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Synergistic function of Kras mutation and HBx in initiation and progression of hepatocellular carcinoma in mice

Oncogene volume 33, pages 5133–5138 (2014)Cite this article

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Abstract

Although the activation of Ras pathway is frequently observed in human hepatocellular carcinoma (HCC), the in vivo role of Ras activation in HCC initiation and progression is underdetermined. To test the consequence of Kras activation in hepatocyte, we generated a hepatocyte-specific KrasG12D transgenic mouse strain and observed spontaneous development of HCC in these mice. Remarkably, HBV X protein (HBx) expression significantly promotes the formation and malignant progression of KrasG12D-driven HCC as shown with the accelerated tumor onset, the increased tumor burden and the more poorly differentiated lesions. At the cellular level, concomitant expression of KrasG12D and HBx results in a robust increase in hepatocellular proliferation. We reveal that the Akt, MAPK, p53 and TGF-β pathways are deregulated in the KrasG12D-driven HCCs. Also, the dysregulation is more pronounced in the HCCs developed in KrasG12D and HBx double transgenic mice. In addition, the altered expressions of β-catenin, CD44 and E-cadherin are only observed in the KrasG12D and HBx double transgenic mice. These results demonstrate a crucial role of Ras activation in hepatocellular carcinogenesis and the functional synergy between KrasG12D and HBx in HCC initiation and progression. The novel genetic mouse models that closely recapitulate the histopathologic progression and molecular alterations of human HCC may potentially facilitate the future therapeutic studies.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81272702; 31171249; 31071295; 81123001), Chinese National Key Program on Basic Research (2011CB504202; 2012CB945103; 2011CB910601) and National High Technology Research and Development program of China (2012AA022402). We thank Xiao-Yan Chang for histopathologic analysis, You-Liang Wang, Xiu-Bin Li, Xiao-Jie Xu, Qi-Long Ye and Xin Chen for technical support.

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  1. H Ye, C Zhang and B-J Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University School of Medicine, Shanghai, China

    H Ye, C Zhang & X Yang

  2. State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China

    H Ye, C Zhang, B-J Wang, X-H Tan, Y Teng & X Yang

  3. Department of Pathophysiology, Second Military Medical University, Shanghai, China

    W-P Zhang

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Correspondence to Y Teng or X Yang.

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Ye, H., Zhang, C., Wang, BJ. et al. Synergistic function of Kras mutation and HBx in initiation and progression of hepatocellular carcinoma in mice. Oncogene 33, 5133–5138 (2014). https://doi.org/10.1038/onc.2013.468

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