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E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma

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Abstract

E2F-1 is a transcription factor involved in DNA synthesis and repair, cell proliferation, and apoptosis. Hyposphorylated pRb represses E2F-1 action in early G1 phase, while in late G1, pRb hyperphosphorylation leads to E2F-1 release and activation. In vitro studies have shown that E2F-1 may act either as oncogene or as tumor suppressor gene. We evaluated immunohistochemical expression of E2F-1 protein in chronic viral liver disease and hepatocellular carcinoma (HCC) and correlated this with clinicopathological parameters, cell proliferation, apoptosis, and the expression of E2F-1-regulators, pRb, and phospho-pRb (Ser795). In liver biopsies from 30 patients with chronic viral hepatitis, including 22 with cirrhosis without HCC, and 57 with cirrhosis with HCC, E2F-1 expression was assessed by immunohistochemistry. In chronic hepatitis and cirrhosis, hepatocytes and cholangiocytes demonstrated mild cytoplasmic and/or nuclear membrane E2F-1 immunostaining. In contrast, all HCC (100 %) showed strong nuclear E2F-1 immunostaining, with or without membrane accentuation, while a minority demonstrated additional moderate cytoplasmic immunostaining. Abnormally low pRb and phospho-pRb expression was seen in 70 % and 67.9 % of HCC, respectively. In HCC, nuclear E2F-1 expression was inversely correlated with phospho-pRb expression (p = 0.001) and positively related to tumor apoptotic index (p = 0.025). No significant correlation was found between E2F-1 expression and patient demographics, HCC etiology, tumor grade, pRb, p53 expression, or cell proliferation. In conclusion, we show that the increased expression of E2F-1 protein in human HCC is correlated with enhanced tumor cell apoptosis supporting a pro-apoptotic role of E2F-1 in human HCC.

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Acknowledgments

We gratefully acknowledge the support of “Kapodistrias” Research Program, Special Accounts Research Fund 70/4/6549, National and Kapodistrian University of Athens (NKUoA), Greece. We thank Prof. V. Gorgoulis, Laboratory of Histology and Embryology, NKUoA, Greece for helpful insights, suggestions, and critical review of the manuscript and Dr. A. Kotsinas, Laboratory of Histology and Embryology, NKUoA, Greece, for his support during the experimental part of the study. The technical expertise of Ms. Kalliopi Apostolopoulou is appreciated.

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Authors and Affiliations

  1. Laboratory of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias str, Goudi, Athens, 11527, Greece

    Marina Palaiologou & Dina G. Tiniakos

  2. 2nd Academic Department of Internal Medicine, Hippokration General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    John Koskinas

  3. Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA

    Menelaos Karanikolas

  4. Liver Transplant Unit, King’s College Hospital, London, UK

    Evangelia Fatourou

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  1. Marina Palaiologou
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  2. John Koskinas
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  3. Menelaos Karanikolas
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  4. Evangelia Fatourou
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  5. Dina G. Tiniakos
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Correspondence to Dina G. Tiniakos.

Additional information

M. Palaiologou, BSc, and Dr. J. Koskinas, MD, PhD, contributed equally to this work.

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Palaiologou, M., Koskinas, J., Karanikolas, M. et al. E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma. Virchows Arch 460, 439–446 (2012). https://doi.org/10.1007/s00428-012-1220-4

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  • DOI: https://doi.org/10.1007/s00428-012-1220-4

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