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PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation

Oncogene volume 34, pages 5524–5535 (2015)Cite this article

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Abstract

Aberrant activation of the Wnt/β-catenin pathway is frequent in hepatocellular carcinoma (HCC) and contributes to HCC initiation and progression. This abnormal activation may result from somatic mutations in the genes of the Wnt/β-catenin pathway and/or dysregulation of the Wnt/β-catenin pathway. The mechanism for the latter remains poorly understood. Prospero-related homeobox 1 (PROX1) is a downstream target of the Wnt/β-catenin pathway in human colorectal cancer and elevated PROX1 expression promotes malignant progression. However, the Wnt/β-catenin pathway does not regulate PROX1 expression in the liver and HCC cells. Here we report that PROX1 promotes HCC cell proliferation in vitro and tumor growth in HCC xenograft mice. PROX1 and β-catenin levels are positively correlated in tumor tissues as well as in cultured HCC cells. PROX1 can upregulate β-catenin transcription by stimulating the β-catenin promoter and enhance the nuclear translocation of β-catenin in HCC cells, which leads to the activation of the Wnt/β-catenin pathway. Moreover, we show that increase in PROX1 expression renders HCC cells more resistant to sorafenib treatment, which is the standard therapy for advanced HCC. Overall, we have pinpointed PROX1 as a critical factor activating the Wnt/β-catenin pathway in HCC, which promotes HCC proliferation and sorafenib resistance.

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Acknowledgements

We thank Prof RH Dashwood of Oregon State University and Prof Long Yu of Fudan University for kindly providing the β-catenin promoter luciferase reporters. This work is supported by the grants from the National Key Project for Infectious Diseases (2012ZX10002-006, 2012ZX10004-503, 2012ZX10002012-003), National Basic Research Program (2012CB519002), Natural Science Foundation of China (31071143, 31170148, 81472226, 81372654 and 81370730), Shanghai Municipal Health Committee (GWDTR201216), Nature Science Foundation from Shandong province (ZR2011HQ006) and Municipal Science and Technology Committee (13ZR1407100).

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  1. Y Liu, X Ye and J-B Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Y Liu, X Ye, H Ouyang, Z Shen, Y Wu, W Wang, J Wu, S Tao, X Yang, K Qiao, J Zhang, J Liu, Q Fu & Y Xie

  2. Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China

    Y Liu

  3. Liver Cancer Institute, Zhongshan Hospital; Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University,

    J-B Zhang

  4. Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China

    J-B Zhang

  5. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    H Ouyang

  6. Department of Immunology, Binzhou Medical University, Yantai, China

    Q Fu

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Correspondence to J Liu, Q Fu or Y Xie.

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Liu, Y., Ye, X., Zhang, JB. et al. PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation. Oncogene 34, 5524–5535 (2015). https://doi.org/10.1038/onc.2015.7

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  • DOI: https://doi.org/10.1038/onc.2015.7

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