Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer

Authors

  • Giridhar Mudduluru MSc,

    1. Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, Deutsches Krebsforschungszentrum and University Heidelberg, Mannheim, Germany
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    • The first three authors contributed equally to this article.

  • Fabian Medved,

    1. Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, Deutsches Krebsforschungszentrum and University Heidelberg, Mannheim, Germany
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    • The first three authors contributed equally to this article.

  • Rainer Grobholz MD,

    1. Department of Pathology, University of Homburg, Saar, Germany
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    • The first three authors contributed equally to this article.

  • Camela Jost,

    1. Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, Deutsches Krebsforschungszentrum and University Heidelberg, Mannheim, Germany
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  • Anette Gruber,

    1. Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, Deutsches Krebsforschungszentrum and University Heidelberg, Mannheim, Germany
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  • Joerg H. Leupold PhD,

    1. Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, Deutsches Krebsforschungszentrum and University Heidelberg, Mannheim, Germany
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  • Stefan Post MD,

    1. Department of Surgery, Mannheim Faculty, University of Heidelberg, Mannheim, Germany
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  • Aaron Jansen PhD,

    1. Gene Regulation Section, Basic Research, National Cancer Institute, Bethesda, Maryland
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  • Nancy H. Colburn PhD,

    1. Gene Regulation Section, Basic Research, National Cancer Institute, Bethesda, Maryland
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  • Heike Allgayer MD, PhD

    Corresponding author
    1. Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, Deutsches Krebsforschungszentrum and University Heidelberg, Mannheim, Germany
    • Department of Experimental Surgery/Molecular Oncology of Solid Tumors (Collaboration Unit, German Cancer Research Center, Deutschen Krebsforchungszentrum-Heidelberg), Mannheim Medical Faculty, Ruprecht Karls University-Heidelberg, 68167 Mannheim, Germany
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    • Dr. Allgayer was supported by Alfried-Krupp-von-Bohlen-und-Halbach-Stiftung, Essen, Germany; Wilhelm-Sander-Stiftung, Munich, Germany; Auguste-Schaedel-Dantscher-Stiftung, Garmisch, Germany; and Hella-Bühler-Stiftung, Heidelberg, Germany; and Dr. Ingrid zu Solms Foundation, Frankfurt, Germany

    • Fax:(011) 49 621 383 3809/1938


  • This article is a US Government work and, as such, is in the public domain in the United States of America.

  • The current study contains the dissertation of Fabian Medved, which was performed in partial fulfillment of the “DrMed” degree at Mannheim Faculty, University of Heidelberg.

Abstract

BACKGROUND.

Programmed cell death 4 (Pdcd4) inhibits malignant transformation, and initial studies of Pdcd4 suggested the regulation of Pdcd4 localization by protein kinase B (Akt). However, supporting patient tissue data are missing, and the diagnostic/prognostic potential of Pdcd4 rarely has been studied. The objectives of the current were 1) to determine Pdcd4 as a diagnostic marker in the adenoma-carcinoma sequence, 2) to support phosphorylated Akt (pAkt)-mediated Pdcd4 regulation in vivo, and 3) to obtain the first prognostic evidence of Pdcd4 in colorectal cancer.

METHODS.

Tumor samples and normal tissues from 71 patients with colorectal cancer who were followed prospectively (median follow-up, 36 months) and 42 adenomas were analyzed for Pdcd4, Akt, and pAkt in immunohistochemical and Western blot analyses.

RESULTS.

A significant reduction in Pdcd4 was observed between normal mucosa and adenomas and between adenomas and tumor samples (P < .01 and P < .01, respectively). Normal mucosa demonstrated strong nuclear Pdcd4, which was reduced significantly in adenomas (P < .01) and almost was lost in tumors (P < .01). pAkt was correlated inversely with Pdcd4 and with the transition of Pdcd4 from nucleus to cytoplasm (P < .01). Kaplan-Meier analysis (using the Mantel-Cox log-rank test) indicated a significant correlation between the loss of total and nuclear Pdcd4 in tumors and overall survival (P < .05 and P < .02, respectively) and disease-specific survival (P < .01 and P < .01, respectively). In multivariate analysis, loss of total or nuclear Pdcd4 was an independent predictor of disease-specific or overall survival.

CONCLUSIONS.

To the authors' knowledge, this is the first study to demonstrate an independent prognostic impact of Pdcd4 and its expression pattern in colorectal cancer. Data from this study support the regulation of Pdcd4 localization by pAkt in vivo. Pdcd4 immunohistochemistry may be useful as a supportive diagnostic tool for the transition between normal, adenoma, and tumor tissues. Cancer 2007. Published 2007 by the American Cancer Society.

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