title: A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy.
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.
authors.affiliation: 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.).
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gillet
authors.affiliation: 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.).
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.affiliation: 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.).
authors.forename: James P
authors.initials: JP
authors.lastname: Madigan
authors.affiliation: 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.).
authors.forename: Sudhir
authors.initials: S
authors.lastname: Varma
authors.affiliation: 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.).
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Bagni
authors.affiliation: 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.).
authors.forename: Katie
authors.initials: K
authors.lastname: Powell
authors.affiliation: 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.).
authors.forename: William E
authors.initials: WE
authors.lastname: Burgan
authors.affiliation: 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.).
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Calcagno
authors.affiliation: 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.).
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.affiliation: 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.).
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: 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.) mgottesman@nih.gov.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D015331:Cohort Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents