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HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

Oncogene volume 30, pages 4410–4427 (2011)Cite this article

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Abstract

Epithelial–mesenchymal transition (EMT) induced by transforming growth factor-β (TGF-β) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-β-driven pathway. A dual-luciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-β coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/Akt/GSK3β signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-β. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (rs=−0.3622, P=0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (rs=0.3064, P=0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-β→PI3K/Akt→GSK3β→Snail→Slug→CD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC.

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Acknowledgements

We thank Professor Xiao-Long Ji (Department of Pathology, General Hospital of the Chinese People's Armed Police Forces, Beijing, China), Professor Wei Zhang (Department of Pathology, Tangdu Hospital of Fourth Military Medical University, Xi’an, China) and Professor Qiao-Nan Guo (Department of Pathology, Southwest Hospital of Third Military Medical University, Chongqing, China) for their pathology analyses. We thank Professor Mien-Chie Hung (Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA) for providing pEGFP-Snail1, and Dr Ling-Min Kong and Xia Ke in our lab for providing pGL3-CD147 (−1761/+37), pGL3-CD147 (−644/+37) and pGL3-CD147 (−338/+37). Financial support: This work was supported by grants from the National Natural Science Foundation of China (Nos. 30870944 and 30671196), and the Hi-tech Research and Development Programme of China (No. 2009CB521706). Writing assistance was provided by American Journal Experts, USA.

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  1. J Wu, N-Y Ru and Y Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China

    J Wu, N-Y Ru, Y Zhang, Y Li, D Wei, Z-N Chen & H Bian

  2. Department of Microbiology, Third Military Medical University, Chongqing, China

    Z Ren

  3. Central Laboratory, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

    X-F Huang

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  1. J Wu
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Wu, J., Ru, NY., Zhang, Y. et al. HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug. Oncogene 30, 4410–4427 (2011). https://doi.org/10.1038/onc.2011.149

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