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Sorafenib Inhibition of Hepatic Stellate Cell Proliferation in Tumor Microenvironment of Hepatocellular Carcinoma: A Study of the Sorafenib Mechanisms

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Abstract

We investigated the mechanism and effects of sorafenib on hepatic stellate cell (HSC) viability and in the liver tumor microenvironment. The expression of α-smooth muscle actin (α-SMA) was measured immunocytochemically in the LX2 cells treated with differing concentrations of sorafenib. Changes in the platelet-derived growth factor (PDGF)-BB and tumor growth factor (TGF)-β1 concentrations were detected in the LX2 supernatant using an enzyme-linked immunosorbent assay (ELISA). Expressions of the extracellular signal-regulated kinase 1 (ERK1), ERK2, and Akt signaling pathways were measured using a western blot assay. The LX2 cells were cocultured with HepG2 cells for 24 h to observe their effects on HepG2 cell invasive ability. (1) After treatment with various concentrations of sorafenib for 12, 24, 36, or 48 h, MTT assay showed that the viability of the treated LX2 cells was lower than in the controls. (2) As sorafenib concentration and time of exposure increased, α-SMA expression became weaker in the treated cells. (3) The PDGF-BB and TGF-β1 concentrations decreased with higher concentration, and longer exposures under the same sorafenib concentration. (4) The ERK1, ERK2, and Akt expressions were identical between the treated and the control groups, but their phosphorylated expression decreased with increased concentrations of sorafenib. (5) The invasive ability of the HepG2 cells induced by the LX2 gradually decreased as sorafenib concentrations increased. Sorafenib suppressed α-SMA expression, inhibited PDGF-dependent signaling pathways in HSCs, downregulated the PDGF-BB and TGF-β1 expression in the HSCs supernatant, and restrained viability of the HSCs, resulting in suppressed proliferation and invasion in the HepG2 cells.

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References

  1. Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., & Parkin, D. M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer, 127, 2893–2917.

    Article  CAS  Google Scholar 

  2. Yang, J. D., Nakamura, I., & Roberts, L. R. (2011). The tumor microenvironment in hepatocellular carcinoma: Current status and therapeutic targets. Seminars in Cancer Biology, 21, 35–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Amann, T., Bataille, F., Spruss, T., Mühlbauer, M., Gäbele, E., Schölmerich, J., et al. (2009). Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma. Cancer Science, 100, 646–653.

    Article  CAS  PubMed  Google Scholar 

  4. Wilhelm, S. M., Adnane, L., Newell, P., Villanueva, A., Llovet, J. M., & Lynch, M. (2008). Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Molecular Cancer Therapeutics, 7, 3129–3140.

    Article  CAS  PubMed  Google Scholar 

  5. Faouzi, S., Lepreux, S., Bedin, C., Dubuisson, L., Balabaud, C., Bioulac-Sage, P., et al. (1999). Activation of cultured rat hepatic stellate cells by tumoral hepatocytes. Laboratory Investigation, 79, 485–493.

    CAS  PubMed  Google Scholar 

  6. Thabut, D., Routray, C., Lomberk, G., Shergill, U., Glaser, K., Huebert, R., et al. (2011). Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology, 54, 573–585.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Olaso, E., Salado, C., Egilegor, E., et al. (2003). Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. Hepatology, 37, 674–685.

    Article  CAS  PubMed  Google Scholar 

  8. Pinzani, M., Gesualdo, L., Sabbah, G. M., & Abboud, H. E. (1989). Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. The Journal of Clinical Investigation, 84, 1786–1793.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Yu, J., Ustach, C., & Kim, H. R. (2003). Platelet-derived growth factor signaling and human cancer. Journal of Biochemistry and Molecular Biology, 36, 49–59.

    Article  CAS  PubMed  Google Scholar 

  10. Boner, J. C. (2004). Regulation of PDGF and its receptors in fibrotic diseases. Cytokine & Growth Factor Reviews, 15, 255–273.

    Article  Google Scholar 

  11. Gressner, A. M., Weiskirchen, R., Breitkopf, K., & Dooley, S. (2002). Roles of TGF-beta in hepatic fibrosis. Frontiers in Bioscience, 7, d793–d807.

    Article  CAS  PubMed  Google Scholar 

  12. Rasanen, K., & Vaheri, A. (2010). Activation of fibroblasts in cancer stroma. Experimental Cell Research, 316(17), 2713–2722.

    Article  PubMed  Google Scholar 

  13. Pinzani, M. (2002). PDGF and signal transduction in hepatic stellate cells. Frontiers in Bioscience, 7, d1720–d1726.

    Article  CAS  PubMed  Google Scholar 

  14. Marra, F., Pinzani, M., DeFranco, R., Laffi, G., & Gentilini, P. (1995). Involvement of phosphatidylinositol 3-kinase in the activation of extracellular signal-regulated kinase by PDGF in hepatic stellate cells. FEBS Letters, 376, 141–145.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 30971340) and CSCO–Bayer Schering Liver Cancer Fund for Young Physicians (2010).

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China

    Zhi-min Geng, Bo Li, Chen Chen, Wen-zhi Li, Lin Wang & Sha Huanchen

  2. Department of General Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China

    Jian-bao Zheng

  3. Department of Cancer Research, Xi’an Medical College, Xin Wang Road, Weiyang, Xi’an, 710021, People’s Republic of China

    Rajiv Kumar Jha

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  1. Zhi-min Geng
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  3. Bo Li
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  4. Chen Chen
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  5. Wen-zhi Li
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Correspondence to Rajiv Kumar Jha or Sha Huanchen.

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Geng, Zm., Jha, R.K., Li, B. et al. Sorafenib Inhibition of Hepatic Stellate Cell Proliferation in Tumor Microenvironment of Hepatocellular Carcinoma: A Study of the Sorafenib Mechanisms. Cell Biochem Biophys 69, 717–724 (2014). https://doi.org/10.1007/s12013-014-9858-y

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