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Hypoxia-inducible factor 1 alpha–activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma
Abstract
Angiopoietin-like protein 4 (ANGPTL4) plays complex and often contradictory roles in vascular biology and tumor metastasis, but little is known about its function in hepatocellular carcinoma (HCC) metastasis. In the present study, we showed that hypoxia-inducible factor 1α (HIF-1α) directly up-regulates ANGPTL4, and its stableness positively correlates with ANGPTL4 expression in HCC tissue. Overexpression of ANGPTL4 significantly increased HCC cell transendothelial migration in vitro and intrahepatic and distal pulmonary metastasis in vivo, whereas silencing ANGPTL4 expression or treatment with a neutralizing antibody specific for ANGPTL4 protein resulted in a reduced transendothelial migration. We also found that serum ANGPTL4 is higher in HCC patients, compared to healthy control, and correlates with intrahepatic metastasis and histological grade. Further, secreted ANGPTL4 promotes transendothelial migration and metastasis of HCC cells in vitro and in vivo through the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) of human umbilical vein endothelial cells and the activation of the VCAM-1/integrin β1 axis. Conclusion: ANGPTL4 is a target gene of HIF-1α and acts as an important regulator in the metastasis of HCC. Serum ANGPTL4 correlates with tumor progression and metastasis and might be used to indicate prognosis in HCC patients. (HEPATOLOGY 2011 54:910–919;)
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Cited by
Passing the Vascular Barrier: Endothelial Signaling Processes Controlling Extravasation
Wettschureck, N., Strilic, B., & Offermanns, S. (2019) · Physiological Reviews · doi:10.1152/physrev.00037.2018 · Cited by 286
Angiopoietin-Like Proteins in Angiogenesis, Inflammation and Cancer
Carbone, C., Piro, G., Merz, V., Simionato, F., Santoro, R., Zecchetto, C., Tortora, G., & Melisi, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020431 · Cited by 200
Aryal, B., Rotllan, N., Araldi, E., Ramírez, C. M., He, S., Chousterman, B. G., Fenn, A. M., Wanschel, A., Madrigal-Matute, J., Warrier, N., et al. (2016) · Nature Communications · doi:10.1038/ncomms12313 · Cited by 93
Géraud, C., Mogler, C., Runge, A., Evdokimov, K., Lu, S., Schledzewski, K., Arnold, B., Hämmerling, G., Koch, P. S., Breuhahn, K., et al. (2013) · Liver International · doi:10.1111/liv.12262 · Cited by 69
Jacouton, E., Mach, N., Cadiou, J., Lapaque, N., Clément, K., Doré, J., van Hylckama Vlieg, J. E. T., Smokvina, T., & Blottière, H. M. (2015) · PLOS ONE · doi:10.1371/journal.pone.0138880 · Cited by 32
Metadata
- Authors
- Li, H., Ge, C., Zhao, F., Yan, M., Hu, C., Jia, D., Tian, H., Zhu, M., Chen, T., Jiang, G., Xie, H., Cui, Y., Gu, J., Tu, H., He, X., Yao, M., Liu, Y., & Li, J.
- Venue
- Hepatology
- Published
- 2011-09-02
- Volume
- 54
- Issue
- 3
- Pages
- 910-919
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W1975726973
- Cited by
- 180
- References
- 0
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- closed
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- Li, H., Ge, C., Zhao, F., Yan, M., Hu, C., Jia, D., Tian, H., Zhu, M., Chen, T., Jiang, G., Xie, H., Cui, Y., Gu, J., Tu, H., He, X., Yao, M., Liu, Y., & Li, J. (2011). Hypoxia-inducible factor 1 alpha–activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma. Hepatology. https://doi.org/10.1002/hep.24479
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