c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma

Authors

  • Hanning You,

    1. Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey, PA
    2. Division of Nephrology, Department of Medicine, The Pennsylvania State University, College of Medicine, Hershey, PA
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  • Wei Ding,

    1. Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey, PA
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  • Hien Dang,

    1. Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey, PA
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  • Yixing Jiang,

    1. Penn State Hershey Cancer Institute, The Pennsylvania State University, College of Medicine, Hershey, PA
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  • C. Bart Rountree

    Corresponding author
    1. Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Hershey, PA
    2. Penn State Hershey Cancer Institute, The Pennsylvania State University, College of Medicine, Hershey, PA
    • Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, 500 University Drive, H085, Hershey, PA 17033
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    • fax: 717-531-0653


  • Potential conflict of interest: Dr. Rountree received grants from Bayer.

  • Supported by National Institutes of Health Grants K08DK080928 and R03DK088013 (to C. B. R.), American Cancer Society Grant MGO-116519 (to C. B. R.), and The Penn State Clinical and Translational Science Institute (C. B. R).

Abstract

c-Met, a high-affinity receptor for hepatocyte growth factor (HGF), plays a critical role in cancer growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with an active HGF/c-Met signaling pathway have a significantly worse prognosis. Although targeting the HGF/c-Met pathway has been proposed for the treatment of multiple cancers, the effect of c-Met inhibition in HCC remains unclear. The human HCC cell lines Huh7, Hep3B, MHCC97-L, and MHCC97-H were used in this study to investigate the effect of c-Met inhibition using the small molecule selective c-Met tyrosine kinase inhibitor PHA665752. MHCC97-L and MHCC97-H cells demonstrate a mesenchymal phenotype with decreased expression of E-cadherin and increased expression of c-Met, fibronectin, and Zeb2 compared with Huh7 and Hep3B cells, which have an epithelial phenotype. PHA665752 treatment blocked phosphorylation of c-Met and downstream phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/Erk pathways, inhibited cell proliferation, and induced apoptosis in c-Met–positive MHCC97-L and MHCC97-H cells. In xenograft models, administration of PHA665752 significantly inhibited c-Met–positive MHCC97-L and MHCC97-H tumor growth, and PHA665752-treated tumors demonstrated marked reduction of both c-Met phosphorylation and cell proliferation. c-Met–negative Huh7 and Hep3B cells were not affected by c-Met inhibitor treatment in vitro or in vivo. In addition, c-Met–positive MHCC97-L and MHCC97-H cells demonstrated cancer stem cell–like characteristics, such as resistance to chemotherapy, tumor sphere formation, and increased expression of CD44 and ABCG2, and PHA665752 treatment suppressed tumor sphere formation and inhibited CD44 expression. Conclusion: c-Met represents a potential target of personalized treatment for HCC with an active HGF/c-Met pathway. (HEPATOLOGY 2011;)

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