HIFs enhance the migratory and neoplastic capacities of hepatocellular carcinoma cells by promoting EMT
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Although the involvement of the epithelial-to-mesenchymal transition (EMT) in HCC progression is established, the mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, modulate the EMT through Twist1, a regulator of the EMT. The levels of HIF-1α and HIF-2α in HCC tissues were higher than those in matched, non-tumor surrounding tissues. In HCC samples, the levels of HIF-1α and HIF-2α negatively correlated with the levels of E-cadherin but positively correlated with the levels of vimentin. In highly metastatic MHCC97H cells, the levels of HIF-1α, HIF-2α, and Twist1 were higher than those in weakly metastatic HepG2 cells. In HepG2 cells, over-expression of HIFs enhanced levels of Twist1 and the EMT, which elevated the migratory and neoplastic capacities of cells. For MHCC97H cells, inhibition of HIFs reduced Twist1 levels and the EMT, which reduced their migratory and neoplastic capacity. Thus, the promotion of EMT by HIFs via Twist1 enhanced the migration and neoplastic capacities of HCC cells.
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Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types.
“Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types”
From Hypoxic control of metastasis (2016) · cites this paper as [71]
Cites
Jemal, A., Bray, F., Ferlay, J., Ward, E., & Forman, D. (2011) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.20107 · Cited by 54,708 · see citing works
Complex networks orchestrate epithelial–mesenchymal transitions
Thiery, J. P., & Sleeman, J. P. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1835 · Cited by 3,947 · see citing works
Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype?
Peinado, H., Olmeda, D., & Cano, A. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2131 · Cited by 3,121 · see citing works
HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and Proliferation
Gordan, J. D., Thompson, C. B., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.07.006 · Cited by 806 · see citing works
Thomas, M. B., Jaffe, D., Choti, M. A., Belghiti, J., Curley, S. A., Fong, Y., Gores, G. J., Kerlan, R. K., Merle, P., O’Neil, B. H., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.7805 · Cited by 394 · see citing works
Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma
van Zijl, F., Zulehner, G., Petz, M., Schneller, D., Kornauth, C., Hau, M., Machat, G., Grubinger, M., Huber, H., & Mikulits, W. (2009) · Future Oncology · doi:10.2217/fon.09.91 · Cited by 307 · see citing works
Zhang, L., Huang, G., Li, X., Zhang, Y., Jiang, Y., Shen, J., Liu, J., Wang, Q., Zhu, J., Feng, X., et al. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-108 · Cited by 293 · see citing works
EMT: A new vision of hypoxia promoting cancer progression
Jiang, J. D., Tang, Y., & Liang, X. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.11.8.15274 · Cited by 254 · see citing works
Zhang, Q., Bai, X., Chen, W., Ma, T., Hu, Q., Liang, C., Xie, S., Chen, C.-L., Hu, L., Xu, S., et al. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt027 · Cited by 248 · see citing works
Lin, C., Tsai, P., Kandaswami, C. C., Lee, P.-P., Huang, C., Hwang, J., & Lee, M. (2011) · Cancer Science · doi:10.1111/j.1349-7006.2011.01861.x · Cited by 185 · see citing works
Bao, L., Yan, Y., Xu, C., Ji, W., Shen, S., Xu, G., Zeng, Y., Sun, B., Qian, H., Chen, L., et al. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.05.007 · Cited by 184 · see citing works
Chen, J., Huang, X., Wang, Q., Huang, J., Zhang, L., Chen, X., Lei, J., & Cheng, Z. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs274 · Cited by 172 · see citing works
Self-citationPhilip, B., Ito, K., Moreno‐Sánchez, R., & Ralph, S. J. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt209 · Cited by 160 · see citing works
Ding, S., Li, Y., Shao, X., Zhou, H., Zeng, R., Tang, Z., & Xia, Q. (2004) · PROTEOMICS · doi:10.1002/pmic.200300653 · Cited by 154 · see citing works
HIF1α and HIF2α independently activate SRC to promote melanoma metastases
Hanna, S. C., Krishnan, B., Bailey, S. T., Moschos, S. J., Kuan, P.-F., Shimamura, T., Osborne, L. D., Siegel, M. B., Duncan, L. M., O’Brien, E. T., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66715 · Cited by 147 · see citing works
Naber, H. P. H., Drabsch, Y., Snaar-Jagalska, E. B., ten Dijke, P., & van Laar, T. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.04.037 · Cited by 135 · see citing works
Dai, C.-X., Gao, Q., Qiu, S., Ju, M., Cai, M., Xu, Y., Zhou, J., Zhang, B., & Fan, J. (2009) · BMC Cancer · doi:10.1186/1471-2407-9-418 · Cited by 133 · see citing works
Self-citationNan, K. (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.1197 · Cited by 123 · see citing works
Zhao, X., Sun, T., Che, N., Sun, D., Zhao, N., Dong, X.-Y., Gu, Q., Yao, Z., & Sun, B. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01052.x · Cited by 115 · see citing works
Ming-li, H., Liu, M., Wang, Y., Mo, Z., Bi, X., Liu, Z., Fan, Y., Chen, X., & Wu, C. (2011) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-011-1195-5 · Cited by 114 · see citing works
Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma
Wang, X. Q., Zhang, W., Lui, E. L. H., Zhu, Y., Lü, P., Yu, X., Sun, J.-S., Yang, S., Poon, R. T. P., & Fan, S. T. (2011) · International Journal of Cancer · doi:10.1002/ijc.27336 · Cited by 95 · see citing works
Microbes-induced EMT at the crossroad of inflammation and cancer
Hofman, P. M., & Vouret‐Craviari, V. (2012) · Gut Microbes · doi:10.4161/gmic.20288 · Cited by 95 · see citing works
Cane, G., Ginouvès, A., Marchetti, S., Buscà, R., Pouysségur, J., Berra, E., Hofman, P. M., & Vouret‐Craviari, V. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01422.x · Cited by 82 · see citing works
Han, Y., Dong, X., Zhong, X., Ye, J., Zhou, Y., Yang, X., Shen, J., & Zhang, J. (2013) · Molecular Carcinogenesis · doi:10.1002/mc.22064 · Cited by 81 · see citing works
Self-citationTang, O., Chen, X., Shen, S., Hahn, M., & Pollock, C. A. (2013) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00302.2012 · Cited by 80 · see citing works
Hyperoxic Treatment Induces Mesenchymal-to-Epithelial Transition in a Rat Adenocarcinoma Model
Moen, I. N., Oyan, A. M., Kalland, K.-H., Tronstad, K. J., Akslen, L. A., Chekenya, M., Sakariassen, P. Ø., Reed, R. K., & Stuhr, L. E. B. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006381 · Cited by 76 · see citing works
Slug promoted vasculogenic mimicry in hepatocellular carcinoma
Sun, D., Sun, B., Liu, T., et al. (2013) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12087 · Cited by 74 · see citing works
Claudin-1 as a promoter of EMT in hepatocellular carcinoma
Stebbing, J., Filipović, A., & Giamas, G. (2013) · Oncogene · doi:10.1038/onc.2012.591 · Cited by 55 · see citing works
Xiang, Z.-L., Zeng, Z.-C., Fan, J., Tang, Z.-Y., He, J., Zeng, H.-Y., & Chang, J. Y. (2012) · Molecular Biology Reports · doi:10.1007/s11033-011-0949-1 · Cited by 52 · see citing works
Xu, Y., Li, Y., Pang, Y., Ling, M., Shen, L., Yang, X., Zhang, J., Zhou, J., Wang, X., & Liu, Q. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037765 · Cited by 47 · see citing works
Self-citationExpression of HIF-2α/EPAS1 in hepatocellular carcinoma
Bangoura, G. (2004) · World Journal of Gastroenterology · doi:10.3748/wjg.v10.i4.525 · Cited by 41 · see citing works
Xu, Y., Li, Y., Pang, Y., Ling, M., Shen, L., Jiang, R., Zhao, Y., Zhou, J., Wang, X., & Liu, Q. (2012) · Archives of Toxicology · doi:10.1007/s00204-012-0810-x · Cited by 39 · see citing works
Self-citationOgunwobi, O. O., & Liu, C. (2011) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2011.11.007 · Cited by 35 · see citing works
Zhang, Q., Xl, B., Ma, T., et al. (2012) · Cited by 34 · see citing works
Xu, Y., Li, Y., Li, H., Pang, Y., Zhao, Y., Jiang, R., Shen, L., Zhou, J., Wang, X., & Liu, Q. (2012) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2012.11.014 · Cited by 29 · see citing works
Self-citationLiu, H., Chen, G., Zhang, W., et al. (2012) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-012-1330-z · Cited by 26 · see citing works
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Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340 · see citing works
Non-redundant functions of EMT transcription factors
Stemmler, M. P., Eccles, R. L., Brabletz, S., & Brabletz, T. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0196-y · Cited by 524 · see citing works
- Authors
- Liu, Y., Liu, Y., Yan, X., Xu, Y., Luo, F., Ye, J., Yan, H., Yang, X., Huang, X., Zhang, J., & Ji, G.
- Affiliations
- Nanjing Medical University (CN)
- Second Affiliated Hospital of Nanjing Medical University (CN)
- Corresponding author
- Zhang, Jianping
- Ji, Guozhong
- Venue
- Tumor Biology
- Published
- 2014-05-20
- Volume
- 35
- Issue
- 8
- Pages
- 8103-8114
- ISSN
- 1010-4283 (ISSN-L)
- 1423-0380
- OpenAlex
- W2121263831
- Cited by
- 37
- References
- 36
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 2
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Tumor Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Alabama at Birmingham
- Government of Jiangsu Province
- Nanjing Medical University
- Nanjing University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- hepatocellular carcinoma, hypoxia-inducible factor, HIF-1α, HIF-2α, epithelial-mesenchymal transition, TWIST1, cell migration, metastasis, E-cadherin, vimentin, MHCC97H cells, HepG2 cells
- MeSH terms
- Zinc Finger E-box-Binding Homeobox 1, Endothelial PAS Domain-Containing Protein 1, Cell Movement, Cells, Cultured, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Nuclear Proteins, Transcription Factors, Homeodomain Proteins, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Twist-Related Protein 1, Epithelial-Mesenchymal Transition
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