Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma

Authors

  • Hideo A. Baba,

    1. Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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    • *Contributed equally to the study.

  • Jeremias Wohlschlaeger,

    1. Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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    • *Contributed equally to the study.

  • Vito R. Cicinnati,

    1. Department of Gastroenterology and Hepatology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
    2. Department of General, Visceral and Transplantation Surgery, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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  • Philip Hilgard,

    1. Department of Gastroenterology and Hepatology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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  • Hauke Lang,

    1. Department of General, Visceral and Transplantation Surgery, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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  • Georgios C. Sotiropoulos,

    1. Department of General, Visceral and Transplantation Surgery, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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  • Atsushi Takeda,

    1. Faculty of Health Science, School of Physical Therapy, Gumma Paz College, Gumma, Japan
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  • Susanne Beckebaum,

    1. Department of Gastroenterology and Hepatology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
    2. Department of General, Visceral and Transplantation Surgery, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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  • Klaus J. Schmitz

    1. Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
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Correspondence
Hideo A. Baba, Institute of Pathology and Neuropathology, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Tel.: +0049 201 723 3577
Fax: +0049 201 723 3378
e-mail: hideo.baba@uk-essen.de

Abstract

Background/Aims: The mammalian target of rapamycin (mTOR) inhibitors play a key role in regulating signal transduction by blocking the mTOR pathway and combining anticancer and immunosuppressive properties. This study was undertaken to determine the prevalence and clinicopathological relevance of phospho-p70S6 (p-p70S6) kinase in hepatocellular carcinoma (HCC) and to investigate the effects of rapamycin on HCC in vitro.

Methods: A total of 196 patients with HCCs were treated either with surgical resection (n=106) or liver transplantation (n=90). Tumour tissue was investigated for p-p70S6, phospho-AKT, Ki-67, Cyclin-D1 and apoptosis, and staining results were correlated with clinicopathologically relevant parameters.

Results: Overall, p-p70S6 was detected in 24.5% (48/196) of HCCs. In the resection group, 26.4% (28/106) of HCC were positive and 22.2% (20/90) in the transplant group. p-p70S6 was significantly associated with elevated Cyclin-D1 immunoexpression and was correlated with decreased overall survival (P=0.011) in patients resected with a clear margin. In multivariate COX regression analysis, p-p70S6 was identified as an independent prognostic parameter in patients resected with a clear margin. Rapamycin induced apoptosis and growth inhibition by G0/G1 cell cycle arrest in vitro. However, in HCC patients p-p70S6 kinase was not associated with proliferation or apoptosis.

Conclusions: Activation of p70S6 kinase indicates aggressive tumour behaviour in patients with clear margin-resected HCC. Identification of p-p70S6 kinase in HCC selects high-risk patients who may benefit from drugs targeting the mTOR pathway.

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