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Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients

Authors

  • Luca Quagliata,

    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
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  • Matthias S. Matter,

    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
    2. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
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  • Salvatore Piscuoglio,

    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
    2. Research Group Human Genetics, Department of Biomedicine, University of Basel and Division of Medical Genetics, University Children's Hospital, Basel, Switzerland
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  • Leila Arabi,

    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
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  • Christian Ruiz,

    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
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  • Alfredo Procino,

    1. Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
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  • Michal Kovac,

    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
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  • Francesca Moretti,

    1. Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland
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  • Zuzanna Makowska,

    1. Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
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  • Tujana Boldanova,

    1. Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
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  • Jesper B. Andersen,

    1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
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  • Monika Hämmerle,

    1. Helmholtz-University-Group “Molecular RNA Biology & Cancer,” German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
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  • Luigi Tornillo,

    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
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  • Markus H. Heim,

    1. Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
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  • Sven Diederichs,

    1. Helmholtz-University-Group “Molecular RNA Biology & Cancer,” German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
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  • Clemente Cillo,

    Corresponding author
    1. Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
    • Address reprint requests to: Luigi M. Terracciano, M.D., Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Schonbeinstrasse 40, 4003 Basel, Switzerland. E-mail: lterracciano@uhbs.ch or Clemente Cillo, Ph.D., Department of Clinical Medicine and Surgery, Federico II University Medical School, Via Pansini 5, 80031 Naples, Italy. E-mail: clecillo@unina.it

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  • Luigi M. Terracciano

    Corresponding author
    1. Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland
    • Address reprint requests to: Luigi M. Terracciano, M.D., Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Schonbeinstrasse 40, 4003 Basel, Switzerland. E-mail: lterracciano@uhbs.ch or Clemente Cillo, Ph.D., Department of Clinical Medicine and Surgery, Federico II University Medical School, Via Pansini 5, 80031 Naples, Italy. E-mail: clecillo@unina.it

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  • Potential conflict of interest: Nothing to report.

  • Supported by Swiss Cancer League (Oncosuisse) grant KLS-2867-08-2011 to L.M.T.; M.S.M. is supported by Schweizerische Stifung für Medizinisch-Biologische Stipendien (PASMP-3_140071); HCC research in the lab of S.D. is supported by the German Research Foundation (DFG TRR77 TP B03).

Abstract

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long noncoding RNAs (lncRNAs) as crucial determinants of HCC development. In this study we report the lncRNA HOXA transcript at the distal tip (HOTTIP) as significantly up-regulated in HCC specimens. The HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression by way of interaction with the WDR5/MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinicopathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients' clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data were obtained from snap-frozen needle HCC biopsies (n = 52) matched with their nonneoplastic counterparts collected from patients who had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP/HOXA13. Conclusion: Our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression with metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis, and paves the way for further investigation about the possible role of HOTTIP as a predictive biomarker of HCC. (Hepatology 2014;59:911–923)

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