.”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [22]
Cites
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380 · see citing works
Biomarkers for epithelial-mesenchymal transitions
Zeisberg, M., & Neilson, E. G. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36183 · Cited by 2,299 · cited 1× · see citing works
“, vimentin).(2) EMT has a crucial role in the progression and metastasis of multiple cancers including HCC.”
BackgroundNF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., Johnson, R. S., Haddad, G. G., & Karin, M. (2008) · Nature · doi:10.1038/nature06905 · Cited by 1,614 · see citing works
Regulation and Destabilization of HIF-1α by ARD1-Mediated Acetylation
Jeong, J.-W., Bae, M.-K., Ahn, M.-Y., Kim, S.-H., Sohn, T.-K., Bae, M.-H., Yoo, M.-A., Song, E. J., Lee, K.-J., & Kim, K.-W. (2002) · Cell · doi:10.1016/s0092-8674(02)01085-1 · Cited by 716 · see citing works
Hepatocyte migration during liver development requires Prox1
Sosa-Pineda, B., Wigle, J. T., & Oliver, G. (2000) · Nature Genetics · doi:10.1038/76996 · Cited by 381 · see citing works
Shimoda, M., Takahashi, M., Yoshimoto, T., Kono, T., Ikai, I., & Kubo, H. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0712 · Cited by 106 · cited 6× · see citing works
“In another earlier work, however, Shimoda et al.18 also used quantitative RT-PCR to evaluate PROX1 mRNA levels in 52 HCC samples and identified a positive correlation between PROX1 mRNA level and better prognosis.”
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Lim, B., Kamal, A., Gomez Ramos, B., Adrian Segarra, J. M., Ibarra, I. L., Dignas, L., Kindinger, T., Volz, K., Rahbari, M., Rahbari, N., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02081-w · Cited by 17 · see citing works
- Authors
- Liu, Y., Zhang, J.-B., Qin, Y., Wang, W., Wei, L., Teng, Y., Guo, L., Zhang, B., Lin, Z., Liu, J., Ren, Z.-G., Ye, Q.-H., & Xie, Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Zhejiang Sci-Tech University (CN)
- Fudan University (CN)
- Corresponding author
- Ye, Qing-Hai
- Xie, Youhua
- Venue
- Hepatology
- Published
- 2013-08
- Volume
- 58
- Issue
- 2
- Pages
- 692-705
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W1968687296
- Cited by
- 105
- References
- 6
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 15 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 19 · 2015: 7 · 2014: 10 · 2013: 1
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- Prox1, hepatocellular carcinoma, metastasis, hypoxia-inducible factor-1α, HDAC1, epithelial-mesenchymal transition, cell migration and invasion, prognostic factors, postoperative recurrence, tumor recurrence
- MeSH terms
- Prospero-Related Homeobox 1 Protein, Animals, Cell Movement, Disease Models, Animal, Female, Follow-Up Studies, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Mice, Nude, Middle Aged, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Recurrence, Local, Prognosis, Cohort Studies, Up-Regulation, Gene Expression Regulation, Neoplastic, Survival Rate, Homeodomain Proteins, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Protein Stability, Histone Deacetylase 1, Heterografts
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