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Molecular Pharmacology

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Research ArticleArticle

A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy

Jean-Pierre Gillet, Jesper B. Andersen, James P. Madigan, Sudhir Varma, Rachel K. Bagni, Katie Powell, William E. Burgan, Chung-Pu Wu, Anna Maria Calcagno, Suresh V. Ambudkar, Snorri S. Thorgeirsson and Michael M. Gottesman
Molecular Pharmacology February 2016, 89 (2) 263-272; DOI: https://doi.org/10.1124/mol.115.101360
Jean-Pierre Gillet
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Jesper B. Andersen
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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James P. Madigan
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Sudhir Varma
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Rachel K. Bagni
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Katie Powell
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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William E. Burgan
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Chung-Pu Wu
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Anna Maria Calcagno
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Suresh V. Ambudkar
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Snorri S. Thorgeirsson
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Michael M. Gottesman
Laboratory of Cell Biology (J-P.G., J.P.M., C-P.W., A.M.C., S.V.A., M.M.G.) and Laboratory of Experimental Carcinogenesis (J.B.A., S.S.T.), Center for Cancer Research, National Cancer Institute, and Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases (S.V.), National Institutes of Health, Bethesda, Maryland; and the Viral Technologies Group and Molecular Detection Group, Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Marylanld (R.K.B., K.P., W.E.B.)
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Abstract

Despite improvements in the management of liver cancer, the survival rate for patients with hepatocellular carcinoma (HCC) remains dismal. The survival benefit of systemic chemotherapy for the treatment of liver cancer is only marginal. Although the reasons for treatment failure are multifactorial, intrinsic resistance to chemotherapy plays a primary role. Here, we analyzed the expression of 377 multidrug resistance (MDR)-associated genes in two independent cohorts of patients with advanced HCC, with the aim of finding ways to improve survival in this poor-prognosis cancer. Taqman-based quantitative polymerase chain reaction revealed a 45-gene signature that predicts overall survival (OS) in patients with HCC. Using the Connectivity Map Tool, we were able to identify drugs that converted the gene expression profiles of HCC cell lines from ones matching patients with poor OS to profiles associated with good OS. We found three compounds that convert the gene expression profiles of three HCC cell lines to gene expression profiles associated with good OS. These compounds increase histone acetylation, which correlates with the synergistic sensitization of those MDR tumor cells to conventional chemotherapeutic agents, including cisplatin, sorafenib, and 5-fluorouracil. Our results indicate that it is possible to modulate gene expression profiles in HCC cell lines to those associated with better outcome. This approach also increases sensitization of HCC cells toward conventional chemotherapeutic agents. This work suggests new treatment strategies for a disease for which few therapeutic options exist.

Footnotes

    • Received August 14, 2015.
    • Accepted December 11, 2015.
  • ↵1 Current affiliation: Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit—URPhyM, Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium.

  • ↵2 Current affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.

  • This research was funded by the Intramural Research Program of the National Institutes of Health (NIH). The project was funded in part with federal funds from the National Cancer Institute NIH [Contract HHSN2612008000001E]. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

  • dx.doi.org/10.1124/mol.115.101360.

  • ↵Embedded ImageThis article has supplemental material available at (molpharm.aspetjournals.org).

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 89 (2)
Molecular Pharmacology
Vol. 89, Issue 2
1 Feb 2016
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Research ArticleArticle

HCC Gene Expression Pattern Suggests New Treatment Strategy

Jean-Pierre Gillet, Jesper B. Andersen, James P. Madigan, Sudhir Varma, Rachel K. Bagni, Katie Powell, William E. Burgan, Chung-Pu Wu, Anna Maria Calcagno, Suresh V. Ambudkar, Snorri S. Thorgeirsson and Michael M. Gottesman
Molecular Pharmacology February 1, 2016, 89 (2) 263-272; DOI: https://doi.org/10.1124/mol.115.101360

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Research ArticleArticle

HCC Gene Expression Pattern Suggests New Treatment Strategy

Jean-Pierre Gillet, Jesper B. Andersen, James P. Madigan, Sudhir Varma, Rachel K. Bagni, Katie Powell, William E. Burgan, Chung-Pu Wu, Anna Maria Calcagno, Suresh V. Ambudkar, Snorri S. Thorgeirsson and Michael M. Gottesman
Molecular Pharmacology February 1, 2016, 89 (2) 263-272; DOI: https://doi.org/10.1124/mol.115.101360
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