Carcinogen-induced hepatic tumors in KLF6+/− mice recapitulate aggressive human hepatocellular carcinoma associated with p53 pathway deregulation

Authors

  • Mirko Tarocchi,

    1. Division of Liver Diseases, Department of Medicine Mount Sinai School of Medicine, New York, NY
    2. Department of Clinical Pathophysiology/Gastroenterology Unit, University of Florence, Florence, Italy
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  • Rebekka Hannivoort,

    1. Division of Liver Diseases, Department of Medicine Mount Sinai School of Medicine, New York, NY
    2. Department of Gastroenterology and Hepatology, University of Groningen, Groningen, Netherlands
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  • Yujin Hoshida,

    1. Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
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  • Ursula E. Lee,

    1. Division of Liver Diseases, Department of Medicine Mount Sinai School of Medicine, New York, NY
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  • Diana Vetter,

    1. Division of Liver Diseases, Department of Medicine Mount Sinai School of Medicine, New York, NY
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  • Goutham Narla,

    1. Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY
    2. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY
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  • Augusto Villanueva,

    1. HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Liver Unit, Hospital Clinic, Barcelona, Catalonia, Spain
    2. Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
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  • Moshe Oren,

    1. Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
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  • Josep M. Llovet,

    1. Division of Liver Diseases, Department of Medicine Mount Sinai School of Medicine, New York, NY
    2. HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Liver Unit, Hospital Clinic, Barcelona, Catalonia, Spain
    3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
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  • Scott L. Friedman

    Corresponding author
    1. Division of Liver Diseases, Department of Medicine Mount Sinai School of Medicine, New York, NY
    • Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave., Room 11-70C, New York, NY 10029-6574
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    • fax: 212-849-2574

Errata

This article is corrected by:

  1. Errata: Correction: Carcinogen-induced hepatic tumors in KLF6+/− mice recapitulate aggressive human hepatocellular carcinoma associated with p53 pathway deregulation Volume 54, Issue 6, 2280, Article first published online: 15 November 2011

  • Potential conflict of interest: Nothing to report.

  • Supported by the National Institutes of Health (Grants RO1DK37340 and RO1DK56621 to S. L. F., Grant R01DK076986 to J. M. L.). R. H. was funded by the Graduate School for Drug Exploration and the Stichting Nicolaas Muleriusfonds, Groningen, Netherlands. A. V. is a recipient of a Sheila Sherlock fellowship from the European Association for the Study of the Liver. D. V. is a recipient of a research fellowship from the Swiss National Fund. G. N. is a recipient of the Howard Hughes Medical Institute Physician-Scientist Early Career Award.

Abstract

Inactivation of KLF6 is common in hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection, thereby abrogating its normal antiproliferative activity in liver cells. The aim of the study was to evaluate the impact of KLF6 depletion on human HCC and experimental hepatocarcinogenesis in vivo. In patients with surgically resected HCC, reduced tumor expression of KLF6 was associated with decreased survival. Consistent with its role as a tumor suppressor, KLF6+/− mice developed significantly more tumors in response to the chemical carcinogen diethyl nitrosamine (DEN) than wild-type animals. Gene expression signatures in both surrounding tissue and tumors of KLF6+/− mice closely recapitulated those associated with aggressive human HCCs. Expression microarray profiling also revealed an increase in Mdm2 mRNA in tumors from KLF6+/− compared with KLF6+/+ mice, which was validated by way of quantitative real-time polymerase chain reaction and western blot analysis in both human HCC and DEN-induced murine tumors. Moreover, chromatin immunoprecipitation and cotransfection assays established the P2 intronic promoter of Mdm2 as a bona fide transcriptional target repressed by KLF6. Whereas KLF6 overexpression in HCC cell lines and primary hepatocytes led to reduced MDM2 levels and increased p53 protein and transcriptional activity, reduction in KLF6 by small interfering RNA led to increased MDM2 and reduced p53. Conclusion: Our findings indicate that KLF6 deficiency contributes significantly to the carcinogenic milieu in human and murine HCC and uncover a novel tumor suppressor activity of KLF6 in HCC by linking its transcriptional repression of Mdm2 to stabilizing p53. (HEPATOLOGY 2011;)

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