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Regulation of a TGF-β1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells

Oncogene volume 35, pages 5468–5479 (2016)Cite this article

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Abstract

Cellular plasticity has an important role in the progression of hepatocellular carcinoma (HCC). In this study, the involvement of a TGF-β1-CD147 self-sustaining network in the regulation of the dedifferentiation progress was fully explored in HCC cell lines, hepatocyte-specific basigin/CD147-knockout mice and human HCC tissues. We demonstrated that TGF-β1 stimulation upregulated CD147 expression and mediated the dedifferentiation of HCC cells, whereas all-trans-retinoic acid induced the downregulation of CD147 and promoted differentiation in HCC cells. Overexpression of CD147 induced the dedifferentiation and enhanced the malignancy of HCC cells, and increased the transcriptional expression of TGF-β1 by activating β-catenin. CD147-induced matrix metalloproteinase (MMP) production activated pro-TGF-β1. The activated TGF-β1 signaling subsequently repressed the HNF4α expression via Smad-Snail1 signaling and enhanced the dedifferentiation progress. Hepatocyte-specific basigin/CD147-knockout mice decreased the susceptibility to N-nitrosodiethylamine-induced tumorigenesis by suppressing TGF-β1-CD147 signaling and inhibiting dedifferentiation in hepatocytes during tumor progression. CD147 was positively correlated with TGF-β1 and negatively correlated with HNF4α in human HCC tissues. Positive CD147 staining and lower HNF4α levels in tumor tissues were significantly associated with poor survival of patients with HCC. The overexpression of HNF4α and Smad7 and the deletion of CD147 by lentiviral vectors jointly reprogrammed the expression profile of hepatocyte markers and attenuated malignant properties including proliferation, cell survival and tumor growth of HCC cells. Our results highlight the important role of the TGF-β1-CD147 self-sustaining network in driving HCC development by regulating differentiation plasticity, which provides a strong basis for further investigations of the differentiation therapy of HCC targeting TGF-β1 and CD147.

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Acknowledgements

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 we thank professor Ye-Guang Chen (School of Life Science, Tsinghua University) for providing pcDNA-Flag-Smad7. This work was supported by grants from the National Natural Science Foundation of China (No. 31401222, 31571434, 31401190 and 81172144) and the National Science and Technology Major Project (No. 2012ZX10002-015, 2012AA020806 and 2015CB553701).

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  1. J Wu, M Lu and Y Li: These authors contributed equally to this work.

Authors and Affiliations

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

    J Wu, M Lu, Y-K Shang, S-J Wang, Y Meng, Z-N Chen & H Bian

  2. Department of Oncology, PLA 323 Hospital, Xi’an, China

    Y Li

  3. Department of Pathology, Fourth Military Medical University, Xi’an, China

    Z Wang & Z-S Li

  4. Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing, China

    H Chen

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Wu, J., Lu, M., Li, Y. et al. Regulation of a TGF-β1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells. Oncogene 35, 5468–5479 (2016). https://doi.org/10.1038/onc.2016.89

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